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

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Presentation on theme: "Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud."— Presentation transcript:

1 Drug – Drug interactions 8 th 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

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4 Basic pharmacology of ARVs Drug classDrugSubstrateInhibitorInducer NRTIsABC, ZDVUGT-- NNRTIsEFV NVP CYP2B6 CYP2B6, CYP3A -CYP3A, UGT PIsRTVCYP3ACYP3A, CYP2D6 CYP1A2, CYP2C9, UGT OtherCYP3A - Integrase inhRALUGT-- CCR5 inhMRVCYP3A--

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 C min –82% Poirier et al. AIDS 2006 Recommendation: ATV/r 400/200mg QD

9 Interactions among ARVs (4): LPV/r + NNRTIs AUC –19% Recommendation: LPV/r 500/125mg or 600/150mg BD 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)

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 Iwamoto et al. Clin Inf Dis 2008 AUC: + 72%

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 ClassARVDose of ARV Effect on methadon AUC Protease inhibitorsAtazanavir400mg 1dd+3% Darunavir/rtv600/100mg 2dd-16% Fosamprenavir/rtv700/100mg 2dd-18% Indinavir800mg 3dd-4% Indinavir/rtv800/100mg 2dd0% Lopinavir/rtv400/100mg 2dd -53% -26% Nelfinavir1250mg 2dd-43% Saquinavir/rtv 1000/100mg 2dd 400/400mg 2dd 1600/100mg 1dd -19% -32% +3% Tipranavir/rtv500/200mg 2dd-48% Non-nucleoside reverse transcriptase inhibitors Efavirenz600mg 1dd -57% -52% Etravirine100mg 2dd+8% Nevirapine200mg 2dd 400mg 1dd -41% -53% -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 > H 2 antagonist > antacids Dose of PPI and timing of H 2 antagonist are relevant too

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

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 M w ) 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?

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23 Three criteria to assess CSF penetration effectiveness (CPE) score Chemical and pharmacological properties CSF concentrations above IC 50 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

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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 1 st 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 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

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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 Talameh et al. J Chrom B 2009 Dumond et al. J AIDS 2009 Raltegravir Maraviroc

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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