The pharmacokinetics of PF‐734200, a DPP‐IV inhibitor, in subjects with renal insufficiency

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Data demonstrating the pharmacokinetics (PK), efficacy and tolerability of PF‐734200, a potent DPP‐IV inhibitor in subjects with normal renal function, have been published or presented. WHAT THIS STUDY ADDS • This study provides better data on the PK of PF‐734200 in subjects with varying degrees of renal insufficiency and in subjects with end‐stage renal disease undergoing haemodialysis. In assessing the effects of renal impairment on the PK of PF‐734200, this study provides evidence for potential dose adjustment of PF‐734200 in patients with certain categories of renal impairment. AIMS PF‐734200 is a potent, selective inhibitor of DPP‐IV. This two‐part study evaluated the pharmacokinetics (PK) of oral 20 mg PF‐734200 in subjects with varying degrees of renal insufficiency or with end‐stage renal disease (ESRD) requiring chronic haemodialysis (HD). The study also assessed the HD clearance of PF‐734200 in ESRD. METHODS Part 1 included subjects with normal renal function or renal insufficiency but not on HD. Subjects received a single dose of 20 mg PF‐734200 while fasting and serum and urine samples were collected. In part 2, period 1, 1 h after HD, a single 20‐mg dose was given to subjects with ESRD and serum samples were collected. After a 7‐day washout, subjects received another dose followed by collection of serum samples (period 2), during which HD was initiated 4 h after dosing. Dialysate samples were collected to quantify amount of drug removed, from which HD clearance was calculated. The fraction of drug dialysed was calculated using an AUC‐based method. RESULTS Systemic exposures of PF‐734200 increased approximately 1.5‐, 2.2‐, 2.1‐ and 2.8‐fold in subjects with mild, moderate, or severe renal insufficiency or ESRD, respectively, compared with subjects with normal renal function. The terminal half‐life increased from 16.2 h in subjects with normal renal function to 36.6 h in subjects with ESRD. Approximately, 29% of PF‐734200 in the body after a single‐dose administration was dialysed by 4 h HD. CONCLUSIONS Systemic exposure of PF‐734200 increases with decreasing renal function. The effect of HD on drug removal is modest.