Antiretroviral Pharmacology Amanda H. Corbett, PharmD, BCPS Clinical Assistant Professor UNC School...
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Transcript of Antiretroviral Pharmacology Amanda H. Corbett, PharmD, BCPS Clinical Assistant Professor UNC School...
Antiretroviral Antiretroviral PharmacologyPharmacology
Amanda H. Corbett, PharmD, BCPSAmanda H. Corbett, PharmD, BCPS
Clinical Assistant ProfessorClinical Assistant Professor
UNC School of PharmacyUNC School of Pharmacy
Oct 19, 2007Oct 19, 2007
Antiretroviral ClassesAntiretroviral Classes
NRTIsNRTIs (Nucleoside (Nucleoside OROR Nucleotide Reverse Nucleotide Reverse Transcriptase Inhibitors, aka “Nukes”)Transcriptase Inhibitors, aka “Nukes”)
NNRTIsNNRTIs (Non-Nucleoside Reverse Transcriptase (Non-Nucleoside Reverse Transcriptase Inhibitors, aka “Non-Nukes”)Inhibitors, aka “Non-Nukes”)
PIsPIs (Protease Inhibitors)(Protease Inhibitors)
Fusion InhibitorsFusion Inhibitors Chemokine Receptor Chemokine Receptor
AntagonistsAntagonists Integrase InhibitorsIntegrase Inhibitors
Mechanism of Action of ARVs
NNRTI
NRTI
Protease Inhibitor
Illustration by David Klemm
Fusion Inhibitor &ChemokineReceptor Antagonist
Integrase Inhibitor
Antiretroviral Drug Approval:Antiretroviral Drug Approval:1987 - 20071987 - 2007
0
5
10
15
20
1987 1991 1993 1995 1997 1999 2001 2003 2006
AZTddI
ddCd4T
3TCSQV
RTVIDVNVP
NFVDLV
EFVABC
APVLPV/r
TDF
T-20ATVFTCFPV
TPV
DRV
MaravirocRaltegravir
Liver MetabolismLiver Metabolism
100%
3A4
CYP
100%
100%
100%
50%
50%
50%
25%
25%
Adapted from Br J Clin Pharmacol 1998:46:101-110
Pgp
small bowel
gut lumen
sinu
soid
portal vein
hepatic vein
NRTIsNRTIsMechanism of ActionMechanism of Action
Nucleoside analogs (like AZT below)Nucleoside analogs (like AZT below) Analog of thymidine, cytosine, adenine, or guanineAnalog of thymidine, cytosine, adenine, or guanine Triphosphorylated inside lymphocytes to active compoundTriphosphorylated inside lymphocytes to active compound Incorporate into the growing HIV viral DNA strand by reverse Incorporate into the growing HIV viral DNA strand by reverse
transcriptasetranscriptase Nucleotide analogNucleotide analog
Currently only tenofovir (TDF)Currently only tenofovir (TDF) Does Does NOTNOT need to be tri-phosphorylated only di-phosphorylated need to be tri-phosphorylated only di-phosphorylated
to active compoundto active compound
After incorporation of After incorporation of the NRTI, viral DNA the NRTI, viral DNA synthesis will be synthesis will be terminated.terminated.
