Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M....
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Transcript of Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M....
Drug – Drug interactions
8th Advanced HIV course, Montpellier, FranceSeptember 10, 2010
David M. Burger
Ass. Professor in Clinical Pharmacology
Radboud University Nijmegen Medical Centre
Outline (30 minutes)
1. Basic pharmacology of ARVs2. Important interactions
• Between ARV drugs/classes with special reference to new drugs
• Other important interactions i. very practical, use examples specific to clinical practices ii. Methadone iii. PPIs iv. OCP v. Anti-epileptics
• (How to improve drug exposure)3. Basic pharmacodynamics
• Brain
• Genital tract
http://www.hiv-druginteractions.org/
Basic pharmacology of ARVs
Drug class Drug Substrate Inhibitor Inducer
NRTIs ABC, ZDV UGT - -
NNRTIs EFVNVP
CYP2B6CYP2B6, CYP3A
- CYP3A, UGT
PIs RTV CYP3A CYP3A, CYP2D6
CYP1A2, CYP2C9, UGT
Other CYP3A CYP3A -
Integrase inh RAL UGT - -
CCR5 inh MRV CYP3A - -
Summary of expected interactions
• All ARVs can be subject to interactions
• NNRTIs reduce drug concentrations
• PIs increase drug concentrations
• With a few exceptions….
• Check Liverpool website and/or send e-mail to [email protected] in case of questions
Interactions among ARVs (1): TDF +ATV/r
AUC -25%
Taburet et al. AAC 2004
Interactions among ARVs (2): TDF + ddI
AUC +48-60%
Pecora et al. Ann Pharmacother 2003
Interactions among ARVs (3): ATV/r + NNRTIs
Cmin –82%
Poirier et al. AIDS 2006
Recommendation: ATV/r 400/200mg QD
Interactions among ARVs (4): LPV/r + NNRTIs
AUC –19%
Recommendation: LPV/r 500/125mg or600/150mg BD
Efavirenz + PIs (n=153):65% received a dose adjustmentVirological response in patients WITH dose adjustment was better than in patients WITHOUT dose adjustment (p=0.05)
Interactions among ARVs (5): Maraviroc (CYP3A substrate)
• Normal dose: 300mg BID
• With an inducer (e.g., EFV): 600mg BID
• With an inhibitor (e.g., LPV/r): 150mg BID
• With both an inducer AND inhibitor: 150mg BID
Interactions among ARVs (6): ATV + Raltegravir
Iwamoto et al. Clin Inf Dis 2008AUC: + 72%
Interactions between ARVs and methadone (1)
• Mechanism: complex pharmacokinetics
• Stereoselective (R- and S-enantiomer)
• Protein binding
• CYP2B6, UGT enzymes involved
• Change in methadone exposure may have variable effect in patients
Interactions between ARVs and methadone (2)
Drug Class ARV Dose of ARV Effect on
methadon AUC
Protease inhibitors Atazanavir 400mg 1dd +3%
Darunavir/rtv 600/100mg 2dd -16%
Fosamprenavir/rtv 700/100mg 2dd -18%
Indinavir 800mg 3dd -4%
Indinavir/rtv 800/100mg 2dd 0%
Lopinavir/rtv 400/100mg 2dd -53%
-26%
Nelfinavir 1250mg 2dd -43%
Saquinavir/rtv 1000/100mg 2dd
400/400mg 2dd
1600/100mg 1dd
-19%
-32%
+3%
Tipranavir/rtv 500/200mg 2dd -48%
Non-nucleoside reverse
transcriptase inhibitors
Efavirenz 600mg 1dd -57%
-52%
Etravirine 100mg 2dd +8%
Nevirapine 200mg 2dd
200mg 2dd
400mg 1dd
-41%
-53%
-49%
Interactions between ARVs and PPIs (1)
• Acid secretion reducing agents are frequently used by HIV patients, incl. OTC
• A few ARVs need gastric acid for solution: ddI, IDV, ATV
• Impact of gastric acid inhibition can be major (>50%)
• PPIs > H2 antagonist > antacids
• Dose of PPI and timing of H2 antagonist are relevant too
Interactions between ARVs and PPIs (2)
Klein et al. J Clin Pharmacol 2008
AUC: - 62% AUC: - 48%
PPIs and raltegravir: a positive interaction
AUC: + 212%
Interactions between ARVs and oral contraceptive pills
• General mechanism: boosted PIs and NNRTIs induce glucuronidation of estrogens and/or progestagens
• Lower levels of hormones are the result with possible less reliable anticonception
• Evidence based exception: medroxyprogesterone i.m. depot (Cohn et la. CPT 2007)
• Other advice: condom use, avoid sub-50 pill
Interactions between ARVs and anti-epileptics
