Candice Jamois (1), Vishak Subramoney (2), Eric Snoeck (3) and Valérie Cosson (1)
(1) Modeling and Simulation group, Pharma Research and Early Development,
Objectives: To develop a population pharmacokinetic-receptor occupancy (PKRO) model describing the relationship between receptor occupancy (RO) in a defined region of interest in brain and drug X plasma concentrations in healthy volunteers to support Phase 2 dose selection by simulating the expected receptor occupancy at steady-state.
Methods: Rich PK profiles from the SAD and MAD studies were used to characterize the PK of Drug X in 96 healthy volunteers. Sparse PET measurements collected in 36 subjects in two PET studies were used to investigate the relationship between drug X plasma concentrations and RO following single and multiple doses.
Non-linear mixed effect approach, using NONMEM 7, was used to characterize the pharmacokinetics (PK) and the exposure-RO relationships of Drug X. PK and PD data were modeled sequentially. After qualification of the models, simulations were performed to illustrate in a large population the expected RO after given doses at steady-state, 24 h post dose, as well as the percentage of subjects above defined thresholds of RO.
Results: PK profile of drug X was accurately described by a one-compartment disposition PK model with first-order elimination and a saturable capacity limited binding. The absorption was described by a sequential zero and first-order process. The PKRO was modeled with a slowly reversible receptor binding model. To support the phase 2 dose rationale, RO were simulated following treatment with several doses of Drug X, until PK steady-state. Based on the results of those simulations, one top dose with maximum RO, one dose with maximal RO in approximately 50% of the simulated subjects and one dose with lower RO were proposed. Among the large simulated population, the maximal RO and the percentages of subjects with RO above thresholds ranging from 40 to 80% were impacting the choice of dose for Phase 2.
Conclusion: In the absence of information on RO differences between healthy volunteers and patients, and on the relationship between RO and clinical endpoints, the modeling of RO in healthy volunteers together with assumption on the level of occupancy required to obtain clinical efficacy is still a valuable tool to support phase 2 dose selection. The population PKRO model will be re-evaluated with upcoming data in patients. Data from the phase 2 study will allow the characterization of the link between target RO and clinical efficacy.
References:
[1] US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research Guidance for Industry: population pharmacokinetics. US Department of Health and Human Services Web site: 1-35.
[2] Beal S, Sheiner L. NONMEM User Guides. In: NONMEM Project Group. University of California at San Francisco: San Francisco; 1992.
[3] Jusko. Pharmacokinetics of capacity limited system. J of Clin. Pharmacol., 1989; 29: 488-493.
[4] Levy G. Pharmacologic target-mediated drug disposition. Clin Pharmacol Ther., 1994; 56 (3) 248-252.
[5] Mager D. Target mediated drug disposition and dynamics. Biochem Pharmacol., 2006; 72 (1):1-10.
Reference: PAGE 21 (2012) Abstr 2541 [www.page-meeting.org/?abstract=2541]
Poster: CNS