NRTI Class ToxicitiesNRTI Class ToxicitiesLactic AcidosisLactic Acidosis– Damage to mitochondria in cellsDamage to mitochondria in cells– Elevated lactate, low pH/bicarbonate, N/V, Elevated lactate, low pH/bicarbonate, N/V,
shortness of breath, if untreated can lead to shortness of breath, if untreated can lead to deathdeath
Hepatomegaly with SteatosisHepatomegaly with Steatosis– Build up of fat droplets Build up of fat droplets inside liver cellsinside liver cells– Enlarged liverEnlarged liver
NRTIsNRTIs
Drug Standard Dose* Dosage forms Common Side Effects
Metabolism/
Elimination
Zidovudine (ZDV/AZT) Retrovir
300mg bid* 300mg tab, 100mg cap, iv, oral soln
Fatigue, malaise, HA myalgia, anemia, GI
Renal
Lamivudine (3TC) Epivir
150mg bid* or 300mg qd
150, 300mg tab, oral soln Well tolerated Renal
Emtricitabine(FTC) Emtriva
200mg qd* 200mg cap Well tolerated Renal
Didanosine (ddI) Videx
400mg EC qd ( 60kg)250mg EC qd (<60kg)*
125,200,250, 400mg cap, pwdr for soln
Pancreatitis, peripheral neuropathy, LA/HS
Renal
*dose reduce for renal dysfunction
•Note: Lactic acidosis can occur with any NRTIs
NRTIsNRTIs
Drug Standard Dose* Dosage forms Common Side Effects
Metabolism/Elimination
Stavudine (d4T) Zerit IR
40mg bid ( 60kg) 30mg bid
(<60kg) *
15,20,30,40 mg cap,oral soln
Peripheral neuropathy,
Pancreatitis, LA/HS,Lipoatrophy, facial
wasting
Renal
Abacavir (ABC) Ziagen
300mg bid, 600mg qd
300mg tabs, oral soln
hypersensitivity Hepatic by alcohol
dehydrogenase and glucuronyl
transferase
Tenofovir(TDF) Viread
300mg qd* 300mg tabs Few SEs, renal toxicity
Renal
*dose reduce for renal dysfunction
NRTI CombinationsNRTI Combinations
Drug Standard Dose* Dosage forms
Lamivudine/Zidovudine (COM) Combivir
1 Tablet bid * 150/300mg tabs
Abacavir/Lamivudine/Zidovudine (TZV) Trizivir
1 Tablet bid* 300/150/300mg tabs
Tenofovir/EmtricitabineTruvada
1 Tablet qd* 300/200mg tabs
Abacavir/LamivudineEpzicom
1 Tablet qd* 600/300mg tabs
Tenofovir/Emtricitabine/EfavirenzAtripla
1 Tablet qd* 300/200/600 mg tabs
*dose reduce for renal dysfunction
Non-nucleoside Reverse Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Transcriptase Inhibitors (NNRTIs)
These agents These agents directly bind to reverse directly bind to reverse transcriptasetranscriptase to inhibit transcriptionto inhibit transcription
NNRTIs do not NNRTIs do not
require require
phosphorylation phosphorylation
to be activeto be active
RT
X
NNRTIsNNRTIs
Drug Standard Dose
Dosage forms Common AEs
Metabolism
Delavirdine (DLV) Rescriptor
400 mg tid 100mg tab, 200mg cap
Rash Potent CYP3A inhibitor; 3A4 substrate
Nevirapine (NVP) Viramune
200 mg qd x 14 d then200 mg bid
200mg tabs, Oral susp
Rash (SJ), hepatotoxicity
CYP3A inducer, auto inducer; 3A4, 2B6 substrate
Efavirenz* (EFV) Sustiva
600 mg qhs 50, 100, 200mg cap, 600mg tab
Vivid dreams, drowsiness or insomnia, rash (SJ), hyperlipidemia
CYP3A, 2B6 inducer; 2B6, 3A4 substrate
*Pregnancy Class D
Protease Inhibitors (PIs):Protease Inhibitors (PIs):Mechanism of ActionMechanism of Action
Protease enzyme cleaves Protease enzyme cleaves HIV precursor proteins HIV precursor proteins (gag/pol polyproteins) into (gag/pol polyproteins) into active proteins that are active proteins that are needed to assemble a needed to assemble a new, mature HIV virus. new, mature HIV virus.
