Robert Adamczyk

822Effect of Steady State Daclatasvir Plus Asunaprevir on the Single Dose Pharmacokinetics of the P-glycoprotein Substrate Digoxin in Healthy Adult Subjects

Background. Daclatasvir (DCV) is a potent hepatitis C virus (HCV) NS5A replication complex inhibitor with pangenotypic (GT 1-6) activity in vitro. Asunaprevir (ASV) is a selective NS3 protease inhibitor with in vitro activity against GT 1, 4, 5 and 6. These two direct-acting antivirals (DAA) are in phase 3 development and regulatory review as a dual-DAA regimen (DCV + ASV) for the treatment of HCV GT 1b. DCV and ASV both inhibit P-glycoprotein (P-gp) and individually increase plasma concentrations of the P-gp substrate digoxin (DIG), increasing DIG Cmax by 65 and 9% and AUCTAU by 27 and 30%, respectively. The combined effect of DCV + ASV on the pharmacokinetics (PK) of DIG was therefore assessed in healthy subjects. Methods. A single sequence, open-label, one-way interaction study assessed the effect of steady-state DCV (60 mg QD) plus ASV (100 mg BID [softgel capsule]) on the PK of single-dose 0.25 mg DIG in healthy subjects. Subjects (N = 16) received DIG on Day 1 and 16, and DCV + ASV on Days 6–20. Serial samples for DIG plasma concentrations were collected up to 120 h postdose on Day 1 and Day 16. Non-compartmental DIG PK parameters were derived. Geometric mean ratios (GMR) and 90% confidence intervals (90%CI) for DIG Cmax and AUCinf were derived from linear mixed effects models. Results. All subjects (69% male, aged 23-45 years) completed the study. DCV + ASV dosed with DIG resulted in a 77% increase in DIG Cmax and a 29% increase in AUCinf (Table). Study drugs were well tolerated; all AEs were mild in intensity except 2 AEs of increased blood creatinine phosphokinase (1 moderate, 1 severe). No AEs were considered study drug-related and all resolved by study end.

Apixaban pharmacodynamic activity in umbilical cord, paediatric, and adult plasma

The objective was to characterise apixaban pharmacodynamic (PD) activity in umbilical cord (UC), paediatric, and adult plasma. Plasma was obtained from blood samples from six UC donors, 70 paediatric (neonates [birth-≤1 month], infants [>1-≤6 months], toddlers [>6 months-≤2 years], young children [>2-≤6 years], children [>6-≤12 years], adolescents [>12-≤18 years]), and six adult (19-45 years) subjects. Plasma spiked with apixaban 0 (baseline), 30, or 110 ng/ml was analysed for anti-factor Xa activity, factor X levels, prothrombin time (PT), and modified PT (mPT). Apixaban had similar concentration-related effects on anti-factor Xa activity across groups (30 ng/ml: 0.223-0.295 IU/ml; 110 ng/ml: 1.212-1.474 IU/ml). Endogenous baseline factor X levels were 43 %-68 % lower in plasma from UC and subjects ≤6 months versus adults. Factor Xa inhibition (percentage change from baseline in apparent factor X levels) was similar for both apixaban concentrations across groups, except UC, neonate, and infant groups, which showed greater inhibition vs adults for apixaban 110 ng/ml. Baseline PT and mPT were similar across groups. Apixaban had no effect on PT at the concentrations tested. Apixaban 110 ng/ml prolonged mPT similarly across groups (44.4-53.2 s to 64.5-70.0 s); no prolongation was found with apixaban 30 ng/ml. Apixaban demonstrated consistent concentration-related effects on other PD endpoints in plasma samples from all age groups, except factor Xa inhibition.

The pharmacokinetics of peginterferon lambda‐1a following single dose administration to subjects with impaired renal function

AIMS This open label study was conducted to assess the effect of renal impairment (RI) on the pharmacokinetics (PK) of peginterferon lambda-1a (Lambda). METHODS Subjects (age 18-75 years, BMI 18-35 kg m(-2) ) were enrolled into one of five renal function groups: normal (n = 12), mild RI (n = 8), moderate RI (n = 8), severe RI (n = 7), end-stage renal disease (ESRD, n = 8) based on estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) equation. Subjects received a single dose of Lambda (180 µg) subcutaneously on day 1 followed by PK serum sample collections through day 29. Safety, tolerability and immunogenicity data were collected through day 43. PK parameters were estimated and summarized by group. Geometric mean ratios (GMR) and 90% confidence intervals (CIs) were calculated between normal and RI groups. RESULTS With decreasing eGFR, Lambda exposure (Cmax , AUC) increased while apparent clearance (CL/F) and apparent volume of distribution (V/F) decreased. Relative to subjects with normal renal function (geometric mean AUC = 99.5 ng ml(-1) h), Lambda exposure estimates (AUC) were slightly increased in the mild RI group (geometric mean [90% CI]: 1.20 [0.82, 1.77]) and greater in the moderate (1.95 [1.35, 2.83]), severe RI (1.95 [1.30, 2.93]) and ESRD (1.88 [1.30, 2.73]) groups. Lambda was generally well tolerated. CONCLUSIONS The results demonstrated that RI reduces the clearance of Lambda and suggests that dose modifications may not be required in patients with mild RI but may be required in patients with moderate to severe RI or ESRD.

