Update on Drug Interactions of HIV/HCV Treatment Regimens Jennifer J. Kiser, PharmD

Transcription

1 Update on Drug Interactions of HIV/HCV Treatment Regimens Jennifer J. Kiser, PharmD Associate Professor University of Colorado

2 Disclosures Dr. Kiser receives research funding (paid to her institution) from ViiV Healthcare. Janssen Scientific Affairs - ended 12/15 Dr. Kiser received research funding (paid to her institution) from Janssen Scientific Affairs (ended 12/15).

3 Objectives Compare the pharmacology of HCV treatments in someone with HIV Describe key drug-drug interactions between HCV and antiretroviral therapies Explore key drug-drug interactions with other medications commonly used among HIV-coinfected persons

4 CYP450 and Drug Metabolism CYP2C CYP1A2 CYP2E1 Key points Majority of drugs metabolized by (or substrates for) CYP3A4 Enzymes can be induced or inhibited CYP2D6 CYP3A4 Adapted from Goodman and Gilman s The Pharmacological Basis of Therapeutics, 9 th ed.

5 CYP450 Inhibition Drug Concentration Inhibiting drug added (RTV) Key Points Time CYP450 inhibition leads to increased levels of drugs metabolized by same enzyme. Drug toxicity possible. Peak effect occurs rapidly, as soon as adequate concentrations of inhibitor are reached

6 CYP450 Induction Drug Concentration Inducing drug added (RIF) Key Points Time CYP450 induction leads to decreased levels of drugs metabolized by same enzyme. Peak effect occurs slowly based upon half-life of drug and time to synthesize new CYP450 enzyme

7 Transporters in the Liver Systemic Circulation Systemic Circulation NTCP OATP1B1 OATP1B3 OATP2B1 OAT2 MRP2 BCRP Bile ABCG5/G8 BSEP MRP3 MRP4 OCT1 P-gp MDR3 Sinusoidal Membrane Canalicular Membrane Like enzymes, transporters can also be inhibited or induced. Adapted from Oswald S. et al. Xenobiotica 2007;37(10-11):

8 Sofosbuvir NS5B Polymerase Inhibitor Uridine nucleotide analog 80% renally eliminated Plasma In plasma, SOF accounts for only ~4% of the drug related material, majority (>90%) is GS ( 007 ) SOF 007 Cell SOF 007-TP Enzymes Transporters Victim Substrate P-gp and BCRP Perpetrator

9 Sofosbuvir and Amiodarone 9 cases (3 on SOF/LDV, 5 on SOF/DCV, 1 on SIM/SOF) bradycardia, fatal cardiac arrest, some cases requiring pacemaker insertion For patients taking amiodarone with no alternative, counseling and cardiac monitoring in an in-patient setting for the first 48 hours of SOF/LDV co-administration is recommended with daily heart rate monitoring x 2 weeks. Mechanism unclear Gilead Dear Healthcare provider letter issued 3/20/15

10 Ledipasvir Minimal metabolism, 70% eliminated unchanged, 1% renally eliminated Enzymes Transporters Victim Unknown pathway, CYP3A4? Substrate P-gp Perpetrator Inhibitor of P-gp, BCRP, OATP1B1/3 Absorption is ph-dependent

11 LDV dosing with gastric acid modifiers Separate antacids by 4 hours. PPI doses comparable to omeprazole 20mg can be administered simultaneously with SOF/LDV under fasted conditions. H2 blocker doses should not exceed the equivalent of famotidine 40mg BID. Avoid if possible. Equivalent PPI Doses Esomeprazole 40mg Pantoprazole 40mg Lansoprazole 30mg Rabeprazole 20mg Omeprazole 20mg

12 PPI use may compromise SVR with SOF/LDV HCV-Target is a multicenter, prospective, observational cohort Odds of SVR in individuals not receiving a PPI were 2.47-times those of individuals taking a PPI HCV Target. Terrault N, et al. AASLD 2015

13 With SOF/LDV, TFV exposures are high in those on PIs NNRTIs Without With LDV/SOF 1,2 LDV/SOF 3 RTV-Boosted PIs Without With LDV/SOF 4-9 LDV/SOF 10 Range of TFV exposures with available safety data EFV RPV ATR CPA N = FPV SQV LPV/r ATV DRV ATV DRV * 24 17* TFV exposures are higher when TDF is coadministered with LDV/SOF compared to without LDV/SOF, but Compared to the range of TFV exposures with available safety data For EFV or RPV: TFV exposures fall within the range 1 For RTV-boosted PIs: TFV exposures partially exceed the range 2 1, Data on File, Gilead Sciences. 2. Hoetelmans RMW, et al. 6 th IWCPHT Quebec City, Canada. Poster # German P, et al. ICPHHT #O6 4. Luber AD, et al. HIV Medicine. 2010;11:193-9 (FPV+RTV) 5. Chittick GE, et al. AAC. 2006; 50(4): (SQV+RTV) 6. Zhu. 9th IWCPHT #023 (ATV+RTV & LPV/r ) * HIV-infected subjects in CASTLE study 7. Kearney B, et al. JAIDS. 2006;43(3): (LPV/r) 10. German P, et al. CROI Agarwala S, et al. 6th IWCPHT #16. (ATV+RTV) 9.. Hoetelmans RMW, et al. BJCP. 2007;64(5): (DRV+RTV)

