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/m(2), 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.