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 pha rmacokinetics of 1-piperidino)-1-piperidino]carbonyloxycamptothecin (C PT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-3 8). The relationship between pharmacokinetic parameters and pharmacody namic effects was also investigated to elucidate the cause of interpat ient variation in side effects. Thirty-six patients entered the study. CPT-11, 100 mg/m(2), was administered by IV infusion over 90 min week ly 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 (AUG) of CPT-11 and percent d ecrease of WBC (r = 0.559). On the other hand, episodes of diarrhea ha d 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 significan t variables for the incidence of diarrhea and that both performance st atus and AUC of CPT-11 were significant variables for percent decrease of WBC. The large interpatient variability of the degree of leukopeni a and diarrhea is due to a great plasma pharmacokinetic variation in C PT-11 or SN-38. The AUCs of CPT-11 and SN-38 obtained from the first a dministration of CPT-11 correlate with toxicities, but it is impossibl e to predict severe side effects before the administration of CPT-11 a t the present time.