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RESEARCH PRODUCT

IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes

Adam DarwichLeon AaronsAleksandra GaletinAmin Rostami-hochaghan Et AlAlison MargolskeeXavier PepinSara CarlertMaria HammarbergConstanze HilgendorfPernilla JohanssonEva KarlssonDonal MurphyChrister TannergrenHelena ThornMohammed YasinFlorent MazuirOlivier NicolasSergej RamusovicChristine XuShriram PathakTimo KorjamoJohanna LaruJussi MalkkiSari PappinenJohanna TuunainenJennifer DressmanSimone HansmannEdmund S. KostewiczHandan HeTycho HeimbachFan WuCarolin HoftYan PangMichael BolgerEva HuehnTycho HeimbachFan WuCarolin HoftYan PangMichael B. BolgerEva HuehnViera LukacovaJames M. MullinKe X. SzetoChester CostalesJian LinMark McallisterSweta ModiCharles RotterManthena VarmaMei WongAmitava MitraJan BevernageJeike BiewengaAchiel Van PeerRichard LloydCarole ShardlowPeter LangguthIrina MishenzonMai Anh NguyenJonathan BrownHans LenneransBertil Abrahmsson

subject

Physiologically based pharmacokinetic modellingIn silicoDrug Evaluation PreclinicalAdministration OralPharmaceutical Science02 engineering and technologyPharmacologyModels Biological030226 pharmacology & pharmacyBiopharmaceutics03 medical and health sciences0302 clinical medicineLow permeabilityHumansComputer SimulationChemistryBiopharmaceutics021001 nanoscience & nanotechnologyBioavailabilityIntestinal AbsorptionPharmaceutical PreparationsColonic absorptionSystem parametersIntestinal surfaceBiochemical engineering0210 nano-technologyForecasting

description

Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp® Simulator, and GastroPlus™) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded “bottom-up” anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (Foral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foral was also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. Foral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data.However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data “as is” in this blinded bottom-up prediction approach.

10.1016/j.ejps.2016.09.037https://pure.manchester.ac.uk/ws/files/46273976/Darwich_2016_IMI_ORBITO_3.pdf