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

Aims: PF-734200 is a potent, selective inhibitor of DPP-IV. This two-part study evaluated the pharmacokinetics (PK) of oral 20mg 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 20mg PF-734200 while fasting and serum and urine samples were collected. In part 2, period 1, 1h 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 4h 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 16.2h in subjects with normal renal function to 36.6h in subjects with ESRD. Approximately, 29% of PF-734200 in the body after a single-dose administration was dialysed by 4h HD.

Conclusions: Systemic exposure of PF-734200 increases with decreasing renal function. The effect of HD on drug removal is modest.