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 (INRand INR) for Warfarin, were calculated using non-compartmental analysis with SAS9.4 (SAS Institute, Inc., Cary, NC, United States). Bioequivalence and safety were assessed in both cohorts. AUC0-last max ®
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 (, AUCand AUC) in the Digoxin and Warfarin cohorts, and for the primary pharmacodynamic parameters (INRand INR) 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. C max0-inf0-last AUC0-last max
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.
