Drug – Drug interactions 8 th Advanced HIV course , Montpellier , France September 10, 2010

1. Drug – Drug interactions8thAdvanced HIV course, Montpellier, FranceSeptember 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud University Nijmegen Medical Centre d.burger@akf.umcn.nl

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

3. http://www.hiv-druginteractions.org/

4. Basic pharmacology of ARVs

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 e-mail to HIVPharmacology@akf.umcn.nl 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 +48-60% 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)

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 • Neurocognitiveimpairment (= brain tissue damage) canneverbedirectlyrelated to [ARV] in CSF • Lipophilic drug (e.g. EFV) distributesfrom CSF to brain tissue (anotherexample: 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 (becausethere is hardlyanyprotein in CSF) • HowmanyARVs 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 pharmacologicalproperties • CSF concentrationsabove IC50 • Clinical studies demonstrating CSF viralload response orimprovement in neurocognitive performance Basedonavailableinformationeach 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: 1353-62

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