14 Guidelines Recommendation on SOF/LDV with TDF SOF/LDV and TDF should be avoided in those with CrCl below 60 ml/min The combination of SOF/LDV with TDF and boosted regimens should be avoided (pending further data) unless antiretroviral regimen cannot be changed and the urgency of treatment is high

15 If you can t avoid TDF + boosted regimen, monitor Baseline parameters should include estimated renal function, electrolytes (including phosphorus), and urinary protein and glucose levels Monitor every 2-4 weeks on therapy Estimated renal function CKD in HIV guidelines suggest using CKD-EPI equation Urinary protein and glucose Lucas GM, et al. CID 2014;59(9):e96-138,

16 Renal Safety of Boosted TDF in HIV/HCV-patients on SOF/LDV Average egfr appeared to decline slightly with the initiation of SOF/LDV, but No difference in egfr in those on TDF plus boosted PI vs. without boosted PI At end of treatment, no difference between groups in those with egfr < 70 ml/min Vivancos-Gallego MJ, et al. CROI, 2/22-2/25, 2016, Boston, MA, #452

17 Tenofovir Alafenamide (TAF) lower TFV plasma levels Tenofovir (TFV) Tenofovir disoproxil fumarate (TDF) Tenofovir alafenamide (TAF) Gut TFV TDF TAF Plasma TFV TDF TAF TFV TDF TAF Lymphoid Cells TFV TFV-MP TFV-DP Intact TAF transits directly into target cells where it is intracellularly activated to tenofovir diphosphate (TFV-DP) 1-3 TAF has 90% lower circulating plasma TFV levels compared to TDF 300mg 4-6 Basolateral transporters (OAT1, OAT3) effectively transfer TFV, but not intact TAF, into renal proximal tubular cells 7 Lower systemic level of TFV, improved renal safety profile Lee W et. Antimicr Agents Chemo 2005;49(5): Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63: Bam R, et al. Antiviral ther Apr 4 [Epub] 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2): Sax P, et al. JAIDS Sep 1;67(1): Ruane P, et al. JAIDS 2013;63: Babusis D, et al. Mol Pharm 2013;10(2): Sax P, et al. CROI Seattle, WA. #143LB 9. Sax P, et al. JAIDS Sep 1;67(1): Mills A, et al. ICAAC Washington D.C. Abstract# H-647c.

18 TAF Possible TDF Alternative in Patients on Cobicistat and Ritonavir TFV was increased by SOF/LDV in those on F/TAF/ELV/cobi by 27%, but TFV AUC with TAF only ~20% of AUC typically seen with TDF (~400 vs ng*hr/ml) Garrison KL, et al. 16 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Alexandria, VA, May 26-28, 2015, abstract 71.

19 Velpatasvir ph dependent absorption More reliant on hepatic metabolism than LDV <1% of the dose is excreted in urine Enzymes Transporters Victim CYP3A4, CYP2C8, CYP2B6 Substrate P-gp, BCRP Perpetrator Inhibitor of P-gp, BCRP, OATP1B1/3 Mogalian E, et al. Clin Pharmacokin Epub Oct 30, 2015

20 VEL absorption is ph-dependent Unlike the current guidance with ledipasvir, recommended to take the 20mg OME equivalent in the fed state VEL exposures in the healthy volunteers receiving 20mg OME in the fed state similar to VEL exposures in Phase 3 trials Mogalian E, et al. ASCPT, 3/8-3/12, 2016, San Diego, CA, #PI-050

21 Velpatasvir Interactions with ARV Cannot be used with EFV Tenofovir Levels Increased Mogalian E, et al. AASLD 11/13-11/17, 2015, Boston, MA #

22 VEL + Boosted ARV Regimens on TFV PK TFV increased when administered as TDF story looks similar to LDV Limitation: raw concentrations not reported, only GMRs, so can t evaluate against the range of TFV exposures with available safety data Mogalian E, et al. CROI, 2/22-2/25, 2016, Boston, MA #100

