Pos. Aware PK 32.2/2/05 · 2016. 3. 7. · 4 Positively Aware Winter 05 tpan.com harmacokinetics...

what's

with it?GOT TO DO

PK[Pharmacokinetics]

what's

with it?GOT TO DO

PK[Pharmacokinetics]

IN THIS SPECIAL ISSUE: ABC's of Pharmacokinetics (PK) / The Nukes, Non-Nukes and PIs: Do They Play Well Together? / Top 3 Websites

Winter 2005

FeaturesSupplement Introduction 2How much? When? How? Why it helps to understand the four classes of HIVdrugs available.

The Non-Nukes 12Like the nukes, the two major players of the non-nucleotides, Sustiva and Viramune, block the transfer of HIVgenetic information.

The Nukes 8Each one works a little differently to block the ability of HIV to replicate itself.

The Protease Inhibitors 18The most complicated of the HIV drugs.These block the ability of HIV to infectmore cells.

This special Positively Aware (PA) supplement is made possible through the exclusive supportof Gilead Sciences. Information, resources and advertising in PA do not constituteendorsement or recommendation of any medical treatment or product. PA recommendsthat all medical treatments or products be discussed thoroughly and frankly with a licensedand fully HIV-informed medical practitioner, preferably a personal physician.

RAM U N

The ABC’s ofPharmacokinetics 4What’s PK got to do with it? Recent data fromPK, the study of what the human body does todrugs to eliminate them from the body, providesus with information which can show us the lifeof a drug through absorption, distribution,metabolism and elimination.

4

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WINTER 2005 CONTENTS

Interim EditorJeff Berry

Associate EditorEnid Vázquez

Interim Executive DirectorRick Bejlovec

Director ofTreatment EducationMatt Sharp

Director of AdvertisingDanny Kopelson

Distribution CoordinatorKeith Green

Guest EditorPatrick G. Clay, PharmD

Contributing WritersPeter L. Anderson, PharmDJean Lee, PharmDJames D. Scott, PharmD

Art DirectionMartha Hoyle and Kevin Putz,Toolbox Inc.

© 2005, Test Positive Aware Network, Inc. For reprint permission, contact Jeff Berry. Six issues mailed bulkrate for $30 donation; mailed free toTPAN members or those unable to contribute. TPAN is an Illinois not-for-profit corporation, providing information and support to anyone concernedwith HIV and AIDS issues. A person’s HIV status should not be assumed based on his or her article or photograph in Positively Aware, membership in TPAN, or contributions to this journal.

Test Positive Aware Network 5537 N. Broadway, Chicago, IL 60640 phone: (773) 989–9400 fax: (773) 989–9494 e-mail: [email protected] http://www.tpan.com

This supplement was the brainchild ofthe late editor of Positively Aware,Charles Clifton. Charles and I met in(appropriately enough) San Francisco,during the Retrovirus conference in2004 to discuss ways to educatepatients about how their body breaksdown medicines. The intent of this sup-plement is to provide foundational gen-eral knowledge about the pharmacoki-netics and pharmacodynamics (seeABC's of Antiretrovirals) of antiretrovi-ral medications. It also gives specificrecommendations on currently avail-able medicines. Why does yourdoctor prescribe Lexiva once aday for you and twice a day foryour partner? Why do you have toeat with Reyataz and cannot eatwith Crixivan? Why is Videx ECgiven sometimes at 250 mg andsometimes at 400 mg daily? Thesewere just some of the questions Charlesand I hoped to be able to answer withthis supplement.

How much (milligrams) of adrug should be taken at one time?The answer most often times is:enough to work, but not too much tocause significant side effects. Mostantiretrovirals are dosed to achieve inthe body a level of drug that falls intowhat is called a “therapeutic range”(see Figure 1: Therapeutic Range).Taking enough of the medicine (hav-ing drug concentrations somewhere onthe graph) will, in most cases, give youan effect. These effects can be good(therapeutic) or bad (toxic).

If the drug level is appropriate forthe virus in your body, you could see alowering of the viral load and/orincreasing of the CD4 count. Thesewould obviously be good therapeuticeffects. Taking too much or not having

enough of the medicine in your body(incorrect dosing or poor adherence)could result in either toxic effects or noeffect. Neither of these are desired out-comes — for you or your doctor! Theparagraph below provides a moredetailed explanation of the graph. It isimportant to understand these con-cepts, as they are pivotal to the infor-mation provided in this supplement.

The drug concentration in theblood rises as you go from left to rightalong the x-axis or bottom of the graph.The actual amount (milligrams per mil-

liliter of blood, see ABC's of Pharmaco-kinetics) varies depending on severalfactors including: the drug, prescribeddose, how long you have been takingthe medicine and how long it has beensince you took your last dose. Thechance of the drug having an effectincreases up to a maximal amount asyou go from bottom to top or up the y-axis. As stated previously, for antiretro-virals this effect is measured by changesin T-cell count and viral load. You prob-ably know that the most you canreduce your viral load is down to lessthan 50 copies per milliliter — so thereis a maximal effect the drug can haveon your virus. Same with T-cells —your body can only make so many overtime and at some point you will have T-cells in the “normal” or non-HIV infect-ed range. These two levels (unde-tectable viral load and normal CD4count) represent a maximal effect of the

anti-HIV medicines. What your maxi-mal effect may be, however, is alsodependent on your history of takingHIV medicines and how much damagethe virus has already done to yourbody. You and your doctor should havetalked about what the goals for yourdrugs are before you started takingthem. Not everyone can or should usean undetectable viral load and “normal”T-cell count as goals.

If the drug you take is not in suf-ficient quantity, you can get sub-opti-mal levels. At this drug concentration,

you would likely not see atherapeutic (good) benefitfrom taking the medicine.Even though you don’t get apositive effect, you can stillsee a negative one. Forinstance, taking low doses ofRetrovir will not change your

viral load or T-cells, but may still causeyou to have anemia.

If too much medicine is taken,then the chance that you will have atoxic effect becomes more likely. Anexample of this is taking too muchCrixivan. Very high levels of Crixivancan cause you to develop stones inyour kidneys (very painful!). Not onlyis this drug’s recommended doses(from the company and in this supple-ment — see Protease Inhibitors) at lev-els that usually don’t allow this to hap-pen, drinking plenty of water immedi-ately after the dose and during the dayhelp minimize this risk

The challenge with HIV medi-cines is that the “therapeutic range” inmany instances is still being discovered.What is the maximum level of drug thatshould be in the body daily to providelong term therapeutic effects? Sadly,this is not known for every drug. What

2 Positively Aware Winter 05 tpan.com

YOU AND YOUR DOCTORSHOULD HAVE TALKED ABOUT WHAT

THE GOALS FOR YOUR DRUGS AREBEFORE YOU STARTED TAKING THEM

Supplement IntroductionPATRICK G. CLAY, GUEST EDITOR

doctors and researchersunderstand more clear-ly for most anti-HIVdrugs is what dose of adrug is associated withtoxicity. Manufacturers’and doctors’ recom-mended and pre-scribed doses reflectthis knowledge. Thisdoes not mean sideeffects cannot happenfrom having therapeu-tic levels of the drug inthe body. As you areprobably aware, long-term side effects ofsome of these medi-cines (lipodystrophyand diabetes, for exam-ple) may result fromtaking the properamount of medicineand having therapeuticlevels of the drugs.Unfortunately, long-term side effects frommedicines, even whendosed appropriately, are not unique toanti-HIV drugs. Diabetics can developresistance to their insulin and thosewith asthma who have to take steroidsare all too familiar with long-term sideeffects of medicines. However, manyside effects are related to the amount ofdrug in the body. Having the optimalamount of drug in your body and keep-ing it that way consistently over timemay offer the most effective way tominimize side effects.

Though this supplement presentsthe most appropriate doses, levels andcombinations of antiretrovirals, long-term therapeutic success is still onlyachievable with continual maximal

adherence. The emphasis on honestcommunication with your doctor, phar-macist and nurse about your HIV medi-cines, other medicines you might betaking (especially ones available overthe counter!) and how these medicinesmake you feel cannot be strongenough. This supplement is meant tohelp you understand more about whathappens to the drugs after they areinside your body. It should be used as areference when you are talking to yourdoctor about current or new medicines.It is the intent of the authors that by pro-viding this educational material, we areable to increase your understanding ofthe medicines used to treat HIV. If by

accomplishing a higherknowledge level aboutantiretrovirals in personsaffected by this virus, weare able to improve oneperson’s outcome or pre-vent one virus frombecoming resistant —then we will say this sup-plement was successful.

Lastly, this supple-ment provides many rec-ommendations that arenot found within thepackage inserts of medi-cines. Many of the rec-ommendations madewithin are based on theauthors’, editor’s andTPAN’s current under-standing of the currentlyapproved anti-HIV medi-cines. This supplementin no way should sup-plant what your doctorhas prescribed for you.At no time should youconsider altering the

dose, frequency or diet instructions foryour anti-HIV medicines without firsttalking with and getting approval fromyour doctor. What we try to emphasizein this supplement are that these medi-cines are different in everyone and yourdoses are likely to reflect this. Only youand your doctor know what is best foryou — that is how your medicines arebest managed.

