Direct antiviral therapy of hcv and relevant drug drug interactions for ivdu

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1 Direct antiviral therapy of hcv and relevant interactions for ivdu Stefan Mauss Center for HIV and Hepatogastroenterology Duesseldorf, Germany

2 Disclosures Advisory board: Abbvie, BMS, Boehringer Ingelheim, Gilead, Janssen, Roche Speaker bureau: BMS, Boehringer Ingelheim, Gilead, Janssen, MSD, Roche

3 Drug Drug Interactions Not welcome in development Frequently based on induction or inhibition of transporters/enzymes in gut or liver May lead to toxicity (increase of levels in particular peak concentrations) May lead to loss of efficacy (decrease of levels in particular trough levels) Only major changes clinically relevant, i. e. >50% depending on safety margin of the respective

peak concentrations) May lead to loss of efficacy (decrease of levels in particular trough

4 Metabolisation of s in gut and liver CYP450 CYP450 P-Glycoprotein

5 Interaction of the cytochrom P450 enzyme family with s Diclofenac, Celecoxib, Tolbutamide, Efavirenz, Ritonavir Omeprazole, Diazepam, Proguanil, Efavirenz, Ritonavir Theophyllin, Caffeine, Ritonavir Codein, Propafenon, Imipramin, Tropisetron, Ritonavir Ethanol, Halothan, Ritonavir Ciclosporin, Erythromycin, HIV Protease Inhibitors, NNRTI, Maraviroc, Nifedipin, Midazolam, Tacrolimus, Naringine, St. Johns Worth etc. CYP450 Iso-Enzymes: 3A4 2D6 2C19 2C9 1A2 2E1 Boceprevir and Telaprevir are substrates and inhibitors of CYP4503A4

Ethanol, Halothan, Ritonavir Ciclosporin, Erythromycin, HIV Protease Inhibitors, NNRTI, Maraviroc, Nifedipin, Midazolam, Tacrolimus,

6 How to evaluate interactions Cell culture experiments Healthy volunteer studies (single dose, 14 days) Panel of marker s - midazolam (CYP3A) - dextromethorphan (CYP1A2) - caffeine (CYP1A2) - omeprazole (CYP2C19) - warfarin (CYP2C9) other s of interest: rifampicin, digoxin, ritonavir In patients the scenario may be substantially different: - polypharmacy - intermittent use of recreational/illicit s - free/protein bound are not separately determined - pharmacokinetics may be affected by hepatic or renal impairment

rifampicin, digoxin, ritonavir In patients the scenario may be substantially different: - polypharmacy - intermittent use of

7 Sites of interaction for telaprevir and boceprevir Effect of telaprevir on transporters and metabolic pathways - Cytochrom P4503A4, 3A5 - P-glycoprotein - organic anion transporters OATP1B1 OATP2B1 Effect of boceprevir on transporters and metabolic pathways - Cytochrom P4503A4, 3A5 - P-glycoprotein Metabolisation of telaprevir - Cytochrom P4503A4 Metabolisation of boceprevir - Cytochrom P4503A4 - Aldo-ketoreductase pathway

boceprevir on transporters and metabolic pathways - Cytochrom P4503A4, 3A5 - P-glycoprotein Metabolisation

8 Telaprevir and Escitalopram Metabolised by CYP4502C19, 3A4, and 2D6

9 Benzodiazepines Midazolam Boceprevir Telaprevir

10 Not recommended with boceprevir/telaprevir Anticonvulsants - Phenytoin (strong CYP3A4 inducer) - Carbamazepine (strong CYP3A4 inducer) - Phenobarbital (strong CYP3A4 inducer) Antibiotics - rifampicine (strong CYP 3A4 inducer) Sedatives - Midazolam (TPV AUC +796%, BCV AUC +430%) - Alprazolam (TPV AUC +35%, BCV no data) Antipsychotics - Pimozid (clearance via CYP3A4, risk of cardiac arrhythmia) Contraceptive - ethinyl estradiol (TPV AUC -28%, BCV AUC -24%)

