Slide 1 Will DAA drug interactions matter in the future? David Back. David Back University of Liverpool UK. University of Liverpool June 2015

Transcription

1 Slide 1 Will DAA drug interactions matter in the future? David Back University of Liverpool UK David Back University of Liverpool June 2015

2 Disclosures Honoraria received for Advisory Boards, lectures from Abbvie, Gilead, Merck, Viiv, Janssen, Teva. Educational Grants for and from Abbvie, BMS, Gilead, Janssen, Merck, Viiv.

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4 Entry/Integrase inhibitors Protease Inhibitors NNRTIs NRTIs DDIs between HCV DAAs and HIV antiretrovirals SIM DAC SOF LDV/SOF 3D Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine Efavirenz * Etravirine Nevirapine Rilpivirine * Atazanavir; atazanavir/ritonivir * Darunavir/ritonavir; darunavir/cobicistat * Fosamprenavir * Lopinavir * Saquinavir * Dolutegravir Elvitegravir/cobicistat * Maraviroc Raltegravir *Known or anticipated increases in tenofovir with boosted regimens and efavirenz and rilpivirine when given LDV/SOF: caution and frequent renal monitoring needed. EASL Recommendations on Treatment of Hepatitis C 2015; Available at /clinical-practice-guidelines (accessed May 2015).

5 However that does not mean that Sofosbuvir has no drug interactions.

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7 LDV/SOF in HCV/HIV Coinfection HCV/HIV DDI Program LDV or SOF Single-Agent DDI LDV/SOF-regimen Based DDIs NNRTI RPV ABC/3TC InSTI PI NNRTI-based regimens PI-based regimens InSTI-based regimens RAL DRV/r EFV/FTC/TDF EFV/FTC/TDF FTC/RPV/TDF ATV/r+FTC/TDF DRV/r+FTC/TDF E/C/F/TAF DTG+FTC/TDF Mathias A. Int Workshop on Clin Pharm of HIV and HCV Therapy; Washington. May

8 Effect of HIV NNRTIs on LDV/SOF Perpetrator Object AUC C max EFV/FTC/TDF SOF/GS LDV 34% 34% RPV/FTC/TDF SOF/GS /LDV ABC/3TC SOF/GS /LDV NOTE: Ledipasvir levels were the same across EFV, RPV and RAL in ION-4: Indicates a difference between healthy volunteers and HCV patients? Above data point to no clinically relevant change in LDV/SOF with EFV/FTC/TDF, FTC/RPV/TDF and ABC/3TC German et al, IWCPHHT 2014 Mathias A. Int Workshop on Clin Pharm of HIV and HCV Therapy; Washington. May

9 Effect of LDV/SOF on HIV NNRTIs Perpetrator Object AUC C max C tau EFV LDV/SOF FTC TFV 98% 79% 163% RPV LDV/SOF FTC LDV/SOF TFV 40% 32% 91% ABC 3TC TFV exposure increases with NNRTI-containing regimens but TFV is higher in RPV based regimen (- DAA) than in EFV based regimen (- DAA). In ION-4 TFV mean conc were higher in RPV than EFV regimens German et al, IWCPHHT 2014 Mathias A. Int Workshop on Clin Pharm of HIV and HCV Therapy; Washington. May

10 Effect of HIV Integrase Inhibitors on LDV/SOF Perpetrator Object AUC C max C tau RAL SOF/GS /LDV DTG + FTC + TDF SOF/GS /LDV SOF 47% 28% NA EVG/COBI/FTC/TAF GS % 66% LDV 79% 65% 93% No clinically relevant change with RAL and DTG + FTC/TDF With ELV/cobi CAUTION due to increase in LDV/SOF and Cobi Kirby et al, AASLD 2012; German et al, IWCPHHT 2014; Garrison et al, IWCPHHT 2015 Mathias A. Int Workshop on Clin Pharm of HIV and HCV Therapy; Washington. May

11 Effect of LDV/SOF on HIV Integrase Inhibitors Perpetrator Object AUC C max C tau LDV/SOF LDV/SOF DTG FTC TFV 65% 61% 115% EVG 46% COBI 53% 225% FTC TAF NA TFV TFV, administered as TDF and not TAF, increases with LDV/SOF Raltegravir given with LDV and SOF separately (decrease of 15% and 27%) Kirby et al, AASLD 2012; German et al, IWCPHHT 2014; Garrison et al, IWCPHHT 2015 Mathias A. Int Workshop on Clin Pharm of HIV and HCV Therapy; Washington. May