• Older anti-epileptics (phenytoin, carbamazepine, phenobarbital) are all known to be strong enzyme inducers: reduce levels of PIs and NNRTIs
• Boosted PIs & NNRTIs can also have effects on anti-epileptic drug levels (both ↑ and ↓)
• Avoid these older drugs as much as possible; if not possible: TDM of both ARVs and antiepileptics
• Alternatives: lamotrigine, levetiracetam
Pharmacodynamics of ARVs
• Brain
• Genital tract
Cerebrospinal fluid / brain
• Blood – brain barrier protects brain from toxic substances
• Characteristics of drugs that are able to penetrate:
• Small molecule (low Mw)
• Lipophilic
• Low protein binding
• No substrate of efflux transporters
Facts and fiction about CSF penetration
• CSF = “easy” to collect, but ≠ brain tissue
• Neurocognitive impairment (= brain tissue damage) can never be directly related to [ARV] in CSF
• Lipophilic drug (e.g. EFV) distributes from CSF to brain tissue (another example: itraconazole in cryptococcal meningitis)
• LPV has 98-99% protein binding in plasma = 1-2% is active. If 1% penetrates CSF then CSF/plasma ratio is 0.01 = OK (because there is hardly any protein in CSF)
• How many ARVs must penetrate CSF?
• 1 is enough (see AZT effect on HIV dementia)?
• >1 to prevent development of resistance?
Three criteria to assess CSF penetration effectiveness (CPE) score
• Chemical and pharmacological properties
• CSF concentrations above IC50
• Clinical studies demonstrating CSF viral load response or improvement in neurocognitive performance
Based on available information each ARV receives a CPE score of 0, 0.5, or 1; CPE score of an ARV regimen is sum of CPE scores
CPE scores
CPE scores of popular regimens
• d4T, 3TC, NVP = 2.0
• ZDV, 3TC, NVP = 2.5
• TDF, FTC, EFV = 1.0
• TDF, FTC, ATV/r = 1.0
• Please note:
• All regimens are ≥ 1.0
• No evidence that 2.5 is better than 1.0
CPE scores (updated 2010)
Letendre et al. CROI 2010 (#430)
CPE ≥ 8 appears important, but none of the preferred 1st line regimens achieves that score…
Letendre et al. CROI 2010 (#430)
HIV drugs and the male genital tract
• Relevant compartment for many reasons:
• Development of resistance (if ARVs do not penetrate)
• Transmission of HIV if not suppressed
• Transmission of HIV resistance
• Semen is “easy” to collect and is a surrogate for distribution of ARVs into the male genital tract
ARV drugs and penetration into male genital tract
• Diffusion or active transport (cf. CSF)
• Lipid solubility
• Ionisation: pH prostate (6.6) is lower than in blood (7.4); weak bases cumulate in prostate (“ion trapping”)
• Protein binding (< 90%)
Lowe et al. AIDS 2004; 18: 1353-62
3.3
Clinical relevance of differences in semen penetration?
• Clinical studies show >90% VL suppression in semen
• No large series of patients with isolated drug resistance in semen
• Male genital tract most likely not a separate compartment
HIV, drugs and the female genital tract
• Like the male genital tract, it is a relevant compartment for many reasons:
• Development of resistance (if ARVs do not penetrate)
• Transmission of HIV if not suppressed
• Transmission of HIV resistance
• Esp. important for pre- (and maybe post-) exposure prophylaxis
• Cervicovaginal fluid (CVF) is “easy” to collect and is a surrogate for distribution of ARVs into the female genital tract
Clinical relevance of differential PK of ARVs in CVF
• Only 1/34 women had detectable HIV-1 RNA in CVF
• She was known to be nonadherent on a ddI, 3TC, EFV regimen
• NRTIs penetrate well
• Sufficient for pre-exposure prophylaxis?
• Selective development of NRTI resistance in CVF?
• What about NRTI-sparing regimens?
Newer ARVs penetrate well into CVF
Talameh et al. J Chrom B 2009Dumond et al. J AIDS 2009
Raltegravir Maraviroc
Conclusions
• Basic knowledge of clinical pharmacology essential to manage your patients
• Check Liverpool website and/or seek expert advice
• ARV penetration into compartments interesting to study; clinical relevance yet unknown