Levasseur L., Byrd J., Binet J-L., Bron D., Flinn I., Johnson S., Petric R., Déglise-Favre A., Suarez J-R., Grever M.
Quintiles Inc, MO. Walter Reed Army Medical Center, DC. Hôpital de la Salpétrière, France. Institut Jules Bordet, Belgium. Johns Hopkins Hospital, MD. Taunton & Somerset Hospital, UK. Aventis, NJ. Aventis, France. Ohio State University, OH.
HMR1275 is a synthetic flavone inhibitor of cyclin-dependent kinases that induces apoptosis in vitro in human chronic lymphocytic leukemia (CLL) cells. The population pharmacokinetics (PK) of HMR1275 administered as a 24-hr intravenous infusion every two weeks at doses ranging between 80 and 140 mg/m2 was investigated during two phase II clinical trials. A total of 575 plasma samples were collected from 69 fludarabine-refractory or intolerant CLL patients at cycles 1, 5, 9 and 12, and analyzed for total plasma HMR1275 concentrations by liquid chromatography-tandem mass spectrometry with detection limit of 5 ng/mL. From these, 543 plasma samples (94%) were used in the non-linear mixed effects modeling (NONMEM). The best structural PK model was a two-compartment model. The random effects were defined by an unstructured 2×2 covariance matrix with elements for clearance (CL) and central compartment volume (Vc) modeled assuming a log-normal distribution. Residual errors were proportionally distributed. Body surface area (BSA) was found to affect the elimination of HMR1275 in CLL patients. The relation, a linear function centered on median BSA (1.93 m2), predicted a 2.6-fold increase in CL from 12.6 to 33.1 L/hr over the range of BSA values observed in the study population (1.4 – 2.4 m2). Bayesian PK parameter estimates were 24.4±9.3 L/hr for CL, 386±51 L for the steady-state volume of distribution, 2.1±0.9 hr for the half-life of distribution, and 25.7±6.2 hr for the half-life of elimination. Information gained from this population PK model, along with in vitro cytotoxicity data, were used in the simulation of alternative dosing strategies that may potentially enhance the clinical efficacy of HMR1275.
Reference: PAGE 10 (2001) Abstr 208 [www.page-meeting.org/?abstract=208]
Poster: poster