Population pharmacokinetics/toxicodynamics (PK/TD) relationship of SAM486Ain phase I studies in patients with advanced cancers

SAM486A (previously termed CGP 48664), a potent inhibitor of S-adenosylmeth ionine decarboxylase, is under clinical development for the treatment of ad vanced refractory malignancies. Hematological toxicity manifested by dose-d ependent neutropenia has been observed in phase I studies. Population metho ds were used to investigate pharmacokinetics (PK) as a prognostic factor fo r safety end point (hematological toxicity) in patients with advanced cance rs. SAM486A plasma concentrations and neutrophil counts were collected from three ascending-dose tolerability and PK studies (study 1: single 5-day co ntinuous intravenous (IV) infusion with doses ranging from 24-700 mg/m(2)/c ycle; study 2:10-minute to 3-hour IV infusion once weekly with doses rangin g from 16-325 mg/m(2)/week; study 3:1-hour IV infusion once daily for 5 day s with doses ranging from 3.6-202.8 mg/m(2)/day). The FK of SAM486A were be st estimated by a population linear three-compartment model with NONMEM (ve rsion 5) using data from 79 patients in studies 1 through 3. The population pharmacokinetic parameters (SD) were CL = 6.2 (0.4) l/h/m(2), Q(2) = 15.4( 1.5) l/h/m(2), Q(3) = 33.6 (5.3) l/h/m(2), V-1 = 9.5 (1.6) l/m(2), V-2 = 67 2 (52) l/m(2), and V-3 = 39.9 (8.3) l/m(2), and the corresponding intersubj ect variability was 45.4%, 74.0%, 85.3% 80.1%, 37.0%, and 103%, respectivel y where CL is total body clearance, Q(2) and Q(3) are intercompartmentaI cl earances, and V-1, V-2, and V-3 are the volumes of distribution in central and peripheral compartments, respectively The intrasubject variability was 24.0%. The cumulative AUC before the onset of neutrophil nadir count (AUC) and the duration of exposure over threshold SAM486A concentrations in the r ange of 0.05 to 0.1 mu M based on Bayesian PK parameter estimates significa ntly correlated with absolute neutrophil count nadir (< 5 x 10(9)/l). AUC s howed the best correlation (R-2 = 0.72) with absolute neutrophil count nadi r by an inhibitory sigmoid E-max model and also correlated with percent dec rease in neutrophil count from baseline to nadir by a simple E-max model (R -2 = 0.53). Logistic regression analysis indicated that AUC and the duratio n of exposure over 0.05 to 0.1 mu M, but not C-max were strong predictors o f grade 4 neutropenia (< 0.5 x 10(9)/l). Drug exposure parameters such as A UC derived from population analysis may be used clinically as a useful pred ictor of drug-induced neutropenia. (C) 2000 the American College of Clinica l Pharmacology.