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

Transcription

1 Page 1 HCV Interaction Studies presented at the 15 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Washington, April This report summarises interaction studies relating to HCV therapy. Abstracts and presentations are available on (if permission has been given by the authors for them to appear). Contents Interactions with HCV drugs... 2 GS 5816 Interaction Studies (Abstract O_07)... 2 Ledipasvir/Sofosbuvir & Food or Acid Reducing Agents (Abstract P_15)... 2 Peginterferon Lambda 1a & Cytochrome P450 activity (Abstract P_17)... 3 Simeprevir, JNJ & TMC647055/r (Abstract P_19)... 3 GSK & Midazolam (Abstract P_20)... 4 BMS & Midazolam (Abstract P_22)... 4 MK 8742 & Ketoconazole (Abstract P_27)... 4 Interactions between HCV and HIV drugs... 5 Sofosbuvir or Ledipasvir & HIV Antiretrovirals (Abstract O_06)... 5 Boceprevir & HIV antiretrovirals (Abstract P_18)... 5 Boceprevir & ETV (Abstract P_21)... 6

2 Page 2 Interactions with HCV drugs GS 5816 Interaction Studies (Abstract O_07) Evaluation of transporter and cytochrome P450 mediated drug drug interactions between pangenotypic HCV NS5A inhibitor GS 5816 and phenotypic probe drugs. Mogalian E, et al. GS 5816 is an HCV NS5A inhibitor with potent in vitro activity against HCV genotypes 1 6 and is in Phase 2 clinical development. This open label, single and multiple dose, five cohort crossover study in healthy subjects evaluated the potential of GS 5816 to be a perpetrator or victim of drug drug interactions using probe substrates (pravastatin, rosuvastatin, or digoxin) or inhibitors and inducers of enzymes and drug transporters (ketoconazole, rifampicin, or ciclosporin). Coadministration of GS 5816 with pravastatin (an OATP1B1/1B3 substrate) increased pravastatin AUC and Cmax by ~35% and ~28%, respectively. A larger increase in the AUC (~170%) and Cmax (~161%) of rosuvastatin (also an OATP/BCRP substrate) was observed following coadministration with GS Coadministration of GS 5816 with digoxin (a P gp substrate) increased digoxin AUC and Cmax by~34% and ~88%, respectively. In the presence of multiple doses of rifampicin (potent CYP3A/CYP2C8/P gp inducer) the AUC and Cmax of GS 5816 decreased by ~82% and ~71%, respectively; whereas, administration of ketoconazole (a potent CYP3A/CYP2C8/P gp inhibitor) increased GS 5816 AUC and Cmax by ~70% and ~29%, respectively. Administration of a single dose of rifampicin (selective OATP1B1/1B3 inhibition) increased GS 5816 AUC and Cmax by ~47% and ~28%, respectively. Coadministration ciclosporin (a mixed OATP/P gp/mrp2/cyp3a inhibitor) and GS 5816 did not alter ciclosporin pharmacokinetics but increased GS 5816 AUC and Cmax by ~102% and ~56%, respectively. These results suggest that GS 5816 is a weak (P gp, OATP) to moderate (BCRP) transport inhibitor and clinically relevant drug drug interactions between GS 5816 and OATP, P gp, and CYP450 substrates are not anticipated. However, as a substrate of CYP3A, CYP2C8, P gp and OATP, the disposition of GS 5816 is affected by potent inhibitors and inducers of these enzyme/drug transporters. Ledipasvir/Sofosbuvir & Food or Acid Reducing Agents (Abstract P_15) Effect of food and acid reducing agents on the relative bioavailability and pharmacokinetics of ledipasvir/sofosbuvir fixed dose combination tablet. German P, et al. A single fixed dose combination tablet composed of the NS5A inhibitor ledipasvir (LDV) 90 mg and NS5B inhibitor sofosbuvir (SOF) 400 mg is being developed for the treatment of HCV infection. Phase 1 studies were conducted to examine the effect of food and acid reducing agents on the relative bioavailability and pharmacokinetics of LDV/SOF. In a randomized, single dose, cross over food effect evaluation, 28 healthy volunteers received LDV/SOF under fasted conditions, with a moderate fat meal (~600 kcal, 25 30% fat) or a high calorie/high fat meal (~1000 kcal, ~50% fat). Food had no effect on the pharmacokinetics of LDV, but SOF AUC and Cmax increased by <2 fold and <1.3 fold, respectively, with food. For GS , a ~18 30% lower Cmax with no change in AUC were observed. As the increase in SOF exposure was modest and GS AUC was not altered, the increase in SOF pharmacokinetics was not considered clinically meaningful. In a single dose, fixed sequence, cross over evaluation of the effect of acid reducing agents, 12 subjects received LDV/SOF alone, simultaneously with famotidine (40 mg single dose) and 12 h after famotidine (40 mg single dose). Coadministration of famotidine (simultaneous or staggered) with LDV/SOF decreased LDV Cmax by ~17 20%, but had no effect on AUC. Administration of simultaneous famotidine increased SOF Cmax by ~15%, but had no effect on SOF AUC or GS AUC and Cmax. Staggered famotidine did not alter SOF or GS AUC or Cmax. In a multiple dose, fixed sequence, crossover evaluation, 16 subjects received LDV/SOF alone and with omeprazole (20 mg once daily). Omeprazole decreased LDV AUC and Cmax by ~4% and 11%, but there was no effect on the AUC or Cmax of SOF or GS LDV/SOF may be administered without regard to meals and can be