12 Effect of HIV Protease Inhibitors on LDV/SOF Perpetrator* Object AUC C max C tau SOF NA ATV/RTV+FTC/TDF DRV/RTV+FTC/TDF GS % LDV 96% 68% 118% SOF 27% 37% NA GS LDV *Similar results when LDV/SOF and ATV/RTV+FTC/TDF or DRV/RTV+FTC/TDF were administered simultaneously or following a 12-hour stagger. German et al, CROI 2015 Mathias A. Int Workshop on Clin Pharm of HIV and HCV Therapy; Washington. May

13 Effect of LDV/SOF on HIV Protease Inhibitors Perpetrator Object* AUC C max C tau ATV 63% LDV/SOF LDV/SOF RTV 45% FTC TFV 47% 47% DRV RTV 48% FTC TFV 50% 64% 59% *Similar results observed when LDV/SOF and ATV/RTV+FTC/TDF or DRV/RTV+FTC/TDF were administered simultaneously or following a 12-hour stagger. German et al, CROI 2015 Mathias A. Int Workshop on Clin Pharm of HIV and HCV Therapy; Washington. May

14 LDV/SOF and ARV Regimen-based DDIs Possible differences between healthy volunteer and HCV patient data Need to understand the implications of the increase in TFV exposure particularly with an NNRTI Regimen Boosted-PI regimen Also remember that TFV exposure is higher with boosted PI-regimens relative to TFV with NNRTI-based regimens Mathias A. Int Workshop on Clin Pharm of HIV and HCV Therapy; Washington. May

15 EASL Guidelines 2015

16 Permitted Antiretrovirals with Simeprevir 1st Agent NRTIs Raltegravir Maraviroc Rilpivirine Tenofovir Emtricitabine Lamivudine Abacavir DRV/r increased SIM exposure by 7-fold EFV decreased SIM exposure by 70% Olysio SmPC Aug 2014

17 EASL Guidelines 2015

18 ALLY-2: Study Design

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20 Eley T; IWCPHHT May 2015

21 AUC GMR = AUC GMR = Eley T; IWCPHHT May 2015

22 Conclusion Dose normalised increases in DCV AUC when DCV was coadministered with DRV/r (41%) or LPV/r (15%) were smaller than previously seen with ATV/r (2.1-fold) The standard 60 mg DCV dose is optimal for patients receiving DRV/r or LPV/r while 30 mg is the optimal dose in patients on ATV/r Eley T; IWCPHHT May 2015

23 DTG exposure increased by 33%. No change in DAC exposure. DTG and DAC can be coadministered without dose adjustment

24 EASL Guidelines 2015

25 ART Evaluated in Drug-Interaction Studies with the AbbVie DAA Regimen Regimen evaluated Nucleoside Reverse Transcriptase Inhibitor (NRTI) Integrase Inhibitor Emtricitabine/Tenofovir* Abacavir/lamivudine Raltegravir* Dolutegravir Protease Inhibitor (PI) Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Atazanavir (with and without ritonavir)* Darunavir (with and without ritonavir)* Lopinavir/ritonavir* Efavirenz/Emtricitabine/Tenofovir Rilpivirine * Also evaluated in the 2D regimen of ombitasvir/paritaprevir/ritonavir. The 2D regimen is being developed for in HCV GT4 subjects with ribavirin (GT4 approved in EU). This regimen is also being developed without ribavirin in HCV GT1b subjects and with ribavirin in HCV GT2 subjects in Japan. Menon R 16TH INTERNATIONAL 16TH INTERNATIONAL WORKSHOP WORKSHOP ON CLINICAL ON CLINICAL PHARMACOLOGY OF HIV && HEPATITIS THERAPY THERAPY 25

26 Recommendations for ART with the AbbVie 3-DAA Regimen Nucleoside Reverse Transcriptase Inhibitor Regimen evaluated Emtricitabine/Tenofovir Abacavir/lamivudine Recommendation No dose adjustment required No dose adjustment required Integrase Inhibitors Protease Inhibitors Non-Nucleoside Reverse Transcriptase Inhibitor Raltegravir Dolutegravir Elvitegravir/cobicistat Atazanavir Darunavir Lopinavir Efavirenz/Emtricitabine/Tenofovir Rilpivirine No dose adjustment required No dose adjustment required Not evaluated No dose adjustment required* No dose adjustment required* Not recommended/contraindicated** Contraindicated Not recommended*** *Dose PI at the same time as OBV/PTV/RTV without additional RTV ** Not recommended (USPI) or contraindicated.(eu SPC). Coadministration of the 3D or 2D was tolerated in over 100 subjects for 14 days. ***EU SPC: Rilpivirine should be used cautiously, in the setting of repeated ECG monitoring. Please refer to the SPC for additional details. Menon R 16TH INTERNATIONAL 16TH INTERNATIONAL WORKSHOP WORKSHOP ON CLINICAL ON CLINICAL PHARMACOLOGY OF HIV && HEPATITIS THERAPY THERAPY 26

27 Design and Results: DDI with Raltegravir Days 1-3 Days 4-17 Raltegravir 3D + Raltegravir 3D: Paritaprevir/ritonavir (150/100 mg QD)+ ombitasvir (25 mg QD) + dasabuvir (400 mg BID) Raltegravir 2.33 ( ) Raltegravir N= ( ) 2.00 ( ) Central Value Ratio with 90% CI C max AUC C trough Cross-study comparisons indicate that DAA exposures were not affected by raltegravir coadministration Menon R 16TH INTERNATIONAL 16TH INTERNATIONAL WORKSHOP WORKSHOP ON CLINICAL ON CLINICAL PHARMACOLOGY OF HIV && HEPATITIS THERAPY THERAPY 27

28 Results and Recommendations: Darunavir with and without RTV Darunavir QD (AM) Darunavir BID Paritaprevir 1.54 ( ) 1.29 ( ) 1.30 ( ) Paritaprevir 0.70 ( ) 0.59 ( ) 0.83 ( ) Ombitasvir 0.86 ( ) 0.86 ( ) 0.87 ( ) Ombitasvir 0.76 ( ) 0.73 ( ) 0.73 ( ) Dasabuvir 1.10 ( ) 0.94 ( ) 0.90 ( ) Dasabuvir 0.84 ( ) 0.73 ( ) 0.54 ( ) Darunavir 0.92 ( ) 0.76 ( ) 0.52 ( ) Darunavir 0.87 ( ) 0.80 ( ) 0.57 ( ) Central Value Ratio with 90% CI C max AUC C trough Central Value Ratio with 90% CI Darunavir C trough is lower when coadministered with the 3D regimen Similar C trough and C max results were observed for darunavir though AUC increased by 34% when darunavir/ritonavir (PM) was administered with the 3D regimen Menon R 16TH INTERNATIONAL 16TH INTERNATIONAL WORKSHOP WORKSHOP ON CLINICAL ON CLINICAL PHARMACOLOGY OF HIV && HEPATITIS THERAPY THERAPY 28

29 Can Darunavir be dosed with the 3D regimen? Up to 50% lower DRV Ctrough without a significant impact on Cmax or AUC is unlikely to negatively impact HIV treatment efficacy (in the maintenance of plasma HIV-1 RNA suppression for patients on a stable DRV-based ART regimen during treatment with 3D) This is being verified in the M study in HCV-HIV co-infected subjects USPI: Coadministration not recommended EU SPC: 800 mg once daily administered at the same time as ombitasvir/paritaprevir/ritonavir + dasabuvir can be used in the absence of extensive PI resistance Ref: PK-PD analyses of darunavir from two Phase 3 trials (ODIN and ARTEMIS) (Sekar V et al., 2008, 15 th Conference on Retroviruses and Opportunistic Infections (CROI); Sekar V et al., 2010, 10 th International Conference on Drug Therapy in HIV) Molto J, Valle M, Ferrer E, et al. Reduced darunavir dose is as effective in maintaining HIV suppression as the standard dose in virologically suppressed HIV-infected patients. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy May Washington, DC. Abstract O_02 Menon R 16TH INTERNATIONAL 16TH INTERNATIONAL WORKSHOP WORKSHOP ON CLINICAL ON CLINICAL PHARMACOLOGY OF HIV && HEPATITIS THERAPY THERAPY 29

30 GRAZOPREVIR/ELBASVIR: RELEVANT METABOLISM AND TRANSPORTER PROPERTIES Yeh W. Int Workshop on Clin Pharm of HIV & HCV Therapy. Washington May 2015 GRAZOPREVIR (GZR) Metabolism CYP3A/P-gp substrate Weak CYP3A inhibitor (34% in midazolam) Transporters Substrate of OATP1B1 Inhibitor of intestinal BCRP ELBASVIR (EBR) Metabolism CYP3A/P-gp substrate Transporters Inhibitor of intestinal BCRP Minimal P-gp inhibition Grazoprevir (100 mg) Elbasvir (50 mg) Petry et al., AASLD 2010; Talaty et al., AASLD 2013; Caro et al., AASLD 2013; Caro et al., AASLD 2013; Yeh et al., CROI 2014 ; Yeh et al., IWCPHHT 2014; Yeh et al., CROI 2015; Yeh et al., IWCPHHT 2015; Caro et al., IWCPHHT 2015

31 GZR/EBR DDI RESULTS WITH COMMONLY USED HIV ART Yeh W. Int Workshop on Clin Pharm of HIV & HCV Therapy. Washington May 2015 Grazoprevir (100 mg) Elbasvir (50 mg) #63 Talaty et al., AASLD 2013; Caro et al., AASLD 2013; Yeh et al., CROI 2014 ; Yeh et al., CROI 2014; Yeh et al., CROI 2015; Yeh et al., IWCPHHT 2015

32 COMMONLY USED HIV ART THAT ARE EXPECTED TO HAVE NO DDI WITH GZR/EBR Yeh W. Int Workshop on Clin Pharm of HIV & HCV Therapy. Washington May 2015 Grazoprevir (100 mg) Elbasvir (50 mg) No DDI study with ABC, 3TC, FTC, but no expected DDI= no dose adjustments GZR and EBR are unlikely to alter the PK of ABC, 3TC, FTC since they are renally cleared No DDI study with etravirine (moderate CYP3A inducer), but etravirine is expected to decrease GZR and EBR exposures based on efavirenz DDI results= not recommended No DDI study with unboosted atazanavir or saquinavir/r - but expected to significantly increase GZR exposures via OATP1B inhibition= not recommended

33 STUDY DESIGN Yeh W. Int Workshop on Clin Pharm of HIV & HCV Therapy. Washington May 2015 Grazoprevir (100 mg) Elbasvir (50 mg) n=218 GZR 100 mg / EBR 50 mg Follow-up D1 TW4 TW8 TW12 FUW4 FUW8 FUW12 An open-label, single-arm, multicenter study across Europe, US and Australia HCV treatment-naive patients with HCV GT1, 4 or 6 infection with or without cirrhosis Co-infected with HIV-1: Stable antiretroviral therapy (ART) included TDF or abacavir, and either 3TC or FTC plus raltegravir, dolutegravir, or rilpivirine

34 Hypertension and heart failure agents Calcium channel blockers Beta blockers Antiplatelet and anticoagulants Antiarrythmics DDIs between HCV DAAs and cardiovascular drugs SIM DAC SOF LDV/SOF 3D Amiodarone Digoxin Flecanide Vernakalant Clopidogrel Dabigatran Warfarin Atenolol Bisoprolol Propranolol Amlodipine Diltiazem Nifedipine Aliskiren Candesartan Doxazosin Enalapril EASL Recommendations on Treatment of Hepatitis C 2015; Available at (accessed May 2015).

35 Mechanism of action of the Amiodarone SOF/DAA interaction 1. GI transporter with increase in amiodarone exposure 2. Local effect on cardiomyocyte accumulation of amiodarone in the heart. 3. Protein binding displacement

36 DDI studies at EASL Honer zu Siederdissen C et al. Clinical significance of drug-drug interactions during therapy with novel DAAs against HCV. Abs P Mensing S et al. Pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin in subjects with HCV genotype 1 infection in Phase 3 studies. Abs P0820

