ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 (150 mg coadministered with ritonavir 100 mg once daily), ombitasvir (25 mg once daily), and dasabuvir (400 mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30 mg) or tacrolimus (2 mg) in healthy volunteers (N = 12 per study). In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C₂₄), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C₂₄ and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. Cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.

ABT-450,a NS3 protease inhibitor,(dosed with low-dose ritonavir,ABT-450/r) identified by Abbott and Enanta,ABT-267,a NS5A inhibitor and ABT-333,a NS5B polymerase inhibitor are directly acting antivirals (DAAs) being developed for the treatment of HCV infection.The effect of DAA combinations on the pharmacokinetics,safety and tolerability of cyclosporine A (CsA) or tacrolimus was assessed in 72 healthy subjects.Figure: No Caption available.Pharmacokinetic sampling: CsA &/or DAA: Day 1 (Period 1), Days 1,14-21 (Period 2). Tacrolimus &/or DAA: Day 1 (Period 1), Days 14-21 (Period 2).The magnitude of interaction between the DAAs and CsA or tacrolimus was comparable across all arms.CsA+DAAs: On Day 15, CsA dose-normalized (DN) AUCinf and DNC24 were 4-6 fold and 13-16 fold, respectively, of CsA exposures when CsA was administered alone.CsA DNCmax was not affected,while t½ increased from 7 to 24 hrs.ABT-450 exposures increased by 12-72% while ABT-333 exposures decreased by 30-34%. ABT-267 and ritonavir exposures were not affected.Tacrolimus+DAAs: On Day 15,tacrolimus DNAUCinf, DNCmax and DNC24 were 57-86 fold, 3.7-4.3 fold and 17-25 fold of tacrolimus exposures when tacrolimus was administered alone,while tacrolimus t½ increased from 29-32 to 232-253 hrs.ABT-450, ABT-333 and ritonavir exposures decreased by 11-51% while ABT-267 exposures were not affected.Adverse events were infrequent and mostly mild,and were consistent with those seen with DAAs,CsA or tacrolimus dosed alone.Concentration-time profiles from these interactions were used to predict dose frequencies that would provide optimal CsA and tacrolimus levels using simulations.When co-dosed with the combination DAA regimens,subjects on CsA should reduce the total daily CsA dose to approximately 1/5th-1/10th of their previous maintenance dose,while subjects on tacrolimus should modify the total daily tacrolimus dose to 0.5 mg/week to maintain Ctrough similar to those prior to DAA co-administration,with appropriate clinical monitoring.These recommendations are being validated in a clinical trial in HCV genotype 1 infected post-transplant subjects on the 3DAA regimen with ribavarin for 24 weeks. DISCLOSURES:Badri, P.: Grant/Research Support, Study desinged, conducted and sponsored by Abbvie, Employee, Full time employee of Abbvie, Stockholder, Hold Abbvie stock or stock option. Cohen, D.: Grant/Research Support, Study designed, conducted and sponsored by Abbvie, Employee, Full time employee of Abbvie, Stockholder, Hold Abbvie Stocks or stock options. Ding, B.: Grant/Research Support, Study designed, conducted and sponsored by Abbvie, Employee, Full time employee of Abbvie, Stockholder, Hold Abbvie stocks or stock options. Podsadecki, T.: Grant/Research Support, Study designed, conducted and sponsored by Abbvie, Employee, Full time employee of Abbvie, Stockholder, Hold Abbvie stocks or stock options. Bernstein, B.: Grant/Research Support, Study designed, conducted and sponsored by Abbvie, Employee, Full time employee of Abbvie, Stockholder, Hold Abbvie stocks or stock options. Awni, W.: Grant/Research Support, Study designed, conducted and sponsored by Abbvie, Employee, Full time employee of Abbvie, Stockholder, Hold Abbvie stocks or stock options. Dutta, S.: Grant/Research Support, Study designed, conducted and sponsored by Abbvie, Employee, Full time employee of Abbvie, Stockholder, Hold Abbvie Stocks or stock options. Menon, R.: Grant/Research Support, Study designed, conducted and sponsored by Abbvie, Employee, Full time employee of Abbvie, Stockholder, Hold Abbvie stocks or stock options.

of African ancestry, IFNL4 ss469415590 genotype predicts HCV clearance better than rs12979860 genotype.Figure 1.