Sincerely,

Patrick G. Clay, [email protected]

Special Issue: Pharmacokinetics 3

0

20

40

60

80

100

Pro

bab

ility

of

hav

ing

eff

ect

(%)

Drug Concentration in the blood

TherapeuticEffect

ToxicEffect

"TherapeuticRange"

Sub-optimalLevels

Figure No. 1: THERAPEUTIC RANGE

Sub-optimal levels: These are drug concentrations that are associated with a low chanceof a therapeutic effect.

Therapeutic effect: In the case of antiretroviral drugs, it is the reduction of HIV-RNA, theincrease in CD4 cells, and the prevention of opportunistic infections.

Therapeutic range: The size of the difference between doses or drug levels that cause atherapeutic effect versus a toxic effect.

Toxic effect: Toxicity from the drug


harmacokinetics (PK) istalked about a lot in theHIV community. PK isthe study of what thehuman body does todrugs to get the drug out

of the body. The main ways the humanbody handles drugs are listed below.These are all a part of PK.

Step 1. Drug absorption: This ishow the drug enters the blood — usual-ly from tablets or capsules inthe stomach and intestines.For some drugs, the amountof acid in the stomach, or theamount of food in the stom-ach, really changes theamount of drug that isabsorbed. This is the reason that somedrugs have “food requirements”, or whysome drugs have warnings not to takeantacids along with the drug. (see Fig-ure 1: Drug Metabolism Pathways):

Step 2. Drug distribution: Thisis how the drug travels in the blood-stream and how it goes into and comesout of other areas of the body. Did you

know that some areas of the body, likethe brain and reproductive organs, arespecially protected from chemicals(including drugs)? It is hard to measuredrug levels in the brain and reproduc-tive organs in people.

One way that drug distribution isstudied in people is by finding outwhat percentage of the drug in theblood is stuck to proteins (called pro-tein binding). This is important

because only drug that is free of pro-teins can travel in and out of otherareas of the body to be effective. Pro-tein binding is often studied when adrug is being developed by a drugcompany. However, protein binding isnot routinely studied after that becauseknowing the total blood concentration(both protein-bound plus protein-free)

is generally good enough. Step 3. Drug metabolism: This

is how the body chemically changes adrug — usually in the intestines andliver. Metabolism involves breaking adrug down or adding a chemical thatmakes it easier to pass it into urine orstool. A lot of drug-drug interactionshappen because one drug interfereswith the metabolism of another drug(called inhibition). Inhibition causes

higher drug levels. On the otherhand, a drug can also speed upthe metabolism of another drug(called induction). Induction caus-es lower drug levels.

The CYP-450 (pronounced“sip”) enzyme system is a well-

known group of human enzymes thatmetabolize drugs and chemicals in thebody. CYP-450 enzymes are mostly inthe intestines and liver.

The CYP-450 enzymes are bro-ken into three families (CYP1, CYP2and CYP3) (see Figure 2: Antiretrovi-rals and CYP450 Isoenzymes). Whendoctors and pharmacists talk about the

THE ABC’S OF

Pharmacokinetics

What’s PK got to do with it?

BY PETER L. ANDERSON, PharmD

PPHARMACOKINETICS IS

WHAT THE BODY DOES TO THE DRUG —

PHARMACODYNAMICS ISWHAT THE DRUG DOES TO THE BODY

CYP-450 system, they often just referto the system as CYP and drop the 450part. Within the CYP-450 system,though, there are different enzymefamilies. To distinguish one familyfrom another, a letter and number areadded to CYP (again, dropping the 450numbering). Some examples of thisare CYP1A2, CYP2D6, CYP3A4, etc.(Note how the 450 is dropped, but theCYP remains.)

Each CYP has a different ability tometabolize a given chemical or drug.For example, CYP3A4 is probably themost important drug metabolizingenzyme because it metabolizes the mostdrugs, including protease inhibitors.

Norvir strongly inhibits CYP3A4and causes most of the other proteaseinhibitors to build up in the blood. Thisis called Norvir boosting. For the pro-tease inhibitors that are boosted byNorvir, the higher blood levels may helpthe “boosted” drug work better. But, forother drugs that are metabolized byCYP3A4, like cholesterol drugs or erec-tile dysfunction drugs, Norvir and pro-tease inhibitors may cause undesirableincreases in blood concentrations (seeProtease Inhibitor article on page 16).

Step 4. Drug elimination: Thisis how the body gets the drug out —usually by passing the drug into theurine (via the kidneys) or stool (via theliver). Sometimes people have somekidney or liver illness. In these people,the blood level of some drugs maybuild to very high levels if the drug

dose is not reduced (see Figure 1: DrugMetabolism Pathways).

PK DEFINITIONSThere are certain terms and tests thatresearchers or doctors use when theystudy PK. The following is a summaryof these PK measurements and whatthey mean. Please refer to Figures 3and 4 for a picture of what all these PKmeasurements represent.

AUC (area-under-the-curve):This is the overall amount of drug in thebloodstream after a dose. AUC studiesare often used when researchers arelooking for drug-drug or drug-foodinteractions. The way to get an AUC

involves collectingmany blood sam-ples (usually everyone or two hours)right after a persontakes a dose upuntil the next doseis due. In eachblood sample, theconcentration of thedrug is measuredwith a machine(discussed later).Then all the drugconcentrations areput onto a graphbased on the timeafter the dose thatthey were collected.A curve is made by

connecting the points on the graph.The AUC for that drug is then calculat-ed as the area under this drug concen-tration curve. An AUC study contains alot of information about PK. It is proba-bly the best way to understand howpeople handle a drug (PK).

Cmax (maximum concentra-tion): This is the highest concentrationof drug in the blood that is measuredafter a dose. Cmax usually happenswithin a few hours after the dose istaken. The time that Cmax happens isreferred to as Tmax. For some antiretro-viral drugs, a high Cmax is thought toincrease the risk of side effects fromthe drug.

Cmin or trough (pronounced“troff”) (minimum concentration):This is the lowest concentration of thedrug in the blood that is measured aftera dose. It happens right before apatient takes the next usual dose. It isnot known for certain, but many peo-ple in the HIV community believe thatkeeping the trough concentration(Cmin) above a certain level is especial-ly important for anti-HIV activity.

Half-life (t 1/2): This is theamount of time it takes for the drugconcentration in the blood to declineby half. The half-life is among the mostimportant PK measurements for howoften a drug has to be dosed (once-a-day or twice-a-day, etc).

Steady-state: This means that aperson has been on a drug for enough

Figure No. 1: DRUG METABOLISM PATHWAYS

Oxidation (Cytochrome P450's)

Drug

Conjugation(Glucuronidation etc.)

Conjugation

Metabolite

PolarSpecies

Renal Elimination(Urine)

BiliaryElimination(Stool)

Non-polarSpecies

Stable Adducts


3A4

2C19 2D6 2C9

1A2 2E1 2A6 2B6 2C8

Induced by:Norvir, Viracept,Sustiva, Viramune

Inhibited by: Norvir, Viracept, Crixivan, Agenerase/Lexiva, Fortovase/Invirase, Rescriptor

Induced by:Norvir, Viracept

Inhibited by: Rescriptor

Induced by:Sustiva,Viramune

Inhibited by: Norvir

Induced by: Norvir, Viracept

Inhibited by: Sustiva, Rescriptor

Induced by:Norvir,Viracept?

Figure No. 2: ANTIRETROVIRALS and CYP450 ISOENZYMES

Pyramid depicts the various CYP 450 enzymes in the body and the drug interactions with antiretrovirals.CYP3A4, shown at the top of the pyramid and largest single part of the pyramid, is very important.Arrows point to the various antiretrovirals and the general affect(s) that medicine has on that enzyme.Note that drugs can be listed as both an inducer and inhibitor and with multiple enzymes.

time (usually one to two weeks) sothat the drug concentration is notbuilding up in the bloodstream any-more. The time it takes to get tosteady-state depends on the half-life ofthe drug. A drug gets to steady state in

about five half-lives.As an illustration, before a

patient reaches steady-state, eachadditional dose may be building thedrug up in the body so each dosewould be giving a higher Cmax, Cmin,

and AUC. But, at steady-state, everydose would give the same Cmax, Cmin,and AUC in the patient because it isnot building up any more.

Adherence: Remarkably, anti-retroviral regimens lose effectivenesseven with a small drop from perfect(or near-perfect) adherence. Forexample, going from 95–100% adher-ence down to 90–95% adherence withprotease inhibitors resulted in a dropin effectiveness (viral load below 400)from 81% to 64%. It seems that theusual drug levels are not much higherthan what’s needed for sustained effi-cacy. Additionally, the half-lives of theagents must have been relatively fast,such that the drug exposure fell belowa level associated with a high proba-bility of efficacy after the missed dose.Obviously, taking as close to 100% ofantiretroviral doses is critically impor-tant.

Once-a-day dosing: Once dailycombination antiretroviral therapies isa newer concept that is targeted toimprove adherence. Several once-dailyregimens are now available where alldrugs have similar dietary require-ments so that the whole regimen canbe taken at the same time (see Figure 7:Options for Once-daily Dosing). Itshould be noted that only approvedonce-daily combinations should beused at this time (such as Truvada plusSustiva as initial therapy). Some otherantiretrovirals are currently approvedfor twice-a-day dosing, but they arebeing studied as once-a-day drugs.These “investigational” regimensshould only be used in very controlledsettings (like in a study). This isbecause it is not yet known if “investi-gational” drugs provide the rightamount of drug exposure for effectiveand safe once-daily dosing (especiallyif a dose is missed). Which is better —once a day or twice a day dosing? Theconservative answer is: both. In studiesdone to date comparing once to twicea day dosing, they come out equal atthe end.

Pharmacodynamics (PD): PDis just a fancy term for drug efficacyand toxicity. PD refers to what thedrugs do to the human body. Forexample, HIV drugs cause HIV viral

Figure No. 3: BLOOD LEVELS of A DRUG OVER TIME

2 4 6 8 10 120

Cmax - maximum concentration (Tmax is the time Cmax happens)Cmax may relate with some side effects

AUC - area under the curve (filled area)Represents overall drug exposure

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once

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Cmin - minimum, or trough concentration. May relate with anti-HIV effectiveness

t 1/2 - half-life (how gradually the line comes down). Time for drug concentration to fall by half. For example, it took 2 hours (on x-axis) to go from 6 (on y-axis) to 3 (on y-axis). Therefore the t 1/2 is about 2 hours for this drug.

Time after dose (hours)

Time (hours)

00 5 10 15 20 25

2000

4000

6000

8000

10000 Toxicity threshold

Cmax (Peak concentration)

Absorptionphase

Cmin (Trough concentration)

Minimally effectiveconcentration

Eliminationphase (t1/2)

AUC (0-12)

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g C

once

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ng/m

L)

Figure No. 4: CONCENTRATION-TIME CURVE at STEADY-STATE

See Figure No. 3 above for explanation

Above are blood levels (Y-axis) of a drug over time (X-axis) after a patient takes a single dose. In this repre-sentation, the patient took the dose at time 0 and would be due for another dose at time 12 (hours). Sincethe time 0 level is about equal to the time 12 level, the patient is at steady state. For AUC measurements,blood levels are usually collected every hour or so. Figure No. 4 below is another way of looking at thesesame concepts.


load to decline and CD4 cells toincrease. Also, drugs sometimes causecertain side effects and toxicity in thehuman body.

WHAT’S PK GOT TO DOWITH IT?

PK is studied a lot in HIV and it isimportant for many reasons.

First of all, the PK of many HIVdrugs is really changedby certain things. Forexample, the blood lev-els of HIV drugs can beincreased or lowered bynot following the foodrequirements with dos-ing, taking antacids withthe drugs, or taking cer-tain other drugs orherbals that cause biginhibition or inductioninteractions (see metab-olism above). It is important to find thedose requirements out so that patientsknow how best to take the drugs.

Secondly, every person who takesHIV drugs is a bit different in the waytheir body handles these drugs (absorp-tion, distribution, metabolism, and/orelimination). This means that a patient

can have high or low blood levels aftertaking the same dose just because ofthe way they handle the drug.

Finally, all of this mattersbecause the levels of drugs in yourbody affect how well the drug worksagainst the virus or whether the drugmight cause side effects. In the case ofhigh levels there could be more sideeffects. Poor efficacy against HIV

could result from low levels. In somespecial cases, your doctor may thinkthat it might be a good idea to meas-ure the blood levels of your drugs.Based on the result, your doctor mayadjust your doses and then re-checkyour blood levels of drug to try andget them right where they want them.

This is called “therapeutic drug moni-toring” (TDM).

MEASURING DRUG LEVELSDetermining your drug levels fromblood samples is usually only done inspecialty labs. These labs use machinetests called “high performance liquidchromatography (HPLC or LC)” andsometimes “mass spectrometry (MS)”.

This is generally how itworks: Your blood is col-lected in a tube. The tubeis spun very fast in a cen-trifuge to get the redblood cells to sink to thebottom of the tube leav-ing the plasma on the top.This is done because thedrug level is actuallymeasured in the plasma.

Once at the lab, thedrug needs to be purified

from the plasma because the plasma isalso full of a lot of other things besidesthe drug (sort of like filtering the drugout). This “filtering” step usually leavesa liquid with the purified drug in it.This purified drug portion is then putinto an HPLC machine that filters thedrug to make it even more purified and

Figure No. 6: SUGGESTED MINIMUM TARGETTROUGH CONCENTRATIONS for PERSONS

with WILD-TYPE HIV-1

DRUG CONCENTRATION (NG/ML)

amprenavir (Agenerase, Lexiva) 400

indinavir (Crixivan) 100

lopinavir/ritonavir (Kaletra) 1000

nelfinavir (Viracept)a 800

ritonavir (Norvir)b 2100

saquinavir (Fortovase, Invirase) 100-250

efavirenz (Sustiva) 1000

nevirapine (Viramune) 3400

a. Measurable active (M8) metabolite. b. Ritonavir given as a single PI.

Sources:

• Acosta EP, and Gerber JG. Position paper on therapeutic drug monitering of antiretroviral agents. AIDS Research Human Retroviruses 2002; 18(12):825-34.

• Back D, Gatti G, Fletcher CV, et al. Therapeutic drug monitoring in HIV infection: current status and future directions. AIDS 2002;16 (suppl 1) S50S37.

• Burger DM, Armoutse RE, Hugen PWH. Pros and cons of therapeurtic drug monitoring of antiretroviral agents. Curr Opin Infect Dis 2002;15(1):17-22.

• Optimizing TDM in HIV clinical care. (May 20, 2003. http://pharmacology.com)

This table provides suggested trough (Cmin) concentrations for people takingthese drugs who do not have a resistant virus.


Hours

Figure No. 5: PLASMA and INTRACELLULAR HALF-LIVES of SELECT NRTI's

1,2) 3) 5)

0

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36

48

60

72

Plasma Intracellular

(ABC (3TCEmtriva

4)(FTC (TDFZiagen Epivir Viread

1 Weller, et al. Antimicrob. Agents Chemother. 2000 Aug;44(8):2052-602 Piliero, et al. 43rd ICAAC, Chicago, A-17973 Yuen et al. Antimicrob. Agents and Chemother. 2004 Jan;48(1):176-824 Wang et al. 14th IAC. 2002. Poster #45465 Hawkins T, et al. 5th International Workshop of Clinical Pharmacology of HIV Therapy, Rome, Italy. 2004 #2.4

This figure depicts the half-lives of select nukes. Note how the half-life in the plas-ma is always much shorter than the half-life within the cell. Two examples of thisare shown with Viread and Emtriva.

Continued on page 19

+

Viread + EmtrivaViread + EpivirZiagen + EpivirViread + VidexVidex + Emtriva Videx + Epivir

Sustiva Reyataz or Reyataz/Norvir

Agenerase/Norvir Invirase/Norvir

or Fortovase/Norvir

Figure No. 7: OPTIONS for ONCE-DAILY THERAPY

Options currently available or with evidence of QD efficacy

The backbone of antiretroviraltherapy remains two nucleosidereverse transcriptase inhibitors (alsocalled nucleosides or “nukes”),whether you are taking a non-nucleo-side or protease inhibitor (Table 2:Antiretroviral Regimens Recommend-ed for Treatment of HIV-1 infection inAntiretroviral Naïve Patients).

HOW THESE DRUGS WORKUpon entering the cell, all but

Viread (also part of Truvada) have tobe activated via a three-step processby enzymes within thecells (three phosphategroups are added byenzymes called kinases).Viread only needs twosteps for activation. Onceactivated, these drugscan then bind to anenzyme (reverse tran-scriptase) within the cellthat prevents the virusfrom making copies.RTIs (nukes) bind to adifferent site on thisenzyme than the non-nucleoside reverse tran-scriptase inhibitors (non-nukes). Also, except asnoted below, each nukeworks slightly differentlyon this enzyme, allowing mostof them to be used together safely andeffectively.

METABOLISMThe “nukes” are mostly metabolized bypathways not used by PIs or NNRTIs.Some of the nukes are metabolized inthe liver but by different methods thanthe PIs or NNRTIs (Retrovir and Emtri-va for example). Ziagen has a uniquemetabolism. It is broken down by the

same enzyme that breaks down alco-hol. Though no interaction occurs ifthey are given together, this is not arecommendation to enjoy an adult bev-erage when you take your Ziagen orZiagen containing-products! Somenukes are not metabolized to any greatextent and are eliminated mostlythrough the urine (Epivir and Vireadfor example). For this reason, the dosesof many nukes should be decreased ifyou have kidney disease. Exactly howsome of these drugs are broken downby the body is still unknown (Zerit for

example). This is why research andTDM (therapeutic drug monitoring)continue to be conducted on drugs thathave even been in use for 10 years.Table 1 shows the pharmacokineticparameters for the nucleosides.

DRUG INTERACTIONS WITH DUAL RTIs

Retrovir: Retrovir and Zerit cannot beused together. These two drugs com-

pete for the same activating kinaseenzymes (see introductory paragraphabove for explanation). When thesetwo drugs are given at the same time,Retrovir prevents Zerit from beingactivated, giving you no benefit fromtaking Zerit.

