Pharmacokinetics, Safety and Tolerability of Cyclosporine or Tacrolimus Following Coadministration of ABT-450/r, ABT-267 and ABT-333 in Healthy Subjects.

Abstract

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.