PIs bind to protease PIs bind to protease preventing the cleavage preventing the cleavage and inhibiting the and inhibiting the assembly of new HIV assembly of new HIV virusesviruses
PI
HIV-1 Protease
XHIV
Lipids, Insulin Resistance Lipids, Insulin Resistance (Lypodystrophy)(Lypodystrophy)
HypercolesterolemiaHypercolesterolemia– Usually hypertriglyceridemia, can have Usually hypertriglyceridemia, can have
increased LDL and decreased HDLincreased LDL and decreased HDL– Treat with Fibric acid derivatives and certain Treat with Fibric acid derivatives and certain
HMGCoA reductase inhibitors HMGCoA reductase inhibitors
Insulin ResistanceInsulin Resistance– Treat with diet/exercise, metformin, TZDs, Treat with diet/exercise, metformin, TZDs,
insulin, sulfonylureasinsulin, sulfonylureas
Lipodystrophy IllustrationsLipodystrophy Illustrations
“Buffalo hump”
“Protease paunch”
“Facial wasting”
Use of Ritonavir as a P450 Inhibitor Use of Ritonavir as a P450 Inhibitor with PIswith PIs
Protease InhibitorsProtease InhibitorsStandard
DoseDosage Forms Metabolism Common AEs**
Saquinavir(Invirase) (1)
1000/ rtv 100 bid or 1600/ rtv 100 qd
200mg caps, 500mg tabs
3A, Pgp substrate; weak 3A inhibitor
GI intolerance
Nelfinavir (Viracept) (1)
1250 bid, 750mg tid 250mg, 625mg tabs, 50mg/g oral pwdr
2C19 (M83A) substrate; weak 3A inhibitor
Diarrhea
Lopinavir/ritonavir(Kaletra) (1,2)
400/100 bid 200/50 mg tabs, 80/20mg/5mL soln
3A, Pgp substrate; 3A inhibitor; 2C9, 2C19 inducer
Dyspepsia, Nausea, vomiting, diarrhea, flatulence
Indinavir(Crixivan) (1-when taken with rtv)
800/ rtv 100 bid, 800mg tid
100, 200, 333, 400mg caps
3A, Pgp substrate; weak 3A inhibitor
Nephrolithiasis Drink 7-8 glasses of water per day; hyperbilirubinemia
(1) Take with Food(2) Must be refrigerated** All PIs except atazanavir can increase lipids and cause insulin resistance
Protease InhibitorsProtease InhibitorsStandard
DoseDosage Forms Metabolism Common
AEs**
Atazanavir (Reyataz) (1)
400qd or 300/ rtv 100qd
100, 150, 200mg caps
3A substrate; 3A and UGT1A1 inhibitor
Hyperbilirubinemia, PR prolongation
Fosamprenavir (Lexiva) (1)
1400mg bid; 700/100 RTV mg bid; 1400/200 RTV mg qd
700mg tabs (Agenerase-APV liq available)
3A4, Pgp substrate; 3A4 inducer/Inhibitor
Rash, GI intolerance, caution with sulfur allergy
Tipranavir(Aptivus) (1,2)
500/200 RTV mg bid
250mg caps 3A4, Pgp substrate; 3A4, inducer/inhibitor??; Pgp inducer
Hepatotoxicity, Increased bleedingcaution with sulfur allergy
Darunavir(Prezista) (1)
600/100 RTV mg bid
300mg tabs 3A4 substrate;3A4 inhibitors
Diarrhea, nausea, HA, nasopharyngitis
Ritonavir(Norvir) (1,2)
Used as a PK booster 100-200mg
100mg caps; 80mg/mL
2D6, 3A4, Pgp substrate; 3A4, Pgp inhibitor
Nausea, vomiting, diarrhea, GI upset
(1) Take with Food (2) Must be refrigerated** All PIs except atazanavir can increase lipids and cause insulin resistance
Dose adjustments to considerDose adjustments to considerRenally-eliminatedRenally-eliminated
NRTIs (except Abacavir)NRTIs (except Abacavir)
Adjust for CrCl <50 ml/min Adjust for CrCl <50 ml/min or dialysisor dialysis
DidanosineDidanosine
EmtricitabineEmtricitabine
LamivudineLamivudine
StavudineStavudine
TenofovirTenofovir
ZidovudineZidovudine
Reference: Drug product info and Reference: Drug product info and DHHS guidelines (see tables)DHHS guidelines (see tables)
Hepatic MetabolismHepatic Metabolism NNRTIsNNRTIs PIsPIs Adjust for certain inducers, Adjust for certain inducers,
substrates, or inhibitors of substrates, or inhibitors of P450 systemP450 system