Zerit: Other than mentionedabove, Zerit has no significant drug-drug interactions with any of the other“nukes”. Your doctor may be able todiscuss other possible reasons whyZerit is not combined with other“nukes”, but these are not for pharma-

cokinetic reasons.Viread: When

Viread and Videx EC aregiven together, increasesin Videx blood levels areseen. An increase in theVidex AUC (area underthe curve, see page 5)varied from 48% to 60%when these two drugswere given togetherwithout and with food,respectively. Studieswere done with lowerdoses of Videx EC andfood. The best combina-tion (250 mg of Videx ECand 300 mg Viread)resulted in no change inthe AUC of Videx com-pared to when 400 mg of

Videx EC was taken by itself. Nomeaningful changes were seen inViread’s pharmacokinetics. There-fore, the drug-drug interaction can beaddressed by adjusting the dose ofVidex EC. When they are used togeth-er, you should be on a lower dose ofVidex (250 mg daily in personsweighing greater than 60 kgs) andtaking these agents with food at thesame time. Long-term safety data are


BY PATRICK G.CLAY, PharmD

EACH ONE WORKS A LITTLE DIFFERENTLY

theNukes


not available on this recommendationhowever, so be sure to discuss thiswith your doctor or pharmacist.

Emtriva: Emtriva and Epivir donot have a “drug interaction” per se,but since they have very similar chem-

ical structures, antiviral activities andcan select for the same resistancemutation, they should not be takentogether (see “How these DrugsWork” above for more detailed expla-nation). No formal drug interaction

studies have been conducted, but itwould be wise to avoid using thesetwo agents as the RTIs of your regi-men until more information is avail-able (studies suggested to be done innon-infected persons!).

Abacavir(ABC)

Ziagen

Trizivirw/ZDV+3TC

Epzicomw/3TC

Ziagen300 mg tablets or20 mg/mL oralsolution

TrizivirABC 300 mg +ZDV 300 mg +3TC 150 mg

EpzicomABC 600 mg +3TC 300 mg

300 mg twotimes/day; or600 mg once daily;

or asTrizivir1 tablet two times/day

Epzicom1 tablet once daily

Take withoutregard to meals;Alcohol increasesabacavir levels41%; abacavirhas no effect onalcohol

1.5 hours 12-26 hours Metabolized by alcoholdehydrogenase and glu-curonyl transferase.Renal excretion of metabo-lites 82% Trizivir & Epzicomnot for patients with CrCl <50 mL/min

Hypersensitivity reaction whichcan be fatal, symptoms mayinclude fever, rash, nausea, vomit-ing, malaise or fatigue, loss ofappetite, respiratory symptomssuch as sore throat, cough, short-ness of breath

Didanosine(ddI)Videx,Videx EC

Videx EC125, 200, 250, or400 mg

Videxbuffered tabs25, 50, 100, 150,200 mg

Videxbuffered powders:100, 167, 250 mg

Body weight ≥ 60 kg: 400 mgonce daily (buffered tablets orEC capsule); or 200 mg twotimes/day (buffered tablets); withTDF: 250 mg/day < 60 kg: 250mg daily (buffered tablets or ECcapsule); or 125 mg twotimes/day (buffered tablets) withTDF: appropriate dose not esta-lished; probably < 250 mg/day

Levels decrease55%; Take 1/2hour before or2 hours after meal

1.5 hours > 20 hours Renal excretion 50%Dosage adjustment inrenal insufficiency

Pancreatitis; peripheralneuropathy; nausea; diarrhea.Lactic acidosis with hepaticsteatosis is a rare but potentiallylife-threatening toxicity associatedwith use of NRTIs.

Emtricitabine(FTC)Emtriva

Truvadaw/ TDF

Emtriva200 mg hardgelatin capsule

TruvadaFTC 200 mg +TDF 300 mg

Emtriva200 mg once daily

TruvadaOne tablet oncedaily

Take withoutregard to meals

10 hours > 20 hours Renal excretionDosage adjustment inrenal insufficiencyTruvada - not for patientswith CrCl < 30 mL/min

Minimal toxicity; lactic acidosiswith hepatic steatosis (rare butpotentially lifethreatening toxicitywith use of NRTIs.)

Lamivudine(3TC)Epivir

Combivirw/ ZDV

Epizicomw/ABC

Trizivirw/ZDV+ABC

Epivir150 mg and300 mg tablets or10 mg/mL oralsolution

Combivir3TC 150 mg +ZDV 300 mg

Epizicom3TC 300 mg +ABC 600 mg

Trizivir3TC 150 mg +ZDV 300 mg +ABC 300 mg

Epivir150 mg twotimes/day; or300 mg daily

Combivir1 tablet two times/day

Epizicom1 tablet once daily

Trizivir1 tablet two times/day


5-7hours

18 -22 hours Renal excretionDosage adjustment inrenal insufficiencyCombivir,Trizivir & Epzicom not forpatients with CrCl < 50mL/min

Minimal toxicity; lactic acidosiswith hepatic steatosis (rare butpotentially lifethreatening toxicitywith use of NRTIs)

Stavudine(d4T)Zerit

Zerit15, 20, 30, 40 mgcapsules or1mg/mL fororal solution

Body weight>60 kg: 40 mg two times/day;

Body weight60 hours Renal excretionDosage adjustment inrenal insufficiencyTruvada - not for patientswith CrCl < 30 mL/min

Asthenia, headache,diarrhea, nausea, vomiting, andflatulence; renal insufficiency; lac-tic acidosis with hepatic steatosis(rare but potentially lifethreateningtoxicity with use of NRTIs)

Zalcitabine(ddC)

Hivid0.375,0.75 mg tablets

0.75 mg threetimes/day


1.2 hours N/A Renal excretion 70%Dosage adjustment inrenal insufficiency

• Peripheral neuropathy;• Stomatitis; • Lactic acidosis with hepatic

steatosis (rare but potentiallylife-threatening toxicity withuse of NRTIs);

• Pancreatitis

Zidovudine(AZT, ZDV)

Retrovir

Combivirw/3TC

Trizivirw/3TC+ABC

Retrovir 100 mg capsules,300 mg tablets, 10 mg/mLintravenous solution, 10mg/mL oral solution

Combivir 3TC 150 mg +ZDV 300 mg

Trizivir 3TC 150 mg + ZDV300 mg + ABC 300 mg

Retrovir300 mg twotimes/day or 200 mg three times/ day

Combivir or Trizivir1 tablet twotimes/day


1.1 hours 7 hours Metabolized to AZTglucuronide (GAZT).Renal excretion ofGAZT Dosage adjustmentin renal insufficiency Combivir & Trizivir - not forpatients with CrCl < 50mL/min

• Bone marrow suppression:macrocytic anemia or neu-tropenia;

• Gastrointestinal intolerance,headache, insomnia, asthe-nia;

• Lactic acidosis with hepaticsteatosis (rare but potentiallylife-threatening toxicity asso-ciated with use of NRTIs.

Generic Name(abbreviation)Trade Name

Formulation DosingRecommendations

Food Effect Serumhalf-life

Intra-cellularhalf-life

Elimination Adverse Events

Table No.1: CHARACTERISTICS of NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTI’S)

Source: Guidelines for the use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, U.S. Department of Health and Human Services, www.hivatis.org

DRUG INTERACTIONS WITHTRIPLE RTIs

Viread and Epivir, when given witheither Videx or Ziagen once a day,resulted in poor rates of efficacy. Theexact mechanism of this has not beendetermined, but it is not believed to beone related to plasma pharmacokinet-ics. Regardless, these medicinesshould not be used as a once-dailyantiretroviral regimen.

DRUG INTERACTIONS WITHRTIs AND NNRTIs

None of the RTIs have any knownimpact on the pharmacokinetics of the

NNRTIs. One potential interaction is thatRescriptor (which needs acid in thestomach for absorption) would need tobe separated from Videx buffered tablets(which reduces acid in the stomach).

DRUG INTERACTIONS WITHRTIs AND PIs

As detailed above in the metabolismparagraph, most of the RTIs are metab-olized by pathways other than thoseused by PIs. Therefore, drug interac-tions resulting from inhibition or induc-tion of CYP metabolism are not usuallyseen between the nukes and PIs. Thereare a few noteworthy exceptions to

this. They are provided below.Viread and Reyataz: When Rey-

ataz is administered with Viread,decreased Reyataz AUCs of 30% and Cminof 40% were seen. To counter this, 300mg of Reyataz was given with 100 mg ofNorvir and 300 mg Viread — all givensimultaneously once daily. This is doneto raise the Reyataz trough concentrationto about the level it usually is when youare not taking Viread. When these threewere given together to HIV-positive per-sons, Reyataz’s AUC and Cmin were actu-ally higher compared to Reyataz alone.However, longer clinical studies ofthese three would be welcome.


Table No. 2: ANTIRETROVIRAL REGIMENS RECOMMENDED for TREATMENT of HIV-1 INFECTION in ANTIRETROVIRAL NAÏVE PATIENTS

NO. OF PILLS

2-3

8-9

2-4

3-6

3-6

5-8

5-8

7-12

7-10

5-8

13-16

2

Preferred RegimensNNRTI-based

PI-based

Alternative RegimensNNRTI-based

PI-based

3NRTI-based

REGIMENS

Sustiva + (Epivir or Emtriva) + (Retrovir or Viread) (AII) – [Note: Sustiva isnot recommended for use in first trimester of pregnancy or in women with high pregnancypotential*]

Kaletra (lopinavir/ritonavir co-formulation) + (Epivir or Emtriva) + Retrovir(AII)

Sustiva + (Epivir or Emtriva) + (Ziagen or Videx or Zerit) (BII) – [Note: Sus-tiva is not recommended for use in first trimester of pregnancy or in women with highpregnancy potential*]

Viramune + (Epivir or Emtriva) + (Retrovir or Zerit or Videx or Ziagen orViread) (BII) - [Note: High incidence (11%) of symptomatic hepatic events observedin women with pre-Viramune CD4 + T cell count more than 250 cells/mm1 and men withCD4 more than 400 cells/mm1 (6.3%). Use with caution in these patients, with close clini-cal laboratory monitoring, especially for the first 18 weeks of therapy]

Reyataz + (Epivir or Emtriva) + (Retrovir or Zerit or Ziagen or Videx) or(Viread + Norvir 100 mg/d) (BII)

Lexiva + (Epivir or Emtriva) + (Retrovir or Zerit or Ziagen or Viread orVidex) (BII)

Lexiva/Norvir + (Epivir or Emtriva) + (Retrovir or Zerit or Ziagen or Vireador Videx) (BII)

Crixivan/Norvir + (Epivir or Emtriva) + (Retrovir or Zerit or Ziagen orViread or Videx) (BII)

Kaletra + (Epivir or Emtriva) + (Zerit or Ziagen or Viread or Videx) (BII)

Viracept + (Epivir or Emtriva) + (Retrovir or Zerit or Ziagen or Viread orVidex) (CII)

Fortovase (SGC) or Invirase (HCG) / Norvir + (Epivir or Emtriva) + (Retro-vir or Zerit or Ziagen or Viread or Videx) (BII)

Ziagen + Retrovir + Epivir – only when a preferred or an alternative NNRTI-or a PI-based regimen cannot or should not be used (CII)

* Women with child-bearing potential implies women who want to conceive or those who are not using effective contraception.Source: www.hivatis.org, see page 9.

In the meanwhile, TDM may beprudent to use to ensure the Reyatazlevel is high enough

Viread levels are increased byReyataz by about 30%. But, Viread (andTruvada) dose adjustments are not rec-ommended. So far controlled clinicaltrials extending beyond 96 weeks havenot shown evidence of toxicityPatients and doctors should just beaware of the increase so they can be onthe watch for a potential increase inViread side effects.

Viread and Kaletra: Kaletra isnot significantly impacted by Viread.Kaletra does impact Viread though.When given together, increases inViread AUC and Cmin were observed tobe about 30% and 51%, respectively. Asnoted above, dose adjustments are notnecessary, but being extra vigilant forany potential increase in Viread sideeffects is probably warranted.

It is not known why these inter-actions between Viread and these twoPIs happen. Formal clinical studiesusing pharmacokinetic or TDM-baseddosing of Reyataz and Kaletra have notbeen conducted to date. These types of

studies may provide a better under-standing of why these interactionsoccur, and hopefully this will be forth-coming. Importantly, Viread has beenshown not to interact with Crixivan,Viracept, or Fortavase or Inviraseboosted with Norvir.

Retrovir: Retrovir does havesome minor interaction with both Vira-cept and Norvir. With Norvir and Vira-cept, Retrovir’s AUC can be decreasedby 25% to 35%, respectively. No dosingchanges are recommended.

Videx: The remaining drug inter-actions possible are the result ofabsorption or dietary issues. Most ofthe protease inhibitors have dietaryrestrictions (food requirements, seeProtease Inhibitors). The exceptionsare Lexiva and Crixivan/Norvir. AsVidex should be taken on an emptystomach and the protease inhibitors areto be given with food, these medicinesshould be separated by a minimum ofone hour when prescribed in combina-tion. As described earlier, if Videx isbeing given with Viread simultaneous-ly with food, then taking the proteaseinhibitors at the same time is accept-

able. If you have any questions, pleasecheck with your doctor or pharmacist.

STARTING AND STOPPING THE MEDICINES

The plasma and intracellular half-lives of these drugs vary considerably(from 7 hours for Retrovir and Zerit toabout 39 to more than 60 hours forEmtriva and Viread) (see Table 1 onpage 9 and Figure 5 on page 7). Whilethere are recommendations for how todeal with the long half-lives of thenon-nukes when stopping a regimen,there are no similar recommendationsfor how to deal with the nukes’ longhalf-lives. This is an area where morestudies are needed.

Patrick G. Clay, PharmD, is an Associ-ate Professor of Medicine and Directorof Clinical Research for the KansasCity University of Medicine and Bio-sciences. He is primarily involved ininvestigations of antiretrovirals ininfected and non-infected persons andhas been working in HIV since 1995.

1 = University of Liverpool: www.hiv-druginteractions.org. Thisinformative and educational HIV phar-macology resource is valuable forhealthcare professionals, scientificresearchers or anyone with an interestin HIV therapy. You can find reports onrecent news and hot topics in HIV, dis-cover comprehensive information andadvice on drug interactions, read aboutadvances in therapeutic drug monitor-ing (TDM), and much more!

2 = Toronto General Hospital: www.tthhivclinic.com/interact_tables.html. This website is primarily forhealth professionals, but is an excellentsite for up-to-date information on anti-HIV medicine drug interactions as wellas herbal medicine interaction data.The information in these charts isintended for use by experienced physi-cians and pharmacists. The tables are

not intended to replace sound profes-sional judgment in individual situations,and should be used in conjunction withother reliable sources of information.Due to the rapidly changing nature ofinformation about HIV treatment andtherapies, users are advised to re-checkthe information contained herein withthe original source before applying it topatient care. Decisions about particularmedical treatments should always bemade in consultation with a qualifiedmedical practitioner knowledgeableabout HIV-related illness and the treat-ments in question.

3=UCSF: http://hivinsite.ucsf.edu/.HIV InSite is developed by the Centerfor HIV Information (CHI) at the Uni-versity of California/San Francisco(UCSF), one of the world's leadinghealth sciences institutions. WithinUCSF, HIV InSite is produced in col-

laboration with the San Francisco Vet-erans Affairs Medical Center, the Posi-tive Health Program at San FranciscoGeneral Hospital and the Center forAIDS Prevention Studies, componentsof the University's AIDS ResearchInstitute. Launched in March 1997,HIV InSite's mission is to be a sourcefor comprehensive, in-depthHIV/AIDS information and knowl-edge. The site has an extensive collec-tion of original material, including theHIV InSite Knowledge Base, a com-plete textbook with extensive refer-ences and related links organized bytopic. Unlike many commercially ori-ented sites, HIV InSite's policy is tolink to the best of the Web, and thou-sands of links to external websites areincorporated into the site's originalcontent. It is the policy of HIV InSiteto allow free, anonymous access to allof the site's content.

Editor’s TOP 3 WebsitesRECOMMENDED DRUG INTERACTION WEBSITES (AND THEY’RE FREE!)



theNon-NukesBY JEAN LEE, PharmD

VIRAM U N

ow do they workagainst the virus?

The non-nucleoside reversetranscriptase inhib-itors (NNRTIs, alsoknown as “non-nukes”) are drugs

that attach to the reverse transcriptaseenzyme. They bind in a site that issomewhat different than the “nukes”,but essentially do the same thing.Although they bind on the sameenzyme as the nukes, because theybind on a different site, they are safely(and recommended to be) combinedwith the nukes. Once bound, the viruscan no longer convert its genetic make-up into your T-cells, thus preventingthe virus from replicating.

There are three drugs in this class:Sustiva (efavirenz, EFV), Viramune(nevirapine, NVP) and less usedRescriptor (delavirdine, DLV). Thesedrugs have differences but also similar-ities. Table 1 shows some unique fac-tors. The similarities of the NNRTI classwill also be reviewed.

DO THEY PLAY WELLTOGETHER?

This part of the article will focus moreon Sustiva and Viramune since theyare prescribed more often thanRescriptor. The following are druginteractions between the NNRTIs andPIs and NRTIs, indicating the variousPK changes and what should be donewith dosing.

NNRTIs AND PIsSustiva

Remember: Sustiva is an inducer,mostly of CYP3A4, so it generallytends to decrease the concentration ofthe other drug!

Sustiva and Reyataz – BecauseSustiva may decrease the AUC of Rey-ataz by 74% and Cmin by 93% (seeABC’s of Pharmacokinetics on Page4), it is recommended that 100 mg ofNorvir is given once daily with theReyataz and Sustiva combination.Also, Reyataz will need to bedecreased from the usual 400 mg dailyto 300 mg daily when Norvir is added(see Protease Inhibitors). Because you

need to take Reyataz with food, youmay want to separate your dose ofReyataz/Norvir and Sustiva. If you can-not or you simply want to take them alltogether, make sure you don’t have ahigh fat snack when you take thesemedicines, as this may increase theconcentrations of Sustiva in your bodyand the chance for side effects (seeTable No. 1).

