Disposition of [G-(3)H]paclitaxel and cremophor EL in a patient with severely impaired renal function.
In the present work, we studied the pharmacokinetics and metabolic disposition of [G-(3)H]paclitaxel in a female patient with recurrent ovarian cancer and severe renal impairment (creatinine clearance: approximately 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/m(2) (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 microM.h (mean +/- S.D.; n = 6; c.v. = 4.29%), and a terminal disposition half-life of approximately 29 h. Both parameters are substantially increased ( approximately 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 microl.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.
Gelderblom
H
H
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, The Netherlands.
Verweij
J
J
Brouwer
E
E
Pillay
M
M
de Bruijn
P
P
Nooter
K
K
Stoter
G
G
Sparreboom
A
A
D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D009400:Nephrosclerosis / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D010051:Ovarian Neoplasms / Q000150:complications / Q000188:drug therapy; D017239:Paclitaxel / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013056:Spectrophotometry, Ultraviolet
D000972:Antineoplastic Agents, Phytogenic; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol