Disposition of [G-H-3]paclitaxel and cremophor EL in a patient with severely impaired renal function

In the present work, we studied the pharmacokinetics and metabolic disposit ion of [G-H-3]paclitaxel in a female patient with recurrent ovarian cancer and severe renal impairment (creatinine clearance: similar to 20 ml/min) du e to chronic hypertension and prior cisplatin treatment. During six 3-weekl y courses of paclitaxel at a dose level of 157.5 mg/m(2) (viz. a 10% dose r eduction), the renal function remained stable. Pharmacokinetic evaluation r evealed a reproducible and surprisingly high paclitaxel area under the plas ma concentration-time curve of 26.0 +/- 1.11 mu M.h (mean +/- S.D.; n = 6; c.v. = 4.29%), and a terminal disposition half-life of similar to 29 h. Bot h parameters are substantially increased (similar to 1.5-fold) when compare d with kinetic data obtained from patients with normal renal function. The cumulative urinary excretion of the parent drug was consistently low and av eraged 1.58 +/- 0.417% (+/- S.D.) of the dose. Total fecal excretion (measu red in one course) was 52.9% of the delivered radioactivity, and mainly com prised known mono- and dihydroxylated metabolites, with unchanged paclitaxe l accounting for only 6.18%. The plasma area under the plasma concentration -time curve of the paclitaxel vehicle Cremophor EL, which can profoundly al ter the kinetics of paclitaxel, was 114.9 +/- 5.39 mu l.h/ml, and not diffe rent from historic data in patients with normal or mild renal dysfunction. Urinary excretion of Cremophor EL was less than 0.1% of the total amount ad ministered. These data indicate that the substantial increase in systemic e xposure of the patient to paclitaxel relates to decreased renal metabolism and/or urinary elimination of polar radioactive species, most likely lackin g an intact taxane ring fragment.