Abstract
Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can serve as a powerful framework for predicting the influence as well as the interaction of formulation, genetic polymorphism and co-medication on the pharmacokinetics and pharmacodynamics of drug substances. In this study, flurbiprofen, a potent non-steroid anti-inflammatory drug, was chosen as a model drug. Flurbiprofen has absolute bioavailability of ~95% and linear pharmacokinetics in the dose range of 50–300 mg. Its absorption is considered variable and complex, often associated with double peak phenomena, and its pharmacokinetics are characterized by high inter-subject variability, mainly due to its metabolism by the polymorphic CYP2C9 (fmCYP2C9 ≥ 0.71). In this study, by leveraging in vitro, in silico and in vivo data, an integrated PBPK/PD model with mechanistic absorption was developed and evaluated against clinical data from PK, PD, drug-drug and gene-drug interaction studies. The PBPK model successfully predicted (within 2-fold) 36 out of 38 observed concentration-time profiles of flurbiprofen as well as the CYP2C9 genetic effects after administration of different intravenous and oral dosage forms over a dose range of 40–300 mg in both Caucasian and Chinese healthy volunteers. All model predictions for Cmax, AUCinf and CL/F were within two-fold of their respective mean or geometric mean values, while 90% of the predictions of Cmax, 81% of the predictions of AUCinf and 74% of the predictions of Cl/F were within 1.25 fold. In addition, the drug-drug and drug-gene interactions were predicted within 1.5-fold of the observed interaction ratios (AUC, Cmax ratios). The validated PBPK model was further expanded by linking it to an inhibitory Emax model describing the analgesic efficacy of flurbiprofen and applying it to explore the effect of formulation and genetic polymorphisms on the onset and duration of pain relief. This comprehensive PBPK/PD analysis, along with a detailed translational biopharmaceutic framework including appropriately designed biorelevant in vitro experiments and in vitro-in vivo extrapolation, provided mechanistic insight on the impact of formulation and genetic variations, two major determinants of the population variability, on the PK/PD of flurbiprofen. Clinically relevant specifications and potential dose adjustments were also proposed. Overall, the present work highlights the value of a translational PBPK/PD approach, tailored to target populations and genotypes, as an approach towards achieving personalized medicine.
Highlights
Intrinsic and extrinsic patient factors (IEFs) such as dosage form, co-medication, and genetic polymorphism may significantly impact drug exposure and subsequently lead to changes in the efficacy or safety of a drug
The validated physiologically based pharmacokinetic (PBPK) model was further expanded by linking it to an inhibitory Emax model describing the analgesic efficacy of flurbiprofen and applying it to explore the effect of formulation and genetic polymorphisms on the onset and duration of pain relief
The reduction is even more pronounced in the fasted state biorelevant media due to their lower buffer capacity (5.6 mmol/L/∆pH in fasted state-simulated intestinal fluids (FaSSIF) V3 versus 18.5 mmol/L/∆pH in European Pharmacopoeia phosphate buffers) [24]. Such a behavior was not observed for the Fasted state-simulated gastric fluid (FaSSGF) Level I and III, the acetate buffer, and the FeSSIF Level I, where the respective pH change was limited to 0.1 pH unit
Summary
Intrinsic and extrinsic patient factors (IEFs) such as dosage form, co-medication, and genetic polymorphism may significantly impact drug exposure and subsequently lead to changes in the efficacy or safety of a drug. The ability to quantify such factors on the exposure and pharmacologic action of a drug would represent a milestone in determining required dose adjustments and implementation of risk management strategies. FLU is entirely absorbed from the small intestine with a fraction absorbed (fa) typically greater than 95%, while its absolute bioavailability ranges between 92% and 96% [1]. Even though it is almost completely absorbed, the intestinal absorption of FLU is considered complex and variable, since it is often associated with double peak phenomena and high inter-individual variability in plasma concentrations (up to 80–100%) [1,2,3]. Further type II biotransformation reactions, such as glucuronidation, are mediated through UGT2B7 and UGT1A9
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