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David M. Burger Ass. Professor in Clinical Pharmacology

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1 Drug – Drug interactions 8th Advanced HIV course, Montpellier, France September 10, 2010
David M. Burger Ass. Professor in Clinical Pharmacology Radboud University Nijmegen Medical Centre

2 Outline (30 minutes) 1. Basic pharmacology of ARVs
2.  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


4 Basic pharmacology of ARVs
Drug class Drug Substrate Inhibitor Inducer NRTIs ABC, ZDV UGT - NNRTIs EFV NVP CYP2B6 CYP2B6, CYP3A CYP3A, UGT PIs RTV CYP3A CYP3A, CYP2D6 CYP1A2, CYP2C9, UGT Other Integrase inh RAL CCR5 inh MRV

5 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 to in case of questions

6 Interactions among ARVs (1): TDF +ATV/r
AUC -25% Taburet et al. AAC 2004

7 Interactions among ARVs (2): TDF + ddI
AUC % Pecora et al. Ann Pharmacother 2003

8 Interactions among ARVs (3): ATV/r + NNRTIs
Recommendation: ATV/r 400/200mg QD Cmin –82% Poirier et al. AIDS 2006

9 Interactions among ARVs (4): LPV/r + NNRTIs
Efavirenz + PIs (n=153): 65% received a dose adjustment Virological response in patients WITH dose adjustment was better than in patients WITHOUT dose adjustment (p=0.05) Recommendation: LPV/r 500/125mg or 600/150mg BD AUC –19%

10 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

11 Interactions among ARVs (6): ATV + Raltegravir
AUC: + 72% Iwamoto et al. Clin Inf Dis 2008

12 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

13 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% Tipranavir/rtv 500/200mg 2dd -48% Non-nucleoside reverse transcriptase inhibitors Efavirenz 600mg 1dd -57% -52% Etravirine 100mg 2dd +8% Nevirapine 200mg 2dd -41% -49%

14 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

15 Interactions between ARVs and PPIs (2)
AUC: - 48% AUC: - 62% Klein et al. J Clin Pharmacol 2008

16 PPIs and raltegravir: a positive interaction
AUC: + 212%

17 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

18 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

19 Pharmacodynamics of ARVs
Brain Genital tract

20 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

21 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?


23 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

24 CPE scores


26 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

27 CPE scores (updated 2010) Letendre et al. CROI 2010 (#430)

28 CPE ≥ 8 appears important, but none of the preferred 1st line regimens achieves that score…
Letendre et al. CROI 2010 (#430)

29 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

30 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%)

31 3.3 Lowe et al. AIDS 2004; 18:

32 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

33 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



36 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?

37 Newer ARVs penetrate well into CVF
Raltegravir Maraviroc Talameh et al. J Chrom B 2009 Dumond et al. J AIDS 2009

38 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

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