23 Daclatasvir Primarily hepatically metabolized (88%), minimal renal elimination (7%) Dose depends on concomitant medications Enzymes Transporters Victim Substrate CYP3A4 Substrate P-gp Perpetrator Inhibitor of P-gp, BCRP, OATP1B1/3

24 Use Full Dose DCV with DRV/r and LPV/r 9/12 patients that relapsed in ALLY-2 were taking DRV/r with a reduced dose of DCV (30mg) 1 Healthy volunteer PK study indicated DCV Cmax and AUC were 62% and 30%, respectively when used at a reduced dose with DRV/r 2 1 Garimella T, et al. AASLD, 11/13-11/17, Boston, MA, #728, 2 Gandhi, et al. International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, 5/26-5/28, 2015, poster #80

25 Grazoprevir/Elbasvir Hepatically metabolized, less than 1% renally eliminated Enzymes Transporters Grazoprevir (Protease Inhibitor) Elbasvir Victim Substrate CYP3A4 Substrate OATP1B1 and P-gp Perpetrator Inhibitor of CYP3A4, UGT1A1 Inhibitor of BCRP Victim Substrate CYP3A4 Substrate P-gp (NS5A Inhibitor) Perpetrator Inhibitor of BCRP and P-gp

26 GZR/EBR Interaction Potential with ARV PK Changes and Recommendation Ritonavir-boosted atazanavir Ritonavir- boosted darunavir Ritonavir-boosted lopinavir Ritonavir-boosted tipranavir Efavirenz Rilpivirine Etravirine Raltegravir Cobicistat-boosted elvitegravir Dolutegravir Maraviroc Tenofovir disoproxil fumarate GZR, EBR, ATV GZR, EBR, DRV GZR, EBR, LPV No data GZR, EBR, EFV GZR, EBR, RPV No data GZR, EBR, RAL No data GZR, EBR, DTG No data GZR, EBR, TFV Kiser JJ,

27 PrOD Primarily hepatically metabolized, minimal renal elimination Ritonavir-boosted Paritaprevir (Protease Inhibitor) Ombitasvir (NS5A Inhibitor) Dasabuvir (Non-nucleoside NS5B inhibitor) Enzymes Transporters Victim Substrate CYP3A4 Substrate P-gp, OATP1B1, BCRP Perpetrator Inhibits CYP2C8, UGT1A1 (ritonavir inhibits CYP3A) Victim Substrate CYP3A4 Substrate P-gp Perpetrator Inhibits CYP2C8, UGT1A1 Victim Substrate CYP2C8>3A4>2D6 Substrate P-gp Perpetrator Inhibits UGT1A1 Inhibits BCRP Inhibits P-gp, OATP1B1/3, BCRP PrO plus ribavirin is approved for genotype 4. Many interactions are similar to PrOD, but not all.

28 PrOD with RPV and RAL Comments ok ok Not recommended theoretical concern for QTC prolongation Khatri A, et al. ICAAC Sept 5-9, 2014, Washington DC

29 PrOD and HIV PI Interactions Comments Drop the ritonavir booster while on PrOD Median DRV trough is 3300 ng/ml without PrOD*, troughs are with PrOD Not recommended too much RTV Khatri A, et al. ICAAC Sept 5-9, 2014, Washington DC, *DRV package insert

30 DRV PK with PrOD in HIV/HCV coinfected patients DRV reductions less than in healthy volunteers 100% achieved SVR 2 patients had HIV between copies/ml on study, but did not appear to be related to DRV exposures Reassuring, but use with caution until results are available from the parent study, n=230 Wyles D, et al. CROI, 2/22-2/25, 2016, Boston, MA #574

31 Therapeutic Classes to Consider Class SOF/DCV GZR/EBR SOF/LDV PrOD Methadone Analgesics? Anxiolytics/Sedative hypnotics/benzos a /X SSRIs? Oral contraceptives X b Immunosuppressants NOT CSA, TAC OK Antiepileptics (old) X X X X Statins /X? c /X Calcium channel blockers /X? a midazolam given orally AUC increased 34%, b progestin-containing only, LFT elevations with ethinyl estradiol, c rosuvastatin not recommended, others not studied Selected based on interaction potential and Lauffenburger JC, et al. Eur J Gastro & Hepatol 2014;26(10):

32 Resources for Drug Interactions University of Liverpool Toronto General Hospital Specific to antiretroviral interactions DHHS Guidelines Drug Interaction Tables

33 Summary The primary consideration in the treatment of HIVcoinfected individuals with DAA is the potential for drug interactions The pharmacology of most DAA is well-defined and interactions are manageable, but there are some unknowns A systematic approach to the identification and management of drug interactions is imperative

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