Population pharmacokinetics of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in cancer patients

Abstract

2508 Background: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3AP) is an inhibitor of ribonucletoide reductatse with activity in hematological malignancies as well as melanoma and prostate cancer. This study describes the population PK of 3AP and the relationship between 3AP disposition and patient covariates. Methods: 40 pts with advanced cancer from two phase 1 studies were included in the PK model building. Pts received 3AP 25–105 mg/m2 IV on day 1. 3AP plasma and erythrocyte levels were sampled at 10 timepoints over a 24-hour period and measured by a validated HPLC method. Data were analyzed by a nonlinear mixed- effects modeling approach with NONMEM system Version V. Xpose10 and S-PLUS were used for goodness-of-fit assessment and model evaluation to obtain clearance (CL), volume of distribution (V) for compartment (C) 1, plasma (V1); V for C2, erythrocytes (V2); and V for C3 (V3). 15 covariates were evaluated, including: weight, BSA, gender, PS, age, ABCB1[C1236T, G2667T, C3436T] genotypes, toxicity, concurrent chemotherapy [irinotecan, doxorubicin], response and number of cycles administered. Normal renal and hepatic function were required for study entry and were not included as covariates. Response was assessed after 2 cycles of therapy. Results: 3AP PK were described as a 3-compartment model with first-order elimination. Estimated paramaters were: V1 =5.68 L/m2 (95%CI 4.3–7.1); V2=18.9 L/m2 (95%CI 14.6–23.2); V3= 40.0 L/m2 (95%CI 23.8–55.4); CL 25.4 L/hr/m2 (95%CI 22.4–28.4). Gender was associated with V; women had a lower V2 (p<0.05). This may be related to a lower hemoglobin in women. The number of cycles administered was associated with decreased CL; those with decreased CL received less than 2 cycles before going off study. Conclusions: Women had a lower V2 than men and pts with decreased CL received less than 2 cycles of therapy, suggesting PK may be helpful in individualizing dosing. ABCB1 genotypes and concurrent irinotecan or doxorubicin do not influence 3AP disposition. Supported by: U01CA062491 “Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis” NCI; CTEP TRI Funding 24XS090, and 1ULRR025011 Clinical and Translational Science Award of the National Center for Research Resources, NIH. No significant financial relationships to disclose.