3 Page 3 administered with famotidine (and other H2RAs) at a dose that does not exceed famotidine 40 mg twice daily. A proton pump inhibitor dose comparable to omeprazole 20 mg can be administered simultaneously with LDV/SOF or up to 2 hours after taking LDV/SOF. Peginterferon Lambda 1a & Cytochrome P450 activity (Abstract P_17) The effects of a single dose of Peginterferon Lambda 1a on Cytochrome P450 activity in healthy subjects. Hruska M, et al. Peginterferon lambda 1a (lambda) is a type III interferon in phase 3 development for HCV infection. An open label, single sequence study was conducted in 21 healthy male subjects to assess the effects of a single subcutaneous dose of lambda (180 mg) on the pharmacokinetics of a modified 'Cooperstown 5+1 cocktail' containing oral substrates of CYP1A2 (caffeine, 200 mg), CYP2C9 (warfarin, 10 mg), CYP2C19 (omeprazole, 40 mg), CYP2D6 (dextromethorphan, 30 mg) and CYP3A4 (midazolam, 5 mg), and their major metabolites. Lambda inhibited the activity of all five CYPs tested, evidenced by increased AUCs and reduced metabolite:parent ratios. Caffeine Cmax decreased by 4%, but AUC increased by 73%; warfarin Cmax and AUC increased by 8% and 40%; omeprazole Cmax and AUC increased by 65% and 111%; dextromethorphan Cmax and AUC increased by 84% and 106%; midazolam Cmax and AUC increased by 46% and 75%. Administration of lambda resulted in asymptomatic, reversible ALT elevations in 45% of subjects, but was otherwise generally well tolerated. These results suggest that lambda has broad effects on human CYP activity in vivo, being a mild inhibitor of CYP1A2, CYP2C9 and CYP3A4, and a moderate inhibitor of CYP2C19 and CYP2D6. Dose adjustments for concomitant drug substrates are unlikely, though caution may be warranted with extensively CYP metabolized drugs with narrow therapeutic indices. Simeprevir, JNJ & TMC647055/r (Abstract P_19) Pharmacokinetics of simeprevir, JNJ and ritonavir boosted TMC when coadministered in healthy volunteers. Kakuda T, et al. Simeprevir is an inhibitor of CYP3A, OATP1B1/3 and P gp. JNJ (JNJ) is an inhibitor of OATP1B1/3 and P gp. TMC (TMC) induces CYP3A and is given with low dose ritonavir (a potent CYP3A inhibitor) to counteract this effect. Due to the complex interplay between CYP and hepatic transporters, the pharmacokinetic interactions of these three direct antiviral agents (DAAs) were assessed. Two groups of healthy subjects received JNJ alone (60 mg once daily) or in combination with simeprevir alone (150 mg once daily, n=24) or with simeprevir/tmc/r (75/450/30 mg once daily, n=24). Co administration of simeprevir increased JNJ Cmax, Cmin and AUC by 1.9, 3.9 and 2.6 fold, respectively. Similarly, simeprevir with TMC/r increased JNJ Cmax, Cmin and AUC by 1.9, 2.9 and 2.3 fold, respectively. Addition of JNJ to simeprevir and TMC/r slightly increased TMC exposure (19 25%). Coadministration of JNJ (with or without TMC/r) slightly increased simeprevir exposure (17 34%). Simeprevir exposures were comparable between the groups, i.e. 150 mg once daily alone vs 75 mg once daily with TMC/r. Simeprevir increased exposure of JNJ by 2.6 fold with no apparent additional effect of TMC/r. The small increase in the plasma concentrations of simeprevir and TMC in the presence of JNJ is not considered to be clinically relevant for either DAA.

