A Pharmacokinetic and Pharmacodynamic Analysis of CPT-11 and Its Active Metabolite SN-38 |
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Authors: | Yasutsuna Sasaki Hideo Hakusui Shoichi Mizuno Masashige Morita Toshimichi Miya Kenji Eguchi Tetsu Shinkai Tomohide Tamura Yuichiro Ohe Nagahiro Saijo |
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Affiliation: | Division of Oncology and Hematology, Department of Medicine, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba 277;Department of Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104;Development Research Laboratories, Daiichi Pharmaceutical Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134;Epidemiology Division;Pharmacology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104 |
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Abstract: | In the present study, an attempt was made to determine the precise pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). The relationship between pharmacokinetic parameters and pharmacodynamic effects was also investigated to elucidate the cause of interpatient variation in side effects. Thirty-six patients entered the study. CPT-11, 100 mg/m2, was administered by IV infusion over 90 min weekly for four consecutive weeks. The major dose-limiting toxicities were leukopenia and diarrhea. There was a positive correlation between the area under the concentration-time curve (AUC) of CPT-11 and percent decrease of WBC ( r =0.559). On the other hand, episodes of diarrhea had a better correlation with the AUC of SN-38 ( r =0.606) than that of CPT-11 ( r =0.408). Multivariate analysis revealed that the AUC of SN-38, AUC of CPT-11 and indocyanine green retention test were significant variables for the incidence of diarrhea and that both performance status and AUC of CPT-11 were significant variables for percent decrease of WBC. The large interpatient variability of the degree of leukopenia and diarrhea is due to a great plasma pharmacokinetic variation in CPT-11 or SN-38. The AUCs of CPT-11 and SN-38 obtained from the first administration of CPT-11 correlate with toxicities, but it is impossible to predict severe side effects before the administration of CPT-11 at the present time. |
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Keywords: | CPT-11 SN-38 Pharmacokinetics Pharmacodynamics AUC |
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