MULTIPLE-DOSE PHARMACOKINETICS OF PENTOXIFYLLINE AND ITS METABOLITES DURING RENAL-INSUFFICIENCY

OBJECTIVE: To characterize pentoxifylline (PTF) and metabolite disposi tion after multiple oral doses given two and three times a day to pati ents with renal dysfunction. DESIGN: An open-label, randomized, crosso ver, parallel group design, SETTING: Community-based clinical research center. PATIENT POPULATION: Subjects with renal function stratified b ased on 24-hour urinary creatinine clearance (Cl-cr: group I = Cl-cr>8 0 mL/min (n = 9); group II = Cl-cr 30-80 mL/min (n = 6); and group III = Cl-cr <30 mL/min (n = 10). METHODS: PTF 400 mg bid or tid was admin istered on days 1-7 and 400 mg bid or tid was given on days 14-20 with a 1-week washout. Timed blood samples were taken on days 1, 7, and 20 . Blood samples were analyzed for PTF and its metabolites (M-I, M-IV, MV) by gas-liquid chromatography. MAIN OUTCOME MEASURES: Maximum plasm a concentration (C-max), time to maximum concentration (t(max)). avera ge steady-state plasma concentration (C-avg(ss)), and area under the p lasma concentration-time curve at steady-state (AUC(ss) were determine d by visual and model independent methods. ANOVA, paired t-test, and l inear regression were used with significance level set at p < 0.05. RE SULTS: The ratio of PTF AUC(ss) (tid):AUC(ss) (bid) and M-I AUC(ss) (b id and rid) were not significantly different between the groups. Signi ficant differences were found in M-IV and M-V C-max, AUC(ss), C-avg(ss ), and AUC(ss) ratios (M-IV:PTF and M-V:PTF) between renal function gr oups (p < 0.05 for all). A change in dosage regimen from tid to bid re sulted in significant changes in M-IV and M-V C-avg(ss) for subjects w ith normal renal function and in those with moderate dysfunction, alth ough not in subjects with severe renal dysfunction. CONCLUSIONS: Renal dysfunction did not cause significant accumulation of PTF or M-I afte r multiple bid and tid dosing; however, M-IV and M-V had significant a ccumulation in patients with renal impairment. Dosage reduction to 400 mg bid for patients with moderate renal impairment and 200-400 mg/d f or severe renal impairment, as well as close clinical monitoring, seem prudent until the complex pharmacologic interactions of PTF and its m etabolites can be further delineated.