37 Clinical significance of drug-drug interactions during therapy with novel DAAs against HCV Methods Concomitant outpatient meds including OTC and herbals assessed in 261 HCV-monoinfected pts evaluated for antiviral treatment at Hannover Med School DDI between the outpatient med and SOF, SMV, DCV, LDV/SOF and 3D & 2D evaluated using and prescribing information. DDIs classified as: 0=Classification not possible due to lack of information, 1=no significant interactions, 2=moderate interaction, may need dose adjustment/monitoring, 3=co-administration not recommended). Hoener Zu Siederdissen C, et al EASL-ILC 2015; Poster presentation P0754

38 Clinical significance of drug-drug interactions during therapy with novel DAAs against HCV Hoener Zu Siederdissen C, et al EASL-ILC 2015; Poster presentation P0754

39 Clinical significance of drug-drug interactions during therapy with novel DAAs against HCV Hoener Zu Siederdissen C, et al EASL-ILC 2015; Poster presentation P0754

40 Pooled Phase 3 Analysis: Pharmacokinetics of 3D + RBV: Objectives and Methods Pooled data from six Phase 3 and one Phase 2 studies (SAPPHIRE-I and II, PEARL-II, -III and IV, TURQUOISE-II and M14-103) To characterize Population PK of OBV/PTV/r and DSV with and without RBV in HCV GT1-infected subjects Population PK examined sources of variability in drug concentrations of the DAAs and RBV ie demographic, pathophysiologic and treatment factors Population PK models built using NONMEM (v7.3) software Covariates investigated included: Body weight, BMI, body surface area (BSA), sex, age, creatinine clearance, pegifn/rbv experienced/naive, GT1a/b, black race, ethnicity, Asian race, cirrhosis, methadone/buprenorphine, use of RBV and co-medications Mensing S, et al. EASL-ILC 2015; Poster presentation P0820.

41 PK of 3D + RBV in GT1 Patients in Phase 3 Studies Model-predicted Steady-State Exposures and Effect of Covariates Compound Covariate Change in exposure AUC, C max, C min Paritaprevir 150mg QD 1130 ng h/ml; 96.9 ng/ml; 18.3 ng/ml 20% less than 10% 100% 120% - 140% 55% 45% Ombitasvir 25mg QD Dasabuvir 250mg BID Reference prediction b 10 year increase 10 kg increase Female Cirrhotic patients Opiod usage Anti-Diabetics Use Reference prediction c Female 10 year increase 10 kg increase Cirrhotic patient Reference prediction d Female 10 year increase 10 kg increase Mild renal impairment (CrCL=75 ml/min) Cirrhotic patient 857 ng h/ml; 48.9 ng/ml; 21.6 ng/ml 55% 10% less than 10% 10% 8150 ng h/ml; 533 ng/ml; 162 ng/ml 14-30% less than 10% less than 10% 10% 30% - 40% a HCV genotype should not affect the pharmacokinetics of ritonavir, thus this finding likely represents random variability and is of limited clinical significance. b male, 54 years, 76kg, non cirrhotic, no opiods, no anti-diabetics, c male, 54 years, 76kg, non cirrhotic, d male, 54 years, 76kg, non cirrhotic, creatinine clearance of 104 ml/min, e male, 54 years, creatinine clearance of 104 ml/min, GT1b f male, non cirrhotic, creatinine clearance of 105 ml/min. Mensing S, et al EASL-ILC 2015; Poster presentation P0820.

42 Effect of Coadministration of Sofosbuvir with the 3D and 2D DAA Regimens 3D on SOf alone or DAAs alone 2D on SOf alone or DAAs alone No dosage adjustment is needed for the 3D or 2D regimens during Coadministration with sofosbuvir King J, et al EASL-ILC 2015; Poster presentation P1351

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44 Classification of DDIs in Liverpool database Data taken from

45 So Will DAA drug interactions matter in the future? David Back University of Liverpool UK YES but we manage them.

46 A stepwise approach to DDI management Is co-medication necessary? NO Stop YES YES- no dose change required Establish monitoring plan Can interaction be managed? NO Are there alternatives? YES- dose change required YES NO - Consult pharmacy to advise new dose - Establish monitoring plan - Change dose back on completion of treatment Change to another clinically appropriate medicine - Accept risk and proceed with care -Be aware of likely off license use of combination; look for toxicities and side effects associated with combined use - Establish robust clinical monitoring plan

47 Thank You Grateful to colleagues involved in Grateful for slides from Dr Wendy Yeh (Merck), Dr Rajiv Menon (Abbvie) and Dr Tim Eley (BMS)