Factors affecting the pharmacokinetics of CPT-11: the body mass index, age and sex are independent predictors of pharmacokinetic parameters of CPT-11.
This study was conducted to describe the relationship between pharmacokinetics of CPT-11 and its active metabolite SN-38, and clinical values with special emphasis on the influence of relative weight referring to the appropriateness of a conventional dose adjustment method by body surface area (BSA). Thirty-six patients received 100 mg/m2 of CPT-11 intravenously over 90 min. Body Mass Index (BMI) was used as a measure of relative weight which is calculated from the equation: BMI=weight(kg)/[height(m)]2. The area under the concentration-time curve (AUC) of CPT-11 was significantly correlated with sex, age, poorer creatinine clearance and indocyanine green retention test (ICG). The peak plasma concentration (Cmax) of CPT-11 was significantly correlated with sex a larger BMI, BSA and age. The AUC of SN-38 was significantly correlated with ICG. The volume of distribution at steady state of CPT-11 inversely correlated with BMI. Multiple regression analysis revealed that the best fitting model with significant independent predictors for AUC of CPT-11 included age and sex (F=6.93, R2=0.29). That of Cmax of CPT-11 included sex and BMI (F=8.96, R2=0.35). The only independent predictor of AUC of SN-38 was ICG (F=7.75, R2=0.19). These results indicated that several factors affect pharmacological behaviors of CPT-11 even in patients with normal organ functions. The dose modification method based solely on BSA is not sufficient to reduce interpatient variability of cancer chemotherapy. The influence of relative weight, sex and age on pharmacokinetics/pharmacodynamics should be taken into consideration in every pharmacological approach to establish the ideal dose modification method.
Miya
T
T
Department of Surgery II, Kyorin University School of Medicine, Mitaka, Tokyo, Japan. toshimichi@mtg.biglobe.ne.jp
Goya
T
T
Fujii
H
H
Ohtsu
T
T
Itoh
K
K
Igarashi
T
T
Minami
H
H
Sasaki
Y
Y
D000328:Adult; D000367:Age Factors; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015992:Body Mass Index; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D012737:Sex Factors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D000077146:Irinotecan; D002166:Camptothecin