Sustiva and Lexiva – Sustivawill decrease Lexiva’s Cmin by 36%. Ifyou are taking Lexiva once daily, it isrecommended to take 300 mg (3 cap-sules) of Norvir with the Lexiva (2tablets). This is more Norvir than is rec-ommended to be taken with Lexivawithout Sustiva (see ProteaseInhibitors). Total dose will be Lexiva1400 mg + Norvir 300 mg once dailywith or without food. Remember that ifyou decide to eat when taking thiscombination, eat a low-fat or no-fatsnack. This only applies to once-dailydosing of this combination. No addi-tional Norvir dosing is needed if youare taking boosted Lexiva twice daily(see Protease Inhibitors).

H

THE TWO MAJOR PLAYERS

Sustiva and Kaletra – Sustivawill lower the Cmin of Kaletra by 39%.Thus you need to add an extra cap-sule of Kaletra for a total of 4 pillstwice daily with food. Since Sustivashould be taken on an empty stom-ach, it is best to separate these med-ications by at least 2 hours. Remem-ber that if you decide to eat whentaking this combination, eat a low-fator no-fat snack.

Sustiva and Crixivan –Sustiva lowers the AUC of Crix-ivan ranging from 33-46%, andCmin ranging from 39-57%. Youhave to either increase the Crix-ivan dose to 1,000 mg every 8hours or, more recommended,use 100 mg–200 mg of Norvirtwice daily (Crixivan 800 mg + Norvir100 mg–200 mg twice daily). The latterregimen allows you to go from threetimes daily to twice daily dosing (byadding Norvir). Your doctor will let youknow if you should take the 100 mg or200 mg dose. If you takeCrixivan/Norvir and Sustiva at the sametime, make sure you take it on anempty stomach, to avoid high Sustivaconcentrations. If you wantto take your Crixivan/Norvirwith some food, it is best toseparate it from the Sustivaby at least 2 hours.Remember that if youdecide to eat when takingthis combination, eat alow-fat or no-fat snack.

Sustiva and Invi-rase and Fortovase –When you take Sustiva withthis drug, it will decreasethe AUC by 62%, thus youcannot use this withoutboosting it! For both Invi-rase and Fortovase, thereare two dosing regimens:Invirase/Fortovase 400 mg+ Norvir 400 mg giventwice daily with food orInvirase/Fortovase 1,000 mg+ Norvir 100 mg giventwice daily with food. Yourdoctor may have you takemore Norvir to make sureyou have adequate Invi-rase/Fortovase in your

body. Since Sustiva should be takenon an empty stomach, it is best to sep-arate the Invirase or Fortovase withNorvir from Sustiva by at least 2 hours.Remember that if you decide to eatwhen taking this combination, eat alow-fat or no-fat snack.

ViramuneRemember: Viramune is an inducer ofCYP3A4, so it may decrease the con-

centration of the other drug!Viramune and Reyataz –

There are no conclusive data with thiscombination, but the drug concentra-tion of Reyataz is expected todecrease due to the inducing effects ofViramune. Thus, at this time, it is rec-ommended to boost 300 mg of Rey-ataz with 100 mg of Norvir (see Pro-tease Inhibitors).

Viramune and Lexiva – Thereare no data with this combination, butthe drug concentration of Lexiva isexpected to decrease due to the induc-ing effects of Viramune. Thus you willlikely need to use a boosted regimen.While 700 mg Lexiva + 100 mg Norviris commonly used, it is unknown if thiswill be sufficient to offset the interac-tion. This may be one of the timeswhere TDM would be useful (see Pro-

tease Inhibitors). Viramune and Kaletra

– Like the interaction withSustiva, if you take Viramuneand Kaletra, we can see adecrease in the Kaletra AUCby 27% and Cmin by 51-55%.Thus, you need more Kaletra!

For this interaction, you should betaking Kaletra 4 capsules twice dailywith food (533 mg/133 mg).

Viramune and Crixivan –When you take these two drugstogether, the Cmin of Crixivan isdecreased by 44%, so you need a dif-ferent dose. You either have toincrease Crixivan to 1000 mg every 8hours or add 100 mg–200 mg of Norvir


ONCE BOUND, THE VIRUSCAN NO LONGER CONVERT

ITS GENETIC MAKEUP INTO

YOUR T-CELLS

Desired troughConcentration

Time Since last dose (hours)

0 6 12 18 24 30 36 42 48

If Dose missed, Combivirlevels drop

If dose taken, Combivir levels rise

Sustiva (EFV)Epivir (3TC)Retrovir (AZT)

Dose taken

Figure No. 1: THEORETICAL PHARMACOKINETICS of SUSTIVA + COMBIVIR (AZT + 3TC)

Dru

g C

once

ntr

atio

n (

mg/m

l)

This figure shows the drug concentration (solid lines) of zidovudine (AZT), lamivudine (3TC) taken twice daily, andefavirenz (EFV) when taken once daily. If the medications are stopped, the concentration of AZT and 3TC will fall (dashedlines), but the concentration EFV will still be present hours later. This graph, however, does not predict how the drugbehaves inside the cell. This represents what happens in the blood only. See ABC’s of PK for more information aboutlevels of drugs inside the cells.

twice daily (Crixivan 800 mg + Norvir100 mg–200 mg twice daily). If you addNorvir, this interaction allows you to gofrom three times daily to twice-dailydosing, taken with or without food.Your doctor will decide which dose ofNorvir you should be taking.

Viramune and Invirase or For-tovase – With this interaction, theAUC of Invirase/Fortovase is decreasedby 38%, thus boosting is needed withNorvir. The amount of Norvir dependson the drug (Invirase or Fortovase) andamount of drug used as listed below. • Invirase 1,000 mg + Norvir 100

mg given twice daily with food• Fortovase 400 mg + Norvir 400

mg given twice daily with food • Fortovase 1,000 mg + Norvir 100

mg given twice daily with foodYour doctor may have you take

more Invirase, Fortovase and/or Norvirto make sure you have adequate Invi-rase/Fortovase in your body. Your doc-tor may also decide to use TDM tomake sure you are getting adequatedrug in your body.

Rescriptor AND PIsConcentrations of PIs may be

increased due to the inhibitory effect ofRescriptor. A PI dose reduction may berequired. Talk to your pharmacist ordoctor about these interactions.

NNRTIs AND RTIsNo clinically significant interac-

tions with either Sustiva, Viramune orRescriptor.

Stopping or switching medicationsStopping medications: Because

Sustiva and Viramune have a long half-life, it will take longer for it to clearfrom your body. If you were to stop allyour antiretrovirals at the same time,some of the nukes with shorter half-lives will be cleared sooner than thenon-nukes (See Figure 1: TheoreticalPharmacokinetics of Sustiva + Com-bivir). For a period of time, you mayonly have the non-nukes in yourblood. Conversely, if you have a nukebackbone that has longer half-lives(See Figure 2: Theoretical Pharmaco-kinetics of Truvada + Sustiva) exten-sion of nucleoside dosing may not benecessary. Depending on the nukebackbone, there is some informationthat if you stop the non-nuke, youmight need to continue the nukes toavoid the development of mutations— but you should discuss this withyour doctor first. There may also bedrug interactions if you quickly switchfrom a non-nuke regimen to a PI regi-men. For example, if you switch fromSustiva to Kaletra, you need to makesure there isn’t any Sustiva around to

interact and lower Kaletra levels. Askyour clinical pharmacist or physicianon how to plan your switch!

Switching between non-nukesSwitching from Sustiva to

Viramune: Some recent informationmay change how you take your Vira-mune if you are switching to it fromtaking Sustiva. You may be able totake the full dose of Viramune fromday one (200 mg twice daily). Thiswould mean you may not have to gothrough the lead-in dosing of 200 mgonce daily for 2 weeks. You might beable do this because the remainingSustiva in the body may lower con-centration of Viramune in the body.By taking the full dose of Viramunefrom day 1 on, drug levels may behigher and closer to normal. This isvery different than what you find inthe package insert for either drug, sobe sure to talk to your doctor or phar-macist about this first! Taking toomuch Viramune too soon mayincrease the risk for side effects (liverproblems for example).

Switching from Viramune toSustiva: Take the full dose of Sustivaon the first day of the switch.

Again, talk to your clinical phar-macist or doctor on how to plan thisswitch.

The metabolism of NNR-TIs makes it very importantwhen it comes to the potentialdrug interactions. The lastthing you’d want is to lowerthe concentration of your HIVmeds and risk developingresistance. Always check withyour doctor or pharmacistwhenever you are prescribeda new medication.

Jean Lee, PharmD is an HIVClinical Pharmacist workingat the McAuley Health Center,Saint Mary's Health Care inGrand Rapids, MI


Desired troughConcentration

Time Since last dose (hours)

0 6 12 18 24 30 36 42 48

Missed dose

Sustiva (EFV)Viread (TDF)Emtriva (FTC)

Dose taken

Figure No. 2: THEORETICAL PHARMACOKINETICSof TRUVADA (TDF + FTC) + SUSTIVA (1X daily)

Dru

g C

once

ntr

atio

n (

ng/m

L)


Table No. 1: REGIMEN and PHARMACOKINETIC PROPERTIES of the NNRTI CLASS

SUSTIVA(efavirenz)

Store at room temperature andavoid high humidity.

600 mg at bedtime (1 pill/day)

Empty stomach or low-fat snackFood, especially high fat food, willincrease absorption, causing higherdrug levels. This may cause morefrequent and intense side effects.

Neurological side effects: (dizzi-ness, drowsiness, altered dreams)Rash: within the first 6 weeks

Higher levels seen if taken withfatty meal with both capsules andtablets.Recommended to take on an emptystomach

Metabolized by liver: CYP3A4, CYP2B6Inducer of: CYP3A4, CYP2B6Inhibitor of: CYP2C9, CYP2C19,CYP3A4

VIRAMUNE(nevirapine)

Store at room temperature.

200 mg once daily x 14 days— todecrease the chance of rash, then200 mg twice daily (2 pills/day)

400 mg once daily outside USWith or without food

Rash within first 6 weeks. Increased liver enzymes withinfirst 18 weeks. Should be moni-tored closely by your provider.

Quick with >90% absorption after adose.Dosing is the same with oral solu-tion and tablets, thus similar PKs.

Metabolized by liver: CYP3A4,CYP2B6Inducer of: CYP3A4, CYP2B6Inhibitor of: None

RESCRIPTOR(delavirdine)

Store at room temperature.

400 mg three times daily (ideallyevery 8 hours for best drug levels)100 mg tabs: (12 pills/day) 200mg tabs: (6 pills /day)With or without food

Only 100 mg tabs can be dissolvedin liquid.

Rash within 1-3 weeks of therapy.Nausea, diarrhea, headache,fatigue, increased liver enzymes

Needs acid for best absorption. Youcan take drug with acidic beverage(OJ, cranberry juice). If you need antacids you shouldtake them at least 1 hour apartfrom this medication.

Metabolized by liver: CYP3A4,CYP2D6Inhibitor of: CYP3A4, CYP2C9CYP2C19, CYP2D6

Drug

Care

Dose

Administra-tion

Primary side effects

Absorption

Metabolism

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urrently, there areeight approved com-pounds for the treat-ment of HIV infec-tions that are in theclass known as pro-tease inhibitors. Ofall classes of HIV

medications, the protease inhibitorsare the most complex in terms of phar-macokinetics, druginteractions and dosingchanges based on thoseinteractions.

MECHANISM OFACTION

All proteaseinhibitors work in thesame manner. Theyblock the activity of theprotease enzyme withinhuman cells or newvirus particles. Thisenzyme is what allowsa virus to undergo finalmaturation for produc-ing new viruses that cango out and infect othercells. When the PIs bindto the enzyme, the newviruses still leave thecell, but they are unableto infect other cells.

GENERAL CONCEPTSIN THE PK OF PRO-TEASE INHIBITORSAll current protease in-hibitors are adminis-tered by mouth. They are all absorbedin the gastrointestinal (GI) tract (stom-ach and intestines). Metabolism, occur-ring after absorption, is typically per-formed by the CYP enzymes found inthe liver and some in the intestines as

well (mainly CYP3A4) (see ABC's ofPK). Sometimes, multiple enzymesmay affect the same PI (see Figure 2page 5). The PI, in turn, may also affecthow these enzymes function. This iswhy PIs can affect the metabolism ofother protease inhibitors and otherdrugs for different illnesses. The pro-tease inhibitor that has the strongesteffect on these enzymes is Norvir. Most

of the time, Norvir will slow down howfast the other protease inhibitors areeliminated (see Figure 1: Boosting Pro-tease Inhibitors). This is called PIboosting. As such, the newer and someolder PIs are studied with and without

Norvir to see if boosting is optional(Reyataz, Lexiva), recommended (Crix-ivan, Fortovase) or required (tipranavir[experimental], Invirase, Kaletra). Thepharmacokinetics of the available pro-tease inhibitors are summarized inTable 1, with and without Norvirboosting. Currently, the only approvedprotease inhibitor for which boosting isnot recommended is Viracept.

There are few druginteractions between PIsand the nucleoside/nucleotide reverse tran-scriptase inhibitors.

Fortovase and Invirase (both are referred to as

saquinavir)It would be best to take For-tovase and Invirase at thesame time as the Norvir.This is because saquinavir isbroken down both byenzymes in the intestinesand the liver. Norvirdecreases the activity ofthese enzymes and allowsmore drug to enter theblood stream and to stay inthe blood longer. If onewere to separate these med-ications, the blood level ofFortovase or Invirase maybe too low to allow themedication to do its job,and may increase the risk ofdeveloping resistance.

Norvir is not the onlyprotease inhibitor that can affect theother protease inhibitors. Many studieshave been done on this topic. Theseinteractions are summarized in Table2. The protease inhibitors also haveeffects on the pharmacokinetics of

C

The ProteaseInhibitor Drugs

BY JAMES D. SCOTT, PharmD

0.01

0.1

1

10

PI Cmin with boost

Dru

g C

once

ntr

ati

on (

mg/m

L)

Hours After Dose0 2 4 6 8 10 12

PI Cmin without boost

Figure No. 1: BOOSTING PROTEASE INHIBITORS

These are representative drug concentration-time curves for “boosted” and “unboosted”PI regimen dosing schemes. The “boosted” regimen usually provides for higher Cmin than“unboosted”. This generally allows for fewer pills to be given per day compared to“unboosted” regimens. Also, there are error bars around each point plotted on this graph.These error bars reflect potentially how different the levels may be from one person to thenext or within the same person. Regimens that are “boosted” generally tend to have lessvariability compared to “unboosted” (smaller error bars).

some of the other antiretrovi-rals. See The Non-Nukes onpage 12 for details of the inter-actions there.

PIs and VireadViread decreases the blood lev-els of Reyataz. The cause of thisis not yet known. When a clini-cian decides to start a patient onboth Viread and Reyataz, theReyataz must be boosted (seeTable 1). Additionally, Reyatazand also the combination prod-uct of Kaletra have been shownto increase levels of Viread. Theclinical implications of this arenot yet known. No dose adjust-ments are recommended at thistime (see The Nukes).

DAY-TO-DAY PHARMACOKINETICS

Food restrictionsMost protease inhibitors do not requirefood to in order to maintain normal,

therapeutic drug levels but, and per-haps as important, it may make themmore tolerable. The two exceptions tothis rule are Reyataz and Viracept. Rey-ataz requires an acidic stomach envi-ronment to be absorbed, and foodstimulates the production of acid. Theamount of food that should be eaten isnot specified by the manufacturer, and

is not likely to be of importance.However, certain amounts of foodintake have been shown toincrease how much Viracept isabsorbed with each dose. A mealof at least 500 calories (20% ofcalories from fat) should be eatenwith each dose of Viracept in orderto achieve normal therapeutic lev-els. Increasing the amount of foodto 1,000 calories will increase Vira-cept levels even further. Crixivan,when not given with Norvir,requires little to no food for opti-mal absorption but food (a low-fatsnack only) may make the pillsmore tolerable.

Missed dosesMissing doses of most proteaseinhibitors has been shown to increasethe likelihood of a person’s viruschanging (resistance developing). Thismakes it less likely that the proteaseinhibitor will work against the virus.Occasionally, everyone who takesmedications for a long period of time


Table No. 1: PHARMACOKINETICS of PROTEASE INHIBITORS

* These doses are supported by clinical trials or experience, but are not FDA approved1. All doses assume that the product is being used in combination with at least two other active antiretroviral agents2. BID = twice a day3. QD = once a day 4. TID = three times a day5. These strengths are typically used to complete doses needed to compensate for various drug interactions requiring dose adjustments6. Once daily dosing of Lexiva with Norvir is not recommended in patients who are protease inhibitor experienced7. Reyataz with Norvir has not been studied in patients receiving HIV treatment for the first time

GENERICNAME

indinavir

saquinavir

saquinavir

lopinavir/ritonavir

fosamprenavir

ritonavir

atazanavir

nelfinavir

DRUG PERTAB/CAPSULE

200 mg5

333 mg5

400 mg

200 mg

200 mg500 mg

133 mg/33 mg

700 mg

100 mg

150 mg 200 mg

250 mg

625 mg

UNBOOSTEDDOSES1

XXXXXXXXXXXXXX2 caps TID4

6 caps TID

Not recommendedNot recommended

3 caps BID

2 tabs BID

6 caps BID

XXXXXXX2 caps QD

5 tabs BID3 tabs TID2 tabs BID

DOSE1

XXXXXXX3 caps BID2*2 caps BID

5 caps BID

5 caps BID2 tabs BID

4 caps BID*

1 tab BID2 tabs QD3,6

XXXXXXX

2 caps QD7

XXXXXXX

Cannot beboosted withNorvir

NORVIR100 MG CAPS

XXXXXXX1-2 caps BID*1-2 caps BID*

1 cap BID

1 cap BID1 cap BID

XXXXXXX

1 cap BID2 caps QD

XXXXXXX

1 cap QDXXXXXXX

Cannot beboosted withNorvir

BOOSTEDBRAND NAME

CRIXIVAN

FORTOVASE

INVIRASE

KALETRA

LEXIVA

NORVIR

REYATAZ

VIRACEPT


will find that they have missed a doseof their medication. When it comes totaking protease inhibitors, it is best totake the missed dose as soon as possi-ble. If the missed dose is not realizeduntil the next dose is due, it is not rec-ommended to take a double dose. Ifmore than one dose has been missed, itis best to consider those doses missed,and start anew with the next dose thatis due. Protease inhibitors should notbe taken without the other antiretrovi-rals that are prescribed, and vice versa.So, if doses of any HIV medication aremissed due to the lack of availability ofany of the components of the regimen,the entire regimen should be stoppeduntil all components are available. Besure to speak with your doctor’s officeor pharmacist as soon as you realizeyou do not have all of your medicines!

