Li Zhu, Malaz AbuTarif, Ming Zheng, Zubin Bhagwagar, Richard Bertz
Bristol-Myers Squibb, Princeton, NJ, USA
Objectives: To develop PK/PD models to characterize the exposure and heart rate (HR) relationship in a thorough QT (TQT) study for BMS-820836, a highly potent and selective triple monoamine reuptake inhibitor for treatment-resistant depression.
Methods: 24-hour ambulatory HR and time-matched PK data were obtained from a double blind, placebo and positive-controlled, parallel group TQT study in 172 healthy subjects. Four parallel groups included 2 BMS-820836 treatment groups (2 and 4 mg), and 2 nested-crossover groups of placebo and 400 mg moxifloxacin single dose. Steady-state PK of BMS-820836 was achieved following a 14-day up-titration scheme. The PK/PD models were developed sequentially. First the population PK model (PPK) was developed based on a pooled dataset that also included 5 additional Phase 1 studies. Individual post-hoc parameter estimates were obtained and were used in the subsequent modeling of HR response data. The non-linear mixed-effects modeling approach was used and estimation was done with the first order conditional estimation with the interaction option implemented in NONMEM V7.2 [1]. Inter-subject variability in the PPK model was described with an exponential function. The residual variability was described with a combined error model in the PPK model and an additive error model in the PD model.
Results: Plasma disposition of BMS-820836 within a dosing interval can be adequately described by a two-compartment model. Absorption was modeled with a zero-order release followed by first-order absorption process. Age, gender and baseline body weight were identified as statistically significant covariates for the PPK model. HR change from baseline was exposure dependent and was modeled with an indirect response model. The drug effect on HR was best described with the use of a stimulatory Emax function on the production rate parameter Km. Circadian rhythm in HR response was modeled with 2 periodic cosine functions. Placebo effect was incorporated in the model. Individual HR profiles and distribution of data were well captured for both dose groups as well as the placebo subjects. Simulations were performed to estimate HR effects expected with unstudied dosing regimens.
Conclusions: The PK/PD models adequately described the disposition of BMS-820836 and its effect on HR. The models provide a useful tool to inform further clinical assessment of the cardiovascular effects of the drug.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2013. Icon Development Solutions, Ellicott City, Maryland, USA.
Reference: PAGE 23 () Abstr 3206 [www.page-meeting.org/?abstract=3206]
Poster: Drug/Disease modeling - CNS