A pharmacokinetic and pharmacodynamic analysis of CPT-11 and its active metabolite SN-38.
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.
Sasaki
Y
Y
Department of Medicine, National Cancer Center Hospital East, Chiba.
Hakusui
H
H
Mizuno
S
S
Morita
M
M
Miya
T
T
Eguchi
K
K
Shinkai
T
T
Tamura
T
T
Ohe
Y
Y
Saijo
N
N
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D006801:Humans; D000077146:Irinotecan; D007564:Japan; D007700:Kinetics; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D011446:Prospective Studies
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin