Navigating the Drug Interactions with New HCV Regimens

Transcription

1 Navigating the Drug Interactions with New HCV Regimens Jennifer J. Kiser, PharmD Associate Professor University of Colorado May 8, 2015

2 Objectives Identify potential drug interactions with HCV agents Determine the management of drug interactions with HCV agents Discuss pharmacologic considerations in HCV treatment in special populations

3 Patient Case 59 yo African American female, HIV/HCV- coinfected TDF/FTC/DRV/r HIV-1 RNA TND CD cells/mm 3 (40%) HCV genotype 1a, treatment-naive HCV RNA = 9,600,000 IU/mL (6.98 log 10 IU/mL) Liver biopsy (~3 years ago) Grade 2 inflammation, stage 2 fibrosis

4 Clinical Labs ALT 37 U/L (7-52) AST 59 U/L (12-39) Alk phos 133 U/L (39-117) Tbili 0.5 mg/dl ( ) Albumin 4.2 g/dl ( ) SCr 0.77 mg/dl ( ) Wt 62 kg, 5 6 Ht CrCl ~ 90 ml/min WBC /L (4-11.1) ANC /L ( ) RBC /L ( ) Hgb 15.8 g/dl ( ) Hct 46% (39.2 to 50.2) Platelet /L ( ) FIB-4 = 0.2 APRI = 0.612

5 Preferred Regimens for Genotype 1a Non-cirrhotic Cirrhotic Naive SOF/LDV x 12 weeks SOF/LDV x 12 weeks 3D x 12 weeks 3D x 24 weeks SIM/SOF x 12 weeks SIM/SOF x 24 weeks Experienced SOF/LDV x 12 weeks SOF/LDV x 24 weeks 3D x 12 weeks 3D x 24 weeks SIM/SOF x 12 weeks SIM/SOF x 24 weeks

6 Which of the following DAA regimens will require changes to ARV therapy? 1. Sofosbuvir plus simeprevir 2. Sofosbuvir plus ledipasvir 3. Paritaprevir/rtv,ombitasvir, dasabuvir (3D) plus ribavirin 4. None of the above 5. 1 and 3 6. All of the above

7 Sofosbuvir NS5B polymerase inhibitor Uridine nucleotide analog 61%-65% protein bound Renally eliminated In plasma, SOF accounts for only ~4% of the drug-related material, majority (>90%) is GS ( 007 ) Very low potential for DDI Victim Perpetrator Enzymes Transporters Substrate P-gp and BCRP

8 ARV Pharmacokinetics with SOF Kirby AASLD 2012

9 Kirby AASLD 2012 SOF and GS Pharmacokinetics with ARV

10 Simeprevir HCV protease inhibitor 99.9% protein-bound, primarily to albumin Eliminated via biliary excretion, 1% renal elimination Primarily a victim not a perpetrator in interactions Enzymes Transporters Victim Substrate CYP3A Substrate P-gp Perpetrator Inhibits P-gp and OATP1B1

11 Darunavir/Ritonavir Increases Simeprevir Exposures 2.6-fold Even after reducing the simeprevir dose by 2/3 Ouwerkerk-Mahadaven S, et al. IDWeek 2012

12 Efavirenz Reduces Simeprevir Exposures by 71% Ouwerkerk-Mahadaven S, et al. IDWeek 2012

13 Ledipasvir NS5A inhibitor Minimal metabolism, 70% eliminated unchanged, 1% renally eliminated Enzymes Transporters Victim Substrate CYP3A? Substrate P-gp Perpetrator Inhibitor of P-gp, BCRP, OATP1B1/3 Kirby B, et al. 8 th International Workshop on Clinical Pharmacology of Hepatitis Therapy, Boston, MA, June 26-28, 2013, German P, et al. 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 19-21, 2014, Washington DC

14 Ledipasvir and SOF/LDV Interactions As a victim: EFV LDV ~34% As a perpetrator: LDV raltegravir 15% (SOF RAL 27%) o Potential for additive reduction in RAL exposures? Increases tenofovir German P 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 19-21, 2014, Washington DC, #10 German P CROI 2015, February 23-26, 2015, Seattle, WA, #82

15 SVR12 (%) SVR12 by Subgroup and Baseline Characteristics % 96% 95% 100% 96% 96% 96% 100% 99% 90% / /276 56/59 36/36 285/ /250 74/77 8/8 215/ /115 Overall Male Female BL HCV BL HCV GT 1a GT 1b GT 4 Non-black Black RNA <800K RNA 800K Statistically significant in multivariate analysis Naggie et al, CROI 2015, Oral #LB-152

16 SVR 12 (%) SVR 12 (%) No Difference in SVR in Blacks vs Non-blacks in Prior Studies LDV/SOF x 12 Wks in ION HCV mono-infection LDV/SOF x 12 Wks in ERADICATE HCV/HIV coinfection /538 89/90 431/ /50 41/42 8/ Overall Black Non-Black 0 Overall Black Non-Black Treatment naive Non-cirrhotic 1 patient who relapsed: 63 yo AA, IL28B TT, on TDF/FTC/RPV 1. Naggie et al, CROI 2015, Oral #LB-152, 2. Lennox et al. AASLD 2014 Oral abstract #237, 3. Osinusi et al. JAMA 2015

17 What Was Different About Black Patients in ION4? Were more black patients on EFV (53% vs 46%) But PopPK similar across ARV regimens Predictors of relapse in black patients IL28TT Elevated baseline ALT (>1/5xULN) ION-4 GWAS and whole-genome sequencing analysis underway

18 Ledipasvir and SOF/LDV Interactions As a victim: EFV LDV ~34% As a perpetrator: LDV raltegravir 15% (SOF RAL 27%) Potential for additive reduction in RAL exposures? Increases tenofovir German P 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 19-21, 2014, Washington DC, #10 German P CROI 2015, February 23-26, 2015, Seattle, WA, #82

19 Tenofovir Exposures Slide Courtesy of Gilead Sciences 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 = TFV exposures higher when TDF coadministered with LDV/SOF vs without LDV/SOF Compared with 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 parqally 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. Chi^ck GE, et al. AAC. 2006; 50(4): (SQV+RTV) FPV SQV LPV/r ATV DRV ATV DRV * 24 17* 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)

20 What If We Can t Switch ARV? 31% on salvage regimen and required boosted PI Cope R, Prasad RK CROI 2015

21 Monitoring Renal Function in Those on SOF/LDV, TDF, and RTV-boosted HIV PIs 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,

22 AbbVie 3D Paritaprevir/rtv (protease inhibitor) Ombitasvir (NS5A inhibitor) Dasabuvir (non-nucleoside NS5B inhibitor) Enzymes Transporters Victim Substrate CYP3A4 Substrate P-gp, OATP1B1 Perpetrator Inhibits CYP2C8, UGT1A1 Inhibits OATP1B1/3, BCRP Victim Substrate CYP3A4 Substrate P-gp Perpetrator Victim Inhibits CYP2C8, UGT1A1 Substrate CYP2C8>3A4>2D6 Substrate P-gp Perpetrator Inhibits UGT1A1 Inhibits OATP1B1, BCRP

23 AbbVie 3D 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

24 AbbVie 3D PI Interactions Comments Drop the ritonavir booster while on 3D Not recommended; DRV trough may be too low. Median DRV trough is 3300 ng/ml*, troughs are with 3D. Not recommended too much RTV Khatri A, et al. ICAAC Sept 5-9, 2014, Washington DC, *DRV package insert

25 ARV Interaction Score Card Simeprevir 1 Sofosbuvir 2 Ledipasvir 3-5 Daclatasvir 6,7 AbbVie 3D 8-10 ATV/r No data No data LDV, ATV a DCV b ABT450 ; ATV DRV/r SIM ; DRV SOF ; DRV LDV, DRV a DCV 3D / ; DRV LPV/r No data No data No data DCV ABT450 ; LPV TPV/r No data No data No data No data No data EFV SIM ; EFV SOF ; EFV LDV ; EFV DCV b No PK data c RPV SIM ; RPV SOF ; RPV LDV ; RPV No data ABT450 ; RPV ETR No data No data No data No data No data RAL SIM ; RAL SOF ; RAL LDV ; RAL No data 3D ; RAL EVG/cobi No data SOF ; ELV/cobi LDV ; ELV/cobi No data No data DTG No data No data No data No data No data MVC No data No data No data No data No data TDF SIM ; TFV SOF ; TFV LDV ; TFV DCV ; TFV 3D ; TFV a Watch renal function, TFV levels increased, b Decrease DCV dose to 30 mg QD with ATV, increase DCV dose to 90 mg QD with EFV, c 3D + EFV led to premature study discontinuation due to toxicities 1 Ouwerkerk-Mahadaven S IDWeek 2012, 2 Kirby B AASLD 2012, 3 Harvoni package insert, 4 German P 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy 2014, 5 German P, CROI 2015, 6 Bifano M, et al. Antivir Ther. 2013;18(931-40, 7 Eley T HIVDART 2014, 8 Khatri ICAAC 2014, 9 Khatri ICAAC 2014, 10 Viekira Pak package insert Slide Courtesy of J Kiser

