A study to evaluate the impact of PB-119 injection (a pegylated exenatide formulation) on the pharmacokinetic profiles of Digoxin and Warfarin sodium in healthy subjects

Objective: To evaluate the impact of multiple-dose PB-119 injection (a pegylated exenatide formulation) on the pharmacokinetics of single-dose Digoxin or Warfarin sodium and on the pharmacodynamics of Warfarin sodium in healthy Chinese adults. Methods: This study is a single-centre, open-label, randomized, two-period, two-sequence, parallel-group design phase I clinical trial of drug interactions, aiming to evaluate the pharmacokinetic and pharmacodynamic effects of multiple administrations of PB-119 injection (a pegylated exenatide formulation) on single-dose oral Digoxin and Warfarin sodium in healthy Chinese adults. Sixteen healthy subjects were enrolled in each of two cohorts: Digoxin (Digoxin 0.5 mg versus Digoxin 0.5 mg + PB-119 150 μg) and Warfarin sodium (Warfarin 5 mg versus Warfarin 5 mg + PB-119 150 μg). Treatments were administered in a fixed sequence. The total duration of the study for each subject was 33 days, consisting of a 14-day screening phase (day −14 to day −1), a 9-day inpatient treatment phase (day 1 to day 9 for the Digoxin cohort; day 1 to day 16 for the Warfarin cohort to allow international normalized ratio follow-up), and a 10-day post-treatment safety follow-up (day 10 or day 17 to day 23 or day 30, respectively). Statistical analysis: Pharmacokinetic parameters for Digoxin and Warfarin sodium, as well as pharmacodynamic parameters (INR AUC0–last and INR max ) for Warfarin, were calculated using non-compartmental analysis with SAS ® 9.4 (SAS Institute, Inc., Cary, NC, United States). Bioequivalence and safety were assessed in both cohorts. Results: The rate and extent of absorption of Digoxin or Warfarin sodium administered alone were comparable to those observed when co-administered with PB-119. The 90% confidence intervals of the geometric mean ratios for the primary pharmacokinetic parameters ( C max , AUC 0–inf and AUC 0–last ) in the Digoxin and Warfarin cohorts, and for the primary pharmacodynamic parameters (INR AUC0–last and INR max ) in the Warfarin cohort, all fell within the predefined bioequivalence range of 80.00%–125.00%. No unexpected or serious adverse events were reported during the study. Conclusions: Multiple-dose PB-119 injection does neither alter the pharmacokinetic characteristics of single-dose Digoxin or Warfarin sodium, nor does it influence the pharmacodynamic characteristics of Warfarin sodium, in healthy Chinese subjects.