Population pharmacokinetics of cutamesine in rats using NONMEM, C-11-SA4503, and microPET

Cutamesine (SA4503) is a selective sigma-1 receptor agonist, currently in Phase II clinical trials for depression and post stroke neurological disturbances. Cutamesine has been found to be effective in several rodent models of amnesia and depression. We used data obtained with carbon-11-labeled cutamesine (11CSA4503) in rats to develop a population pharmacokinetic (PK) model. Nonlinear mixed effects modeling (NONMEM) provides a tool for analyzing repeated measurements data in which the relationship between the explanatory and response variables can be modeled as a single function, allowing the parameters to differ between individuals. This modeling framework can be useful to scale preclinical drug kinetic information to clinical settings. METHODS: MicroPET scans of the brain region of male Wistar Hannover rats (age 1.5-32 months) were made and11C-SA4503 time-activity curves were obtained for the entire brain, A femoral artery cannula was used for blood sampling, and metabolite-corrected plasma time-activity curves were obtained. The PK model using NONMEM was constructed in two steps. In the first step, one-, two- or three-compartment PK models were explored to describe the plasma time course. In the second step, the model was extended to include brain11C-SA4503 time course data, while allowing brain distribution to influence plasma PK and vice versa. Bootstrap resampling (n=1000) technique was used as a model evaluation tool. The effects of covariates (age, weight, presence or absence of pituitary tumors) on PK parameters will be investigated for the final model. RESULTS: Plasma PK was best described by a twocompartment model. When brain PK was included, a three-compartment model performed best. The three compartments were: a central compartment (plasma) and two brain compartments (free and bound). Population PK parameters (relative standard error), not accounting for covariates are: central clearance (CL) 17.4 ml min-1(13%), central volume of distribution (VC) 25.3 ml (23%), brain volume of distribution (Vbr) 84.9 ml (23%), clearance into brain (Qin) 61.8 ml min-1(12%), clearance out of brain (Qout) 14.4 ml min-1(38%), clearance into bound compartment (Qon) 5.83 ml min-1(27%), clearance out of bound compartment (Qoff) 1.55 ml min-1(4%). Population estimates of the model are in close agreement with the median values of successful bootstrap replicates. CONCLUSION: Population PK modelling can be used successfully to analyze PET data of11C-labeled cutamesine.