A Pooled Analysis of Pharmacokinetic Variability Information for Common Probe Substrates Used in Drug-Drug Interaction Studies.

Sample size estimates for drug-drug interaction (DDI) studies are often based on variability information from the literature or from historical studies, but small sample sizes in these sources may limit the precision of the estimates obtained. This project aimed to create an intra-subject variability library of the pharmacokinetic (PK) exposure parameters, area under the curve, and maximum plasma concentration, for probes commonly used in DDI studies. Data from 66 individual DDI studies in healthy subjects relating to 18 common probe substrates were pooled to increase the effective sample size for the identified probes by 1.5- to 9-fold, with corresponding improvements in precision of the intra-subject PK variability estimates in this library. These improved variability estimates will allow better assessment of the sample sizes needed for DDI studies in future.

THU0194 A Novel Reversibile Bruton's Tyrosine Kinase (BTK) Inhibitor (BMS-986142) Provides Favorable Safety, Pharmacokinetic, and Pharmacodynamic Profiles in Healthy Subjects

Background BTK is an attractive, novel therapeutic target for autoimmune disease, based on the established mechanistic data via B cell receptor (BCR)-dependent and Fc receptors (FcR)-dependent pathways (Whang et al. Drug Discov Today, 2014;19:1200–4). BMS-986142, a new small molecule reversible inhibitor of BTK, is being developed for the treatment of rheumatoid arthritis (RA) and auto-immune diseases. To support clinical development of BMS-986142, it is important to demonstrate sufficient pharmacodynamic (PD) activity, acceptable pharmacokinetic (PK) profile, and low drug-drug interaction potential with methotrexate (MTX) prior to testing in patients. Objectives Here we present the outcomes from two phase 1 studies investigating safety, tolerability, PK, PD, and its effect on MTX PK following oral administration of BMS-986142 in healthy subjects. Methods In Study 1, healthy volunteers (18–50 y) were randomized to receive single doses of BMS-986142 (5 to 900 mg or placebo) or multiple doses of BMS-986142 (25 to 350 mg or placebo once daily [QD] for 14 days) to assess the safety, tolerability, PK, and PD (as measured by CD69 inhibition). In Study 2, safety and tolerability was assessed in healthy males (18–50 y) receiving single doses of MTX alone (7.5 mg) and in combination with BMS-986142 (350 mg QD) while assessing the effect of BMS-986142 on the PK of MTX. Results BMS-986142 was well tolerated in both studies. In Study 1, a grade 3 SAE (psychosis, 75 mg BMS-986142) not related to study drug was reported in 1 subject; 1 grade 3 AE (blood creatinine phosphokinase elevation, placebo) was also reported. Three drug related grade 1 AEs (headache-SAD, 900mg; back pain-MAD, 200 mg; cough-MAD, placebo) were reported in Study 1. There were no grade 3 AEs reported in Study 2. AEs reported at least twice among all dosing groups are presented in the table. BMS-986142 was rapidly absorbed with peak concentrations occurring within 2 hours and gradually eliminated with a half-life of up to 11 hours, enabling QD dosing in the patient studies. BMS-986142 showed linear PK following either a single- or multiple-dose administration. A dose- and concentration-dependent decrease in CD69 expression was observed following the administration of BMS-986142. Daily administration at 350 mg led to near complete coverage above the IC50 for CD69 inhibition throughout the dosing interval without time-dependent changes. BMS-986142 did not affect the PK of MTX, as the peak concentrations and total exposure were comparable when administered with and without BMS-986142 (adjusted geometric mean ratios [90% CI]: Cmax, 1.046 [0.910, 1.202]; AUC(0-T), 1.041 [0.950, 1.139]). Study 1 Study 2 SAD MAD Placebo BMS-986142 Placebo BMS-986142 BMS-986142 n=12 n=36 n=8 n=24 n=12 Subjects with AEs 2 8 4 8 4 Dizziness 0 1 0 0 2 Headache/tension headache 1 5 1 1 2 Nausea 0 1 0 0 2 Diarrhea 0 1 0 1 0 Cough 0 1 1 1 0 Upper respiratory infection 0 2 0 1 0 Thermal burns 0 1 0 1 0 Conclusions BMS-986142 was found to be safe and well tolerated at the doses tested in two phase 1 studies in healthy subjects. It showed favorable PK/PD profile including lack of interaction with MTX and can be safely administered in RA patients that are on background MTX. Overall, BMS-986142 has the potential to show clinical activity in treating autoimmune diseases. Disclosure of Interest S. K. Lee Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, J. Xing Employee of: Bristol-Myers Squibb Company, I. Catlett Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, R. Adamczyk Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, A. Griffies Employee of: Bristol-Myers Squibb Company, A. Liu Employee of: Bristol-Myers Squibb Company, B. Murthy Shareholder of: Bristol-Myers Squibb Company, Employee of: Bristol-Myers Squibb Company, M. Nowak Employee of: Bristol-Myers Squibb Company