Aims: To evaluate the effect of renal impairment on the pharmacokinetics and safety of pioglitazone and its metabolites M-III and M-IV with impaired renal function and normal renal function.
Methods: In a phase-I, open-label, parallel-group study, six healthy subjects with normal renal function (creatinine clearance> 80 ml min-1), nine patients with moderate renal impairment (creatinine clearance 30-60 ml min-1) and 12 patients with severe renal impairment (creatinine clearance < 30 ml min-1) received single and multiple oral doses of pioglitazone 45 mg. The serum pharmacokinetic profiles of pioglitazone and its metabolites M-III and M-IV were assessed for the first and last dose administered (day 1 and day 12, respectively).
Results: Pharmacokinetic data revealed no significant accumulation of pioglitazone or its metabolites M-III and M-IV in patients with renal impairment. There was no significant difference in the pharmacokinetic profile of pioglitazone in subjects with normal and with moderately impaired renal function. After single oral doses, mean area under the concentration-time curve (AUC) values were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (13 476 vs 17 387, P = 0.371; -23%; confidence interval (CI) -57, 38), M-III metabolite (13 394 vs 15 071, P = 0.841; -11%; CI -74, 194) and M-IV metabolite (27 991 vs 49 856, P = 0.006; -44%; CI -62, -17). After repeated oral doses of pioglitazone, mean AUC values (microg.h l-1) were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (8744 vs 14,565, P = 0.004; -40%; CI -57, -16), M-III (3991 vs 7,289, P = 0.0009; -45%; CI -60, -25) and M-IV (21 080 vs 25 706, P = 0.181; -18%; CI 39, 10). The tolerability and safety profile of pioglitazone was comparable between groups.
Conclusions: Pioglitazone was well tolerated in patients with varying degrees of renal impairment. Although mean serum concentrations of pioglitazone and its metabolites are increased in patients with severe renal impairment, adjustment of starting and maintenance doses in these patients is probably unwarranted.