Predicting etoposide toxicity: relationship to organ function and protein binding.
OBJECTIVE
To investigate the effect of organ function on total and free etoposide pharmacokinetics and hematologic toxicity.


METHODS
Seventy-two patients who received single-agent intravenous (i.v.) etoposide over 5 or 8 days (total dose, 500 mg/m2) were studied. Pharmacokinetic parameters were derived after analysis of total plasma etoposide by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection, and etoposide protein binding by ultrafiltration of an etoposide-spiked, pretreatment serum sample, followed by HPLC analysis. Free etoposide area under the concentration-time curve (AUC) was derived from the total AUC and protein binding.


RESULTS
Patients with renal impairment (serum creatinine level > 130 mumol/L) had a lower plasma etoposide clearance (13.6 v 18.5 mL/min/m2; P = .016), resulting in an increased total-drug and free-drug AUC (total etoposide AUC 615 v 452 micrograms/mL.hr; P = .016; free etoposide AUC 26.0 v 17.6 micrograms/mL.hr; P = .026) and increased hematologic toxicity (nadir neutrophil count 0.3 v 1.9 x 10(9)/L; P = .005). Patients with albumin levels less than 35 g/L had no change in total etoposide kinetics but had an increase in unbound etoposide (5.2% v 4.1%; P = .01), resulting in an increase in free etoposide AUC (27.5 v 16.5 micrograms/mL.hr; P = .003) and more profound toxicity (nadir neutrophil count 0.6 v 1.9 x 10(9)/L; P = .004). In patients with normal albumin and creatinine, increased toxicity in those older than 65 years was associated with a reduced drug clearance, and in those with increased liver enzymes by a trend toward an increase in free etoposide AUC.


CONCLUSIONS
Increased hematologic toxicity after etoposide in patients with abnormal organ function is mediated by an increase in free etoposide AUC. A reduction in dose is clearly indicated in such patients.
Joel
S P
SP
Department of Medical Oncology, St Bartholomew's Hospital, London, United Kingdom.
Shah
R
R
Clark
P I
PI
Slevin
M L
ML
D000328:Adult; D000368:Aged; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000097:blood; D005047:Etoposide / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity*; D005260:Female; D006207:Half-Life; D006402:Hematologic Diseases / Q000209:etiology*; D006801:Humans; D007677:Kidney Function Tests; D007958:Leukocyte Count / Q000187:drug effects; D008111:Liver Function Tests; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects; D011237:Predictive Value of Tests; D011485:Protein Binding; D012044:Regression Analysis
D005047:Etoposide; D003404:Creatinine