Multiple-Dose Pharmacokinetics of Pentoxifylline and its Metabolites during Renal Insufficiency

Abstract

OBJECTIVE:

To characterize pentoxifylline (PTF) and metabolite disposition after multiple oral doses given two and three times a day to patients with renal dysfunction.

DESIGN:

An open-label, randomized, crossover, parallel group design.

SETTING:

Community-based clinical research center.

PATIENT POPULATION:

Subjects with renal function stratified based on 24-hour urinary creatinine clearance (Cl_cr): group I = Cl_cr >80 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 administered 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, M-V) by gas-liquid chromatography.

MAIN OUTCOME MEASURES:

Maximum plasma concentration (C_max), time to maximum concentration (t_max), average steady-state plasma concentration (C^ss_avg), and area under the plasma concentration-time curve at steady-state (AUC_ss) were determined by visual and model independent methods. ANOVA, paired t-test, and linear regression were used with significance level set at p < 0.05.

RESULTS:

The ratio of PTF AUC_ss (tid):AUC_ss (bid) and M-I AUC_ss (bid and tid) were not significantly different between the groups. Significant differences were found in M-IV and M-V C_max, AUC_ss, C^ss_avg, and AUC_ss ratios (M-IV:PTF and M-V:PTF) between renal function groups (p < 0.05 for all). A change in dosage regimen from tid to bid resulted in significant changes in M-IV and M-V C^ss_avg for subjects with normal renal function and in those with moderate dysfunction, although not in subjects with severe renal dysfunction.

CONCLUSIONS:

Renal dysfunction did not cause significant accumulation of PTF or M-I after multiple bid and tid dosing; however, M-IV and M-V had significant accumulation in patients with renal impairment. Dosage reduction to 400 mg bid for patients with moderate renal impairment and 200-400 mg/d for severe renal impairment, as well as close clinical monitoring, seem prudent until the complex pharmacologic interactions of PTF and its metabolites can be further delineated.