Modeling and Simulation of Drug X and its Metabolite in Plasma and Urine
Mary Lor(1), Jean R. Lavigne(1)
(1)Clinical Pharmacology Department, Celerion, Montreal, Qc, Canada
Objective: To construct a pharmacokinetic (PK) model using plasma and urine data from healthy subjects to characterize the PK of Drug X and its metabolite.
Methods: Single ascending oral doses of Drug X were administered to 3 groups (n=30) over 2 periods. Plasma and urine samples were collected over 72 hours. Concentrations of Drug X and its metabolite were analyzed using a validated LC/MS/MS method. Different models were developed and tested using ADAPT II1 and a population analysis was performed using IT2S2. Simulations were performed to determine the length of time that a given plasma concentration was maintained following daily oral drug administration.
Results: The structural PK model that best characterized the PK of Drug X was a 2 compartment model with 2 absorption peaks; each associated with a lag time and a 1st order absorption rate constant. The best model selected for the metabolite concentrations was a 1 compartment model. Drug X was eliminated in urine, converted to the metabolite and eliminated by other pathways while the metabolite was eliminated in urine and other pathways. All eliminations were non-linear. Many subjects exhibited multiple peaks in the plasma concentration-time profiles which were most likely due to intra-subject variability in the absorption of Drug X from the gastrointestinal tract. In order to provide an adequate description of the observed data, the final PK model was integrated with 2 absorption rates and 2 delay constants.
Conclusion: Drug X was best described by a 2 compartment model with 2 absorption rates; each associated with a lag time and a 1st order absorption rate constant while the metabolite was best described by a 1 compartment model. Drug X and its metabolite both exhibit non-linear elimination. Clearance of Drug X appeared to be predominately non‑renal in nature. The elimination t½ increased with increasing dose.
References:
1. D'Argenio DZ, Schumitzky A. ADAPT-II Users Manual. Biomedical Simulations Resource, University of Southern California, Los Angeles, 1997.
2. Collins DG, Forrest A. IT2S User's Guide. State University of New York at Buffalo, Buffalo: 1995.
