Wan-Su Park (1), Jongtae Lee (1), Sangil Jeon (2), Taegon Hong (1), Seunghoon Han (1), Dong-Seok Yim (1)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary’s Hospital, (1) PIPET (Pharmacometrics Institute of Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul, Korea, (2)Clinical Trial Center, International St. Mary’s Hospital, Catholic Kwandong University, Incheon, Korea
Objectives: PET is a tool frequently used to characterize the PK-PD relationship of plasma drug concentration and receptor occupancy in the brain. However, both the number of subjects and PET scans per subject are limited due to its high cost and time-consuming scanning procedures. We tried to determine the effect of PET scanning time points on the reliability of PD parameter estimates and to identify the scanning time point design that gives the most reliable PD parameter estimates.
Methods: We compared the performance of designs with various sets of sampling time points using the stochastic simulation and estimation method in Perl-speaks-NONMEM. Biases, relative standard errors, relative estimation errors, and root mean square errors were used to compare the performance of designs.
Results: Unlike the results of a previous report [1-4], we found that rather complicated designs where each subject or group of subjects are allocated to different scanning time points were not superior to the simple, conventional fixed-time designs regardless of whether effect compartment or receptor binding models were used.
Conclusions: The conventional fixed-time designs that have been used so far may give robust PD parameter estimates for occupancy data obtained from human PET studies of CNS drugs.
References:
[1] Lim K, Kwon J, Jang I, et al. Modeling of brain D2 receptor occupancy-plasma concentration relationships with a novel antipsychotic, YKP1358, using serial PET scans in healthy volunteers. Clinical Pharmacology & Therapeutics. 2007;81(2): 252-258.
[2] Kim E, Howes OD, Kim B-H, et al. Predicting brain occupancy from plasma levels using PET: superiority of combining pharmacokinetics with pharmacodynamics while modeling the relationship. Journal of Cerebral Blood Flow & Metabolism. 2011;32(4): 759-768. 6.
[3] Johnson M, Kozielska M, Reddy VP, et al. Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of the Dopamine D2 Receptor Occupancy of Olanzapine in Rats. Pharmaceutical research. 2011;28(10): 2490-2504.
[4] Zamuner S, Di Iorio V, Nyberg J, et al. Adaptive-optimal design in PET occupancy studies. Clinical Pharmacology & Therapeutics. 2010;87(5): 563-571.
Reference: PAGE 24 (2015) Abstr 3497 [www.page-meeting.org/?abstract=3497]
Poster: Methodology - Study Design