Sedatives - Midazolam (TPV AUC +796%, BCV AUC +430%) - Alprazolam (TPV AUC +35%, BCV no data) Antipsychotics -

11 Safe choices Antidepressants - Escitalopram (TPV AUC -35%, BCV no relevant interaction) - Citalopram (same metabolic pathway as escitalopram) - sertraline (CYP4502D6) - paroxetine (CYP4502D6) Anticonvulsants - Gabapentin (not metabolised by CYP450) - Levetiracetam (not metabolised by CYP450) - Pregabalin (not metabolised by CYP450) Sedatives - Zolpidem (TPV AUC -47%, BCV no data) Antipsychotics - Olanzapine (not metabolised by CYP450)

Gabapentin (not metabolised by CYP450) - Levetiracetam (not metabolised by CYP450) - Pregabalin (not

12 Opioid maintenance Heroin - metabolised mainly by CYP3A4 - dose increase possible, no data Methadone - metabolised mainly by CYP3A4, high protein binding - TPV: AUC -29% (mainly by displacement of protein bound methadone) - BCV: AUC -22% Buprenorphine - metabolised by CYP3A4 und 3A5, inhibitor of CYP3A4 - TPV: AUC -4%, no effect on TPV concentrations - BCV: AUC +19%, no effect on BCV concentrations

protein bound methadone) - BCV: AUC -22% Buprenorphine - metabolised by CYP3A4 und 3A5, inhibitor of

13 Concomittant substance abuse Documented in urine of patients on hcv therapy

14 Ilegal substances Tetrahydrocannabinol (THC) - metabolised by CYP2C9, 2C19 and 3A4 - due to multiple pathways relevant interactions not likely Amphetamine (MDMA)/Ecstasy (PMA, PMMA) - metabolised by CYP3A4 and CYP2D6 and monoaminooxidases - interactions can not be excluded - narrow safety margin, fatal toxicities possible (cardiac, liver, hyperthermia) Cocaine/Crack - hydrolysis by CYP450 enzymes (degradation and activation of toxic metabolites), inhibitor of CYP2D6 - interactions possible, but clinical outcome difficult to predict Barbiturates - metabolised by CYP3A4, strong inducers of CYP3A4 - interactions likely, significant dose increase of barbiturates likely, dose decrease of TPV and BCV likely

hyperthermia) Cocaine/Crack - hydrolysis by CYP450 enzymes (degradation and activation of toxic metabolites), inhibitor of CYP2D6 - interactions possible, but clinical outcome

Pharmakokinetic interactions between TVR/BOC and antiretrovirals Tenofovir- Emtricitabine/Lamivudine oder Abacavir-Lamivudine plus NNRTI PI/r Integrase inhibitors Maraviroc, T-20

15 Pharmakokinetic interactions between TVR/BOC and antiretrovirals Tenofovir- Emtricitabine/Lamivudine oder Abacavir-Lamivudine plus NNRTI PI/r Integrase inhibitors Maraviroc, T-20 Telaprevir Efavirenz * Etravirine Rilpivirine Atazanavir/r other PIs Raltegravir? Boceprevir Efavirenz Etravirine Rilpivirine Atazanavir/r other PIs Raltegravir? *increase TVR to 1125 mg tid

Maraviroc, T-20 Telaprevir Efavirenz * Etravirine Rilpivirine Atazanavir/r other PIs

16 Management strategies of interactions Select a few safe s as your first choice for frequent indications Discontinue s with CYP3A4 interactions whenever possible Minimize polypharmacy Inform patients clearly about possible interactions with recreational and illegal substances

interactions whenever possible Minimize polypharmacy Inform patients

HCV Interaction Studies presented at the 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Washington, April 2014.

Page 1 HCV Interaction Studies presented at the 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Washington, April 2014. This report summarises interaction studies relating