Adjust for insufficiencyAdjust for insufficiencyIndinavirIndinavir
FosamprenavirFosamprenavirAtazanavirAtazanavir
AvoidAvoidAmprenavir oral solnAmprenavir oral soln
Foasmprenavir (+/- ritonavir)Foasmprenavir (+/- ritonavir)TipranavirTipranavir
New ARV Targets Against HIVNew ARV Targets Against HIV
Fusion InhibitorFusion InhibitorFuzeon (Enfuvirtide, T-20)Fuzeon (Enfuvirtide, T-20)
See Kilby and Eron, NEJM 2003;348:2228-38
Fuzeon : Enfuvirtide (T-20)Fuzeon : Enfuvirtide (T-20)
FDA-approved fusion inhibitor; 36 AA peptideFDA-approved fusion inhibitor; 36 AA peptide– Requires 106 steps to manufactureRequires 106 steps to manufacture
Dose: 90 mg sq bidDose: 90 mg sq bidside effects: side effects: – injection site rxn, hypersensitivity (rare)injection site rxn, hypersensitivity (rare)
resistance: changes in gp41 (cell surface resistance: changes in gp41 (cell surface protein) protein)
HIV TropismHIV Tropism
Chemokine Receptor AntagonistsChemokine Receptor AntagonistsMarviroc (SelzentryMarviroc (Selzentry®®))
CCR5 or CXCR4 receptors on cell surface CCR5 or CXCR4 receptors on cell surface
Virus will bind to one of the 2 receptors Virus will bind to one of the 2 receptors – Some patients’ virus will bind to either receptorSome patients’ virus will bind to either receptor
Marviroc blocks viral entry at CCR5Marviroc blocks viral entry at CCR5
Dosed 300mg BIDDosed 300mg BID– 150mg BID with P450 inhibitors150mg BID with P450 inhibitors– 600mg BID with P450 inducers600mg BID with P450 inducers
Integrase InhibitorsIntegrase Inhibitors
Raltegravir (Isentress™)Raltegravir (Isentress™)
Dosed 400mg BID (1 tab BID)Dosed 400mg BID (1 tab BID)
No induction or inhibition on CYP450 No induction or inhibition on CYP450 enzymes or Pgpenzymes or Pgp
Metabolized by UGT1A1 (glucuronidation)Metabolized by UGT1A1 (glucuronidation)– Only affected by drugs that inhibit or induce Only affected by drugs that inhibit or induce
UGTs (ie, rifampin)UGTs (ie, rifampin)
Drug InteractionsDrug Interactions
Antiretroviral Metabolism, Antiretroviral Metabolism, Induction, and InhibitionInduction, and Inhibition
DrugDrug SubstrateSubstrate InhibitsInhibits InducesInduces
EfavirenzEfavirenz 2B6, 3A42B6, 3A4 3A43A4 3A4, 2B63A4, 2B6
NevirapineNevirapine 3A4, 2B63A4, 2B6 3A43A4
RitonavirRitonavir 2D6, 3A4, Pgp2D6, 3A4, Pgp 3A4, 2D6, Pgp3A4, 2D6, Pgp 2D6 (at high 2D6 (at high doses only)doses only)
SaquinavirSaquinavir 3A4, Pgp3A4, Pgp 3A4 3A4
NelfinavirNelfinavir 2C19 (M82C19 (M83A4)3A4) 3A43A4
AmprenavirAmprenavir 3A4, Pgp3A4, Pgp 3A4 (in vitro)3A4 (in vitro) 3A4 (in vivo)3A4 (in vivo)
FosamprenavirFosamprenavir 3A4, Pgp3A4, Pgp 3A4 (in vitro)3A4 (in vitro) 3A4 (in vivo)3A4 (in vivo)
Lopinavir/ritonavirLopinavir/ritonavir 3A4, Pgp3A4, Pgp 3A43A4 2C9, 2C19, 1A22C9, 2C19, 1A2
AtazanavirAtazanavir 3A4, Pgp3A4, Pgp 3A4, UGT, 1A23A4, UGT, 1A2
TipranavirTipranavir 3A4, Pgp3A4, Pgp 3A43A4 Other enzymesOther enzymes
DarunavirDarunavir 3A4, Pgp3A4, Pgp 3A43A4
MaravirocMaraviroc 3A4, Pgp3A4, Pgp
Substrate Inhibitor Inducer
3A4 Macrolides,cyclosporine, CCB, statins, azoles, PDE5 inhibitors, aprepitant, midazolam, triazolam
Cimetidine, Macrolides, FQs, SSRIs, CCB, azoles, aprepitant
rifamycins, phenytoin, carbamazepine, St. John’s wort, aprepitant, garlic
2D6 Opiates, nortriptyline, amitriptyline, tramadol, trazodone, paroxetine, metoprolol, propranolol, carvedilol
Haldol, SSRIs, cimetidine, amiodarone
rifamycins, phenytoin, CBZ, St. John’s wort
1A2 Amitriptyline, clozapine, caffeine, clozapine, imipramine, R-warfarin, theophylline, proprnaolol
