Parameterization of a physiologically-based pharmacokinetic (PBPK) model for the simulation of ibuprofen pharmacokinetics under exercise and heat stress with validation from clinical data
A. Edginton (1), C. Boscarino (2), P. Sidhu (1), W. Riggs (3), A. Szeitz (3), B. Cheung (2), H. Peng (2)
(1) School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada; (2) Defence Research and Development Canada, Toronto, Canada; (3) Pharmaceutics and Biopharmaceutics, The University of British Columbia, Vancouver, British Columbia
Objectives: Military personnel in areas such as the Middle East are subject to heat and exercise stress. The need for altered dosing of medications in this sub-population may be required to maintain therapeutic plasma concentrations. This study aims to parameterize a physiologically-based pharmacokinetic (PBPK) model using ibuprofen as a proof-of-concept allowing for changes in physiological parameters associated with operational stresses using clinical data for model evaluation.
Methods: PBPK models for R- and S-ibuprofen were built using PK-Sim®. Model coupling in MoBi® allowed for the R- to S-ibuprofen chiral inversion to be described. Literature information on the physiological changes associated with heat and exercise stress were incorporated to simulate these conditions. These included changes in cardiac output, hematocrit, organ-specific blood flows and albumin concentrations. A prospective pharmacokinetic clinical trial was completed by DRDC where volunteers were subjected to exercise (15 minute walk, 5 minute rest for 2.5 hours at 42oC followed by 6 hours at 42oC) following per oral administration of 400 mg racemic ibuprofen. R- and S-ibuprofen plasma concentrations were determined by UPLC/MS/MS. Thus far, simulated pharmacokinetic profiles generated from the PBPK model were tested against the clinical data from the pilot study to evaluate changes in relevant pharmacokinetic parameters such as R- and S-ibuprofen half-life and area under the plasma concentration vs. time profile.
Results: 4 volunteers completed the pilot study and contributed 47 ibuprofen concentrations. Half-life [mean (CV%); S-IBU 2.1 (4) h, R-IBU 2.5 (32) h] and AUCt_end [S-IBU 2912 (18) mg*min/L, R-IBU 1099 (26) mg*min/L] were obtained. Ibuprofen pharmacokinetics in the volunteers was similar to that from non-stressed individuals in the literature. The PBPK model altered for operational stress (e.g. reduced portal flow, increased muscle and skin flow, increased hematocrit) echoed results from the clinical trial simulating no changes in ibuprofen pharmacokinetics.
Conclusion: A PBPK model parameterized to simulate changes in drug pharmacokinetics under operational stress echoed the results from the pilot clinical trial such that ibuprofen pharmacokinetics were consistent with non-stress individuals from the literature. A full scale trial is ongoing using each volunteer as their own control (non-stress arm) to further elucidate potential drug pharmacokinetic changes and to provide data for model evaluation. The model will also be used to focus resources with respect to future clinical trials to rank those commonly used drugs in the field that have the greatest chance of requiring dose adjustment.