4 Page 4 GSK & Midazolam (Abstract P_20) In vitro drug interaction profile of the HIV integrase inhibitor, GSK , and demonstrated lack of clinical interaction with midazolam. Reese M, et al. GSK is a potent HIV integrase inhibitor in Phase 2 clinical development as a long acting injectable formulation for the treatment and prevention of HIV infection. In vitro and in silico studies were conducted to assess the drug metabolism and transport of GSK and its interaction potential. An in vivo study in 12 healthy volunteers was performed to investigate the effect on GSK (30 mg once daily) on a single oral dose of midazolam (3 mg). GSK is primarily metabolised by UGT1A1 and to a lesser extent by UGT1A9, with minimal CYP mediated metabolism. GSK is a substrate for P gp and BCRP but due to its high permeability these transporters are not expected to affect GSK intestinal absorption. In vitro GSK is not a CYP inducer and does not inhibit (IC50 >30 µm) the transporters P gp, BCRP, MRP 2/4, OATP1B1/3, OCT1/2, BSEP; or any CYP or UGT enzymes (except UGT1A3; IC50 = 12uM). GSK inhibits the renal transporters MATE1/2 K (IC50 = µm) and OAT1/3 (IC50= µm). In vivo, GSK had no effect on the pharmacokinetics of midazolam. Other than sensitive OAT substrates with a narrow therapeutic index (e.g. methotrexate), these in vitro and in vivo studies demonstrate a low interaction potential for GSK BMS & Midazolam (Abstract P_22) The effect of steady state BMS , a non nucleoside HCV NS5B polymerase inhibitor, on the pharmacokinetics of midazolam, in healthy Japanese and Caucasian males. Abutarif M, et al. BMS , an inhibitor of HCV NS5B polymerase, is currently under clinical investigation as part of an all oral regimen with daclatasvir and asunaprevir. BMS inhibits CYP3A and induces CYP3A4 in vitro. This study assessed the effect of BMS (150 mg or 300 mg twice daily) on the pharmacokinetics of oral midazolam (5 mg single dose) in Caucasian and Japanese HCV uninfected subjects. Individual ratios of midazolam parameters with versus without BMS appeared similar between Japanese and Caucasians, and these two groups were pooled for analysis. In the 150 mg group (n=15), BMS decreased midazolam Cmax and AUC by 34% and 50%, respectively, whereas in the 300 mg group (n=16), midazolam Cmax and AUC were decreased by 48% and 56%, respectively. The ratio of midazolam to 1 hydroxymidazolam increased from 0.36 to 0.78 in the lower dose group, and from 0.43 to 1.20 in the higher dose group. These results suggest that BMS is a moderate inducer of CYP3A4 in vivo in healthy Japanese and Caucasian subjects. Concomitant use of BMS and CYP3A substrates should be undertaken with caution, especially for medications with a narrow therapeutic index. MK 8742 & Ketoconazole (Abstract P_27) Pharmacokinetic interaction of HCV NS5A inhibitor MK 8742 and ketoconazole in healthy subjects. Yeh WW, et al. This study evaluated the effect of ketoconazole (400 mg once daily), a potent inhibitor of CYP3A4 and P gp, on the single dose pharmacokinetics of MK 8742 (50 mg) in 10 HCV negative male subjects. Coadministration increased the AUC and C24 of MK 8742 by 31% and 38%, but decreased Cmax by 12%. One subject had an anomalous decrease in MK 8742 exposure following ketoconazole administration: when this subject was excluded from the statistical analysis, AUC was shown to increase by 80%. These results demonstrate that MK 8742 is a CYP3A4 substrate in humans with modest increases in concentrations following coadministration of strong CYP3A4 inhibitors.