1187 ABT-450/RITONAVIR (ABT-450/R) COMBINED WITH PEGYLATED INTERFERON ALPHA-2A/RIBAVIRIN AFTER 3-DAY MONOTHERAPY IN GENOTYPE 1 (GT1) HCV-INFECTED TREATMENT-NAIVE SUBJECTS: 12-WEEK SUSTAINED VIROLOGIC RESPONSE (SVR12) AND SAFETY RESULTS E. Lawitz, F. Poordad, E. DeJesus, K. Kowdley, I. Gaultier, D. Cohen, W. Xie, L. Larsen, T. Pilot-Matias, R.M. Menon, T. Podsadecki, B. Bernstein. Alamo Medical Research, San Antonio, TX, Cedars-Sinai Medical Center, Los Angeles, CA, Orlando Immunology Center, Orlando, FL, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, Abbott, Abbott Park, IL, USA E-mail: lawitz@alamomedicalresearch.com

Background: This study monitored for resistance for up to 12 weeks of treatment with danoprevir (DNV) plus low-dose ritonavir (r) in combination with PegIFNa-2a/RBV in genotype (GT) 1 treatmentnaive patients and prior null responders.Materials and Methods: Three cohorts of treatment-naive HCV GT1 patients were randomised to receive DNV/r (n = 31) or placebo/r + PegIFNa-2a/RBV (n = 3) for 15 days with DNV/r regimens of 100/100 mg q12 h (cohort 1), 200/100 mg q24 h (cohort 2), and 200/100 mg q12 h (cohort 3).A fourth cohort (n = 24) included prior null responder GT1 patients who received 100/100 mg q12 h DNV/r or placebo/r + PegIFNa-2a/RBV for 12 weeks.The NS3/4A and/or NS3 protease coding region was amplified and population sequence was performed on all baseline samples.Population sequence and phenotypic analyses were performed on on-treatment and follow up samples from DNV/r/PegIFNa-2a/RBV-treated patients that experienced:i. viral load rebound, ii.non response or iii.partial response.Results: Low-dose DNV/r + PegIFNa-2a/RBV provided robust virological response in all cohorts.No viral breakthrough was observed in treatment-naive patients (cohorts 1-3, 22 GT1a and 9 GT1b) after 2 weeks of DNV combination therapy.Of the 24 (8 GT1a and 16 GT1b) prior null responder patients treated with DNV/r for up to 12 weeks, four GT1a patients experienced a viral breakthrough (two patients by week 3, one by week 4 and one by week 8 of treatment).This was associated with the selection of R155K in the NS3 protease region and ~250-fold EC 50 shift compared to the baseline samples.The R155K resistance mutation persisted for up to 12 weeks after cessation of therapy.Viral breakthrough was observed in one GT1b patient.Population sequence of the NS3/4A region of 58 patients at baseline did not show any DNV resistance mutations.Conclusions: DNV/r + PegIFNa-2a/RBV provided a robust virological response in GT1b and GT1a treatment-naive patients with no viral breakthrough observed.In prior null responders, robust response was observed in GT1b patients whereas resistance related viral breakthrough was observed in 4/8 GT1a patients.R155K mutation persisted for 12 weeks after the cessation of therapy, emphasising the need for a second direct-acting antiviral agent in this population.

POSTERSgenotype-1b HCV infected patients given 10 mg GS-5885/placebo.GS-5885 was well tolerated with significant antiviral activity: Figure: HCV RNA Viral Load Reduction.HCV RNA declined sharply with median decrease of -3.1 to -3.3 log 10 IU/mL (Day 2) and up to -2.0 (1a) and -2.8 (1b) log 10 IU/mL (Day 6) at GS-5885 doses ≥3 mg.The major resistance mutants were M28T, Q30R/H, L31M, and Y93C.Blinded preliminary safety data through Day 7 employed for dose escalation decision-making after 3, 10, and 30-mg cohorts of HCV-1a infected patients showed: no serious adverse events (AEs), no discontinuations due to AEs, infrequent AEs occurring in ≥2 patients headache (5 patients), difficult blood draw (3 patients), and frequent urination and upper respiratory infection in 2 patients each.In the 10-and 30-mg GS-5885 HCV 1a dose groups, 2/24 (8%) patients had transient treatment-emergent Grade 3/4 laboratory abnormalities.One with a Grade 3 ALT (10-mg cohort) due to a clinically insignificant 14 U/L increase returning to baseline on drug, and a second with Grade 3 creatine phosphokinase (30-mg cohort) on Day 7 off-drug associated with weight lifting.HCV RNA change from baseline GS-5885 log 10 IU/mL 1 mg (n = 10) 3 mg (n = 10) 10 mg (n = 10) 30 mg (n = 10) Meanx.x -3.1 -2.8 -3.0 Median x.x -3.1 -3.1 -3.2 Range x.x, x.x -3.7, -2.5 -3.7, -1.6 -3.9, -0.9Conclusions: GS-5885 is a potent HCV NS5A inhibitor demonstrating a 1000-fold (3 log 10 ) reduction in HCV RNA after three, once daily, low oral doses.

Conclusion: Administration of narlaprevir (with or without ritonavir) plus Peg-IFN for two weeks followed by SOC for 24 or 48 weeks resulted in 81% and 38% SVR in treatment-naïve and experienced patients, respectively.