26 Surprise! She has other comorbidites and takes other medications GERD Omeprazole 20 mg BID Chronic pain Oxycodone 5-10 mg Q6H prn Psychotropics Sertraline 50 mg QD Quetiapine 100 mg QHS Hypertension Amlodipine 5 mg QD

27 Which of the following DAA regimens will require changes to concomitant medications? Omeprazole, oxycodone, sertraline, quetiapine, amlodipine 1. Sofosbuvir plus simeprevir 2. Sofosbuvir plus ledipasvir 3. Ritonavir-boosted paritaprevir, ombitasvir, dasabuvir (3D) plus ribavirin 4. None of the above 5. All of the above

28 Potential Interactions with the Patient s Other (Non-ARV) Medications SIM/SOF SOF/LDV 3D Omeprazole dose * dose? Oxycodone No data No data No data Sertraline No data No data No data Quetiapine No data No data No data Amlodipine No data No data dose * SOF/LDV can be taken simultaneously with PPI in the fasted state with doses that do not exceed 20 mg omeprazole

29 Interaction Potential of DAA Class SIM/SOF SOF/LDV 3D Methadone Oral contraceptives X a Immunosuppressants NOT CSA, TAC OK Warfarin No data Gastric acid modifiers X b Rifamycins X X X Antiepileptics X X X HMG Co-A reductase inhibitors Calcium channel blockers? c /X No data a Progestin-containing only, LFT elevations with ethinyl estradiol, b NTE omeprazole 20 mg and famotidine 40 mg, c Rosuvastatin not recommended, others not studied

30 Identifying and Managing Interactions Kiser JJ, Burton JR, Jr, Everson GT. Nature Reviews Gastroenterol Hepatol 2013;10:

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

32 What if our patient had decompensated cirrhosis? Would this change your treatment? 1. SOF/LDV x 24 weeks 2. SOF/LDV/RBV x 12 weeks 3. 3D + RBV x 24 weeks 4. SIM/SOF x 24 weeks

33 Minimal Effects of Liver Disease on SOF/LDV Pharmacokinetics SOF 007 LDV Fold Change and 90% CI 36% Lawitz E EASL 2012, P German AASLD 2013

34 P e r c e n t S V R Adding RBV to SOF/LDV Improves SVR in Decompensated Cirrhotics % 96% 98% 97% 64% D e c o m p 1 2 w k s E x p 1 2 w k s E x p 2 4 w k s N a i v e 1 2 w k s P a t i e n t P o p u l a t i o n N a i v e 2 4 w k s Gane E 49 th EASL April 9-13, 2014, London UK; Afdhal N NEJM and Flamm SL, et al. AASLD Nov 7-11, 2014, Boston, MA, abstract 239

35 Simeprevir in Hepatic Impairment Compared with healthy matched controls, simeprevir AUC in moderate and severe hepatic impairment is 2.4 and 5-fold higher, respectively BUT only 1.3 and 2.8-fold higher than concentrations observed in Child-Pugh A cirrhotics in OPERA-1 study. Ouwerkerk-Mahadaven S. et al. EASL 2013

36 3D Hepatic Impairment 10-fold 4-fold

37 What if our patient had renal impairment? Would you use 1. 3D + RBV 2. SOF/SIM 3. SOF/LDV 4. Something else

38 Khatri A, AASLD D in Renal Impairment

39 Cornpropst M, et al. EASL 2012 SOF in Renal Impairment

40 Summary There are several important pharmacologic considerations in the treatment of HCV A systematic approach to the identification and management of drug interactions is essential While there are a lot of data to make informed treatment decisions, there are still some unanswered questions