Multiple-dose pharmacokinetics of pentoxifylline and its metabolites during renal insufficiency.
OBJECTIVE
To characterize pentoxifylline (PTF) and metabolite disposition after multiple oral doses given two and three times a day to patients with renal dysfunction.


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


METHODS
Community-based clinical research center. PATIENT POPULATIONS: Subjects with renal function stratified based on 24-hour urinary creatine clearance (Clcr): group I = Clcr > 80 mL/min (n = 9); group II = Clcr 30-80 mL/min (n = 6); and group III = Clcr < 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.


METHODS
Maximum plasma concentrations (Cmax), time to maximum concentration (tmax), average steady-state plasma concentration (CavgSS), and area under the plasma concentration-time curve at steady-state (AUCSS) 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 AUCSS (tid):AUCSS (bid) and M-I AUCSS (bid and tid) were not significantly different between the groups. Significant differences were found in M-IV and M-V Cmax, AUCSS, CavgSS, and AUCSS 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 CavgSS 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 accumulations 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.
Paap
C M
CM
School of Pharmacy, University of Colorado, Denver 80262, USA.
Simpson
K S
KS
Horton
M W
MW
Schaefer
K L
KL
Lassman
H B
HB
Sack
M R
MR
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010431:Pentoxifylline / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000378:metabolism*
D010431:Pentoxifylline