Pharmacokinetic/Pharmacodynamic Model for the Time Course of Myelosuppression of New Anticancer Drug (CKD-602)

새로운 항암제 CKD-602의 골수독성에 대한 약동/약력학적 모델 연구

Background : CKD-602 (7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin), a new derivative of camptothecin, is a topoisomerase I inhibitor that has shown antitumor activity in many tumors. Because the major dose-limiting toxicity of CKD-602 has been known to be the myelosuppression, particularly neutropenia and thrombocytopenia, a PD model describing the entire time course of myelosuppression rather than a single nadir count is valuable. Methods : CKD-602 at doses ranging from $0.5\;to\;0.9\;mg/m^2/d$ were infused for 30 minutes on 5 consecutive days every 3 weeks to patients with advanced solid malignancies. PK analysis was performed using 26 blood samples per patient on days 1 and 5 in 12 patients of a phase I study, and 2 blood samples per patient in 6 patients of a phase IT study. Complete blood counts for myelosuppression model were conducted once a week or more until recovery in 18 patients of phase I/II studies. Model building was done by evaluating the goodness-of-fit criteria considering the change in MOFV (minimum objective function value). A modified posterior predictive check technique was used to validate the final PK/PD model. Results : The PK of CKD-602 was best described using a 3 compartments model. The derived PK parameters were used in the AUC-dependent PD model which had 4 compartments corresponding to two mitotic compartments of bone marrow (BM), one maturation-storage compartment of BM, and one peripheral blood compartment The baseline value of neutrophilis was used as the covariate of the rate constant in the mitotic compartment The AUCs required for a 50% reduction of the neutrophils and platelets were 5.05 ng*hr/mL and $l.64{\times}10^{-1}\;ng*hr/mL$, respectively. Conclusion : This mechanistic model successfully described the systemic exposure of CKD-602 to the entire time course of myelosuppression using both dense sampling data and sparse sampling data. This population pharmacokineticpharmacodynamic modeling of CKD-602 can be useful in predicting a safe dosage regimen or evaluation of new drugs.