5 Page 5 Interactions between HCV and HIV drugs Sofosbuvir or Ledipasvir & HIV Antiretrovirals (Abstract O_06) Drug interactions between direct acting anti HCV antivirals sofosbuvir and ledipasvir and HIV antiretrovirals. German P, et al. The interactions between the HCV directly acting antivirals ledipasvir and sofosbuvir and various HIV antiretrovirals were investigated in groups of HIV/HCV negative subjects. Coadministration of ledipasvir (90 mg once daily) and RAL (400 mg twice daily) to 28 subjects had no effect on ledipasvir exposure and only a small (<20%) effect on RAL pharmacokinetics. Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and EFV/FTC/TDF (600/200/300 mg once daily) to 29 subjects had no effect on the pharmacokinetics of sofosbuvir and its main circulating metabolite GS331007, nor on the pharmacokinetics of EFV and FTC. However, ledipasvir exposure decreased by 34% and TDF exposure increased by ~1.8 to 2.6 fold. Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and RPV/FTC/TDF (25/200/300 mg once daily) to 29 subjects had no effect on the pharmacokinetics of ledipasvir, sofosbuvir, GS331007, RPV or FTC, but increased TDF exposure by ~1.3 to 1.9 fold. The increases in TDF exposure were comparable to those achieved when FTC/TDF is administered with ritonavir boosted PIs, which do not warrant dose adjustment. Results from this study and a previous study between sofosbuvir and HIV antiretrovirals demonstrate that ledipasvir/sofosbuvir may be administered with EFV, RPV or RAL, with a backbone of FTC/TDF. Boceprevir & HIV antiretrovirals (Abstract P_18) Boceprevir and antiretroviral pharmacokinetic interactions in HIV/HCV coinfected persons AIDS clinical trials group study A5309S. Kiser JJ, et al. This study evaluated the pharmacokinetics of boceprevir and ARVs in HIV/HCV infected patients receiving EFV (n=19), RAL (n=17), ATV/r (n=11), DRV/r (n=5) and LPV/r (n=2). Boceprevir had no effect on EFV pharmacokinetics. RAL AUC and Cmax increased by 56% and 87%, respectively, but there was no significant effect on Cmin (10% increase). ATV AUC, Cmin and Cmax decreased by 30%, 43% and 16%, respectively, with the change in Cmax not being significant. DRV AUC, Cmax and Cmin decreased by 42%, 32% and 64%, respectively. When compared to historical data from healthy volunteers, EFV decreased boceprevir AUC, Cmax and Cmin by 11%, 27% and 21%, respectively, whereas ATV/r had no effect on boceprevir pharmacokinetics. In the presence of RAL, boceprevir AUC, Cmax and Cmin increased by 18%, 4% and 8%, respectively. DRV/r increased boceprevir Cmin by 93% but had no significant effect on AUC (3% increase) or Cmax (15% decrease). No statistical tests were performed in the two subjects on LPV/r due to the small sample size, but reductions in both boceprevir and LPV were observed. With the exception of increased RAL exposure, the effects of boceprevir on ARV PK in HIV/HCV co infected patients were similar to those observed in healthy volunteers. A greater decline in boceprevir Cmin with EFV and a reduction in boceprevir exposures with DRV/r were expected, but not observed. The impact of these drug interactions on antiviral safety and efficacy in co infected individuals undergoing HCV treatment is currently being investigated.

6 Page 6 Boceprevir & ETV (Abstract P_21) Enzyme induction not alterations in protein binding contribute to reduced etravirine exposures with boceprevir. Hammond KP, et al. The aim of this study was to determine if enzyme induction or alterations in protein binding were responsible for the reduction in ETV concentrations when combined with boceprevir. ETV and metabolite concentrations and protein binding were determined in 20 HIV/HCV negative subjects who received boceprevir (800 mg every 8 h) and ETV (200 mg every 12 h) alone and in combination. Four metabolites were detected in human plasma: two di oxygenated (HP M1 and HP M2) and two di alkyl hydroxy (HP M3 and HP M4) products. However, HP M3 was present only in trace amounts and not quantified. HP M2 was predominately produced via the CYP2C19 pathway, while HP M4 was produced by all cytochromes P450 tested with a formation rate trend of CYP2D6 < CYP2B6 < CYP3A5 << CYP2C19 < CYP3A4 ~ CYP2C9. Ratios of ETV parent:metabolite AUCs were higher in the presence of boceprevir, suggesting that boceprevir induces cytochromes P450 in vivo, primarily CYP2C9/19. An increase in the ETV fraction unbound was not observed with boceprevir. Thus, enzyme induction, not an increased fraction of unbound ETV, contributes to the reduced ETV exposures with boceprevir.