DRUG LEVEL TESTINGDrug level testing (also called thera-peutic drug monitoring, or TDM, alsosee ABC’s of PK) is available to mostclinicians. There are recommendedtrough concentrations for several PIsfor patients who do not have drugresistant virus (see Figure 6 on page 7).However, TDM for PIs is not yet rou-tinely recommended. It might be use-ful in certain circumstances (see ABC'sof PK). In patients who have had manyantiretrovirals in the past (treatmentexperienced), what may ultimatelyguide targets for drug concentrations isthe amount of resistance that the per-son’s virus has. Unfortunately, theresistance test that shows the amountof drug needed to decrease the growthof the virus (a phenotype) has manylimitations of its own. These limits, in

turn, limit the usefulness of TDM forprotease inhibitors. Currently, TDM isbest done using trough levels (Cmin).

SPECIAL CIRCUMSTANCESThere are two of the protease inhibitorsto which special discussion should begiven. Amprenavir is the active drugthat makes up both Lexiva and Agen-erase. Lexiva, which was approved inOctober 2003, is a “prodrug” of Agen-erase. A special chemical group wasadded to the Agenerase molecule. Thismolecule allows it to be made into atablet formulation that is more com-pact, as well as allowing for betterabsorption from the GI tract. Once Lex-iva is absorbed, the extra chemicalgroup is removed in the blood, releas-ing the active drug, amprenavir. Assuch, once the drug is absorbed, it has

DRUG AFFECTED

INDINAVIR (IDV)

RITONAVIR (RTV)

SAQUINAVIR(SQV)

NELFINAVIR(NFV)

FOSAMPRENAVIR(FPV)

LOPINAVIR/RITONAVIR (LPV)

Table No. 2: DRUG INTERACTIONS between PROTEASE INHIBITORS, with CLINICAL COMMENTS when AVAILABLE

RITONAVIR(RTV)

IDV levels ,combo is used clin-ically (see Table 1for dosing)

X

SQV levels ,combo is usedclinically(see Table 1 fordosing)

Variable effects ofNFV, this combo isnot rec’d

APV levels ,combo is usedclinically(see Table 1 fordosing)

RTV ’s LPV, addi-tional RTV has beenused with LPV/r(LPV 3 caps/RTV100 mg BID)

SAQUINAVIR(SQV)

SQV levels , nochange in indinavir(no dose recom-mendations)

SQV levels ,combo is usedclinically(see Table 1 fordosing)

X

Levels of both ,some data supportthis combo(NFV 1250 mgBID, SQV 800 TIDor 1200 mg BID)

APV levels (no dose rec’s)

SQV levels ,some data supportthis combo(LPV 3 caps/SQV1000 mg BID)

NELFINAVIR(NFV)

Levels of both ,some data support-ed this combo(IDV 1200 mg/NFV1250 mg BID)

Variable effects ofNFV, this combo isnot rec’d

Levels of both ,some data supportthis combo(NFV 1250 mgBID, SQV 800 TIDor 1200 mg BID)

X

No data with FPV,expect APV levels

LPV levels , NFVlevels , thiscombo is not sup-ported

LOPINAVIR/RIT-ONAVIR (LPV/r)

IDV levels ,some data support-ed this combo(use IDV 600 mgBID)

RTV ’s LPV, addi-tional RTV has beenused with LPV/r(LPV 3 caps/RTV100 mg BID)

SQV levels ,some data supportthis combo(LPV 3 caps/SQV1000 mg BID)

LPV levels , NFVlevels , thiscombo is not sup-ported

APV levels , LPVlevels , combo isnot rec’d at thistime

X

ATAZANAVIR(ATV)

Not rec’d to givethese two togetherdue to side effects

ATV levels ,combo is usedclinically(see Table 1 fordosing)

SQV levels , noclinical rec’s yet1

No data

Limited data, norec’s yet

No data

1. While one clinical trial using the combination of ATV and SQV results in poor clinical results, the doses ofthis combination may not have been optimal. Additional studies are underway to identify the optimal dosefor this combination.

the same pharmacokinetics as ampre-navir. The pro-drug formula greatlyreduces the number of pills taken.

The second product is saquinavir.It is available under two brand names,manufactured by the same pharmaceu-tical company. Invirase, which resem-bles a typical capsule formulation con-taining a powder, was first approved inlate 1995 (in fact, it was the first pro-tease inhibitor approved in the U.S.).This formulation is referred to as a

hard-gel capsule. Though Invirase waseffective at killing the virus, very little ofit was actually absorbed into the bloodstream. To improve this aspect, Forto-vase was developed. Fortovase offerssignificantly improved absorption com-pared to Invirase, and quickly becamethe preferred formulation. When Forto-vase and Invirase are boosted byNorvir, the blood levels of saquinavirare similar. As such, Invirase and Forto-vase come close to being equal over the

past few years with perhaps greater tol-erability of the boosted Invirase com-pared to boosted Fortovase.

Jim Scott, PharmD, is an Assistant Pro-fessor of Pharmacy Practice at theWestern University of Health Sciences,and Director of the AdherenceImprovement Program at the JeffreyGoodman Special Care Clinic, in LosAngeles, CA. He has been working withHIV patients for over 10 years.


then pumps the drug to a detector.There are a lot of different kinds

of detectors. The common ones forHIV drugs are a mass spectrometer(MS) and an ultraviolet lightabsorbance detector (UV). A MSdetects drugs according to how heavyit is (and also the positive and negativecharge of the drug). The detector givesa signal based on how much drug isthere. The signal is compared with sig-nals that the detector gives for knownamounts of drug that are also put ontothe machine (called a standard curve).This gives the drug level in the patient.

IMPORTANT THINGS ABOUTPK AND TDM

One important point is that TDM is notreally useful for nukes in most cases.This is because nukes have three phos-phate groups attached while inside cellsin order to become active against HIV(called triphosphates). Therefore, thebest way to do TDM for nukes would beto measure the nuke-triphosphates thatare in cells, not the plasma level of thenuke. But, this is very hard to do, soTDM for nukes is not usually done.

Since nuke-triphosphates insidecells are really important for anti-HIVactivity, it is important for researchers tomeasure the half-life of the triphosphatein patients to understand whether thenuke can be given once a day, twice aday, and so on. For many nukes, thehalf-life of the triphosphate in cells isquite a bit longer than the half-life inplasma, so the nuke can be given onceor twice a day (see Figure 5: Plasma andIntracellular Half-lives of Select NRTIs).

As an example, Ziagen (abacavir)

has a fast half-life (about 1.5 hours) inplasma, but the half-life of the triphos-phate in cells is about 20 hours. So,abacavir can be given once a day.

On the other hand, PIs and NNR-TIs are not chemically changed incells to become active, so the plasmalevels can be used for TDM. But, TDMis not routinely used in the U.S. forseveral reasons. First, TDM has notreally been studied much in patients,so doctors are not yet sure about TDMin all their patients.

Secondly, it is not yet clear exact-ly how to use the information TDMprovides. There are some questionsthat are still unanswered regardingTDM, including: 1.) What are the target levels for effi-

cacy in patients with resistantviruses? Right now, levels that arerecommended in treatment guide-lines are only for viruses that arenot resistant. If a person has aresistant virus, precisely howmuch of the drug should theyhave in their body is unknown.

2.) How is it best to adjust doses tomeet targets — for example,should Norvir boosting be themain way to increase levels for PIs?

3.) Are Cmax levels useful for reduc-ing toxicity?

4.) Is an expert needed to do TDM?5.) And, should laboratories be

required to pass the same quality-assurance test to get officialapproval to do the levels? Although TDM may not be used

routinely in all patients, there are somesituations where TDM may be useful.These include: childhood, obesity, very

small body size, elderly, pregnancy,liver or kidney diseases, and drug-druginteractions. Also, TDM may be used inpatients with an unexpected adverseeffect or poor efficacy. For these occa-sions, as mentioned above, there aresuggested target levels for PIs and NNR-TIs in situations where there is no drugresistance (see Figure 6: Suggested Min-imum Target Trough Concentrationsfor Persons with Wild-type HIV-1).

Finally, if TDM is to be undertak-en, there are some very importantthings to do. First, if the level is for effi-cacy, it is very important to get the levelas close to the trough as possible. Thisis the best way to interpret the level.

If the level is for toxicity, and aCmax is desired, it would be best towatch the dose being taken and toobtain the level thereafter. In general, itis very important to realize that theTDM test completely depends on accu-rately recording when the patient lasttook their dose and accurately record-ing when the blood was collected.Other drugs that might have beentaken with the dose should also berecorded. Since the current state ofTDM for HIV is in the developmentphase, it would be best to obtainexpert advice if undertaking TDM.

Peter L. Anderson, PharmD, is anAssistant Professor of Pharmacy,Department of Clinical Pharmacy,University of Colorado Health SciencesCenter, Denver. His main experience ispharmacokinetics and pharmacody-namics of anti-HIV drugs and hasbeen involved in the field for 6 years.

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