Simultaneous Population Pharmacokinetic Modelling of Parent Compound and Metabolite in Plasma and Urine for a New Drug Candidate
J. Areberg, L.E. Broksø Kyhl
Dep. Clinical Pharmacology & PK, H. Lundbeck A/S, Denmark
Objectives: To construct a model that could describe the population pharmacokinetics of a potential drug candidate. Since the major metabolite apparently peaked earlier than the parent compound for many of the subjects, special attention was on the absorption of the parent compound and the metabolite.
Methods: Rich plasma concentration profiles for parent compound and the major metabolite for a new drug candidate from 113 healthy subjects (77 men, 36 women, age range [18,77]) were available. In addition, the amount of the parent compound and the major metabolite had been measured in urine for 67 of the 113 subjects. Population pharmacokinetic modelling was performed by means of non-linear mixed effect methods using the software NONMEM, version VI (Globomax). Plasma and urine data for both parent compound and metabolite were modelled simultaneously using own defined differential equations in NONMEM (ADVAN6 TRANS1).
Results: The final model consisted of 8 compartments: gastrointestinal for parent compound (1,dosing compartment), gastrointestinal for metabolite (2), central (3,5) and peripheral (4,6) for both parent compound and metabolite and urine for both parent compound (7) and metabolite (8). All transfers were described with first-order processes. A transfer directly from the gastrointestinal compartment for the parent compound to the gastrointestinal compartment for the metabolite was essential to be included in order to describe earlier plasma peaks for the metabolite. Inter-subject variability was modelled with exponential terms while a proportional error model was used for plasma data and a combined additive and proportional error model was used for urine data.
Conclusion: A model was created that adequately describe the population pharmacokinetics of the parent compound and the major metabolite for a new drug candidate. The model indicates that the parent compound undergoes gastrointestinal metabolism, which can explain the observation that the major metabolite in many cases apparently peaks before the parent compound