FQs, azoles, macrolides, rifamycins, phenytoin, CBZ, smoking, St. John’s wort
2C19 Omeprazole, phenytoin SSRIs, azoles, fluvastatin, omeprazole, topiramate
rifamycins, CBZ, phenytoin
2C9 S-warfarin, sulfonylureas, phenytoin, carvedilol
Amiodarone, SSRIs, azoles, amiodarone
Phenytoin, CBZ, rifammycins, aprepitant
Cytochrome P450: Non-Antiretrovirals
Protease Inhibitors and Acid Protease Inhibitors and Acid SuppressionSuppression
Do Not combine Do Not combine Atazanavir Atazanavir and and Proton Pump Proton Pump InhibitorsInhibitors– May Combine May Combine ATVATV and and Famotidine Famotidine but dose but dose
adjustments are REQUIREDadjustments are REQUIRED
May use May use Indinavir Indinavir with with PPIs PPIs but ONLY if but ONLY if coadministered with coadministered with RTVRTV
May use Fosamprenavir with EsomeprazoleMay use Fosamprenavir with Esomeprazole– Separate FPV from H2 blockers if used concomitantlySeparate FPV from H2 blockers if used concomitantly
Dose Adjustments Between ARVsDose Adjustments Between ARVsDrug ADrug A Drug BDrug B RecommendationRecommendation
TenofovirTenofovir DidanosineDidanosine Dose ddI as 250mg Dose ddI as 250mg QD with TDF 300mg QD with TDF 300mg QDQD
Tenofovir Tenofovir AtazanavirAtazanavir Use RTV 100mg QD Use RTV 100mg QD with ATV + TDFwith ATV + TDF
EfavirenzEfavirenz
(Nevirapine)(Nevirapine)
AtazanavirAtazanavir Use RTV 100mg QD Use RTV 100mg QD with ATV + EFVwith ATV + EFV
EfavirenzEfavirenz
(Nevirapine)(Nevirapine)
FosamprenavirFosamprenavir Use RTV with FPVUse RTV with FPV
EfavirenzEfavirenz
(Nevirapine)(Nevirapine)
Lopinavir/ritonavirLopinavir/ritonavir Increase LPV/RTV to Increase LPV/RTV to 3 tabs BID3 tabs BID
Important Drug InteractionsImportant Drug InteractionsDo NOT use Do NOT use Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic with with most most PIs or DLVPIs or DLVDo NOT combine Do NOT combine RifampinRifampin with with PIsPIs– LPV/RTV may be dose increased and combined with RifampinLPV/RTV may be dose increased and combined with Rifampin– Conflicting data with EFV and NVPConflicting data with EFV and NVP
Use other Use other P450 inducersP450 inducers with CAUTION when combining with with CAUTION when combining with PIs PIs and NNRTIsand NNRTIsDo NOT use Do NOT use Fluticasone Fluticasone or or AlfuzosinAlfuzosin with with RitonavirRitonavirCaution with Caution with Azoles, Clarithromycin, Oral Contraceptives, Phenytoin, Azoles, Clarithromycin, Oral Contraceptives, Phenytoin, Carbamazepine, Phenobarbital, Methadone, PDE5 inhibitors, Carbamazepine, Phenobarbital, Methadone, PDE5 inhibitors, Atorvastatin, Beta blockers, Atorvastatin, Beta blockers, when combined with PIswhen combined with PIsAvoid Herbal Products with Known or Suspected InteractionsAvoid Herbal Products with Known or Suspected InteractionsWhen combining Protease Inhibitors, Often Dose Adjustments are When combining Protease Inhibitors, Often Dose Adjustments are NecessaryNecessary
Importance of AdherenceImportance of Adherence
Therapeutic Drug MonitoringTherapeutic Drug Monitoring
Not widely used in the USNot widely used in the US
Recommended in certain situations for PIs Recommended in certain situations for PIs and NNRTIsand NNRTIs
What makes a drug a good candidate for What makes a drug a good candidate for TDM?TDM?
When should TDM be performed for When should TDM be performed for antiretrovirals?antiretrovirals?
Why TDM in HIV therapy?Why TDM in HIV therapy?
Adapted from Acosta EP, et al AIDS Res Human Retro 2002