Development of a population pharmacokinetics model and an R-Shiny simulation platform for moxifloxacin pharmacokinetics in non-human primates.

Assessment of potential liability of prolonged cardiac repolarization for a new drug is critical in drug research and development. Moxifloxacin is used as a positive control in well controlled in-vivo experiments to evaluate cardiac safety in preclinical species. A limited number of pharmacokinetic (PK) samples are collected in these experiments due to practical challenges, thus limiting the full utilization of extensive QT data collected every minute. Therefore, the objective of this work was to develop a population pharmacokinetics model of moxifloxacin in non-human primates (NHP) to enable concentration-QTc evaluation of all available telemetered ECG data. A user-friendly R Shiny simulation platform was developed which allows researchers to predict full PK profiles using limited PK data. A cardiovascular telemetry study was conducted in NHPs (n = 48, 50% females) with pharmacokinetic samples from 47 NHPs collected on 4 separate periods after an 80 mg/kg oral dose of moxifloxacin. Periods 1 (at 6 and 24 h on Day 3) and 2 (at 6 and 24 h on Day 10) had sparse PK samples and Periods 3 and 4 (Days 15 and 17) collected serial PK samples for 48 h post dose. Population PK modeling was performed using R package nlmixr2, R package rxode2 (Version 2.1.3) was used for simulations, and R Version 4.3.0 was used. The simulation platform was created using Shiny for R. Moxifloxacin PK in NHPs (body weight range: 2.83–6.67 kg) was best described with a one compartment, first-order absorption, and first-order elimination model. Between-subject variabilities were estimated for absorption rate (ka), clearance (CL), and volume (V) with a correlation between CL and V. Body weight (BW) was used to allometrically scale CL and V. BW was a covariate on ka; ka decreased with increase in BW. Fidelity of the model was confirmed using goodness of fit plots, visual predictive check, and parameters had an acceptable standard error. As only one dose level of moxifloxacin was used in modeling, PK data in literature at other dose levels (10, 30, 50, and 90 mg/kg) were overlaid on simulations to confirm dose-linearity and externally validate the PK model. An R Shiny simulation platform was developed that simulates the PK profiles of moxifloxacin after oral dosing. In addition, users can input sparse PK data in the simulation platform to generate a full PK profile for the NHP based on estimated post-hoc PK parameters. In summary a comprehensive population PK model to describe moxifloxacin PK in NHPs was developed and validated against published data not used in the model development. A user-friendly R Shiny simulation platform implemented the developed model to allow users to generate full PK profiles.