Abstract
In the present work, we studied the pharmacokinetics and metabolic disposition of [G-3H]paclitaxel in a female patient with recurrent ovarian cancer and severe renal impairment (creatinine clearance: ∼20 ml/min) due to chronic hypertension and prior cisplatin treatment. During six 3-weekly courses of paclitaxel at a dose level of 157.5 mg/m2 (viz. a 10% dose reduction), the renal function remained stable. Pharmacokinetic evaluation revealed a reproducible and surprisingly high paclitaxel area under the plasma concentration-time curve of 26.0 ± 1.11 μM.h (mean ± S.D.; n = 6; c.v. = 4.29%), and a terminal disposition half-life of ∼29 h. Both parameters are substantially increased (∼1.5-fold) when compared with kinetic data obtained from patients with normal renal function. The cumulative urinary excretion of the parent drug was consistently low and averaged 1.58 ± 0.417% (± S.D.) of the dose. Total fecal excretion (measured in one course) was 52.9% of the delivered radioactivity, and mainly comprised known mono- and dihydroxylated metabolites, with unchanged paclitaxel accounting for only 6.18%. The plasma area under the plasma concentration-time curve of the paclitaxel vehicle Cremophor EL, which can profoundly alter the kinetics of paclitaxel, was 114.9 ± 5.39 μl.h/ml, and not different 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 administered. These data indicate that the substantial increase in systemic exposure of the patient to paclitaxel relates to decreased renal metabolism and/or urinary elimination of polar radioactive species, most likely lacking an intact taxane ring fragment.
Footnotes
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Send reprint requests to: Alex Sparreboom, Ph.D., Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, P.O. Box 5201, 3008 AE Rotterdam, the Netherlands. E-mail: sparreboom{at}onch.azr.nl
- Abbreviations used are::
- AUC
- area under the plasma concentration-time curve
- Received May 3, 1999.
- Accepted July 28, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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