Table 7

List of compounds for which Full PBPK models were used to address pharmacological and toxicological questions

CompoundModel purposeA priori criteria?Model Quality AssessmentConclusionsCitation
AcetaminophenAssessing various calibration strategies for linking PBPK models to toxicodynamic models of hepatotoxicityNoQualitative discussion of the agreement between simulated and observed Cmax, and metabolite ratiosPredicted liver toxicity in agreement with observed(Péry et al., 2013)
CyclosporineSimulation of receptor occupancy in accute graft-versus-host organs and kidneys after intermittent or continuous infusionNoMann-Whitney test to compare means, chi-square test to compare proportions, bias and precision, number of simulations within 2-fold of the observed, weighted residualsA greater therapeutic index was predicted following continuous infusion(Gérard et al., 2010)
CyclosporineEstablish a connection between the likelihood and severity of graft-versus-host disease and cyclosporine exposures in circulation, graft-versus-host target organs and lymphoid tissuesNoStudent's t-test to compare means, chi-square test to compare proportions, Akaike information criterion for model selectionBlood cyclosporine levels can be used as an indicator of therapeutic efficacy(Gérard et al., 2011)
EfalizumabDevelop a PD linked PBPK model to predict efficacy of efalizumabYesObserved data within the predicted 5th and 95th centileThe model predicted the efficacy of efalizumab in treatment of psoriasis(Chetty et al., 2015)
FormamideEvaluate the relationship between dose and hepatic exposureNo40mg/day dose was proposed bases on a safety index(Yan et al., 2012)
LevofloxacinExploratory study to predict the extent of tissue exposure of levofloxacin in humans as a basis for future PK/PD work.YesFold error in PK parameters less than 2Levofloxacin penetrated well into tissues, including the liver kidneys and spleen(Zhu et al., 2015a)
MoxifloxacinSimulate tissue concentrations versus time in patients with intra-abdominal infectionsYesFold error in PK parameters less than 2Concentrations in intra-abdominal tissues were predicted to be higher than the minimum inhibitory concentration for common pathogens(Zhu et al., 2015b)
MoxifoxacinEvaluate the effect of macrophages on tissue concentrations of moxifloxacin to enhance understanding of the effects of disease on PK/PDNoSimulated concentration versus time profiles were evaluated for bias and precisionMacrophage concentrations are predicted to effect tissue concentration of moxifloxacin(Edginton et al., 2009)
NicotineDevelop a PBPK model to describe nicotine exposure and receptor binding in the brainNoQualitative discussion of the agreement of the predicted and observed dataPK/PD modeling allowed for prediction of nicotine receptor occupancy in the brain(Teeguarden et al., 2013)
“S1”Predicting brain extracellular fluid concentrations as a starting point for PK-PD modelingNoUnclear whether the PBPK model would accurately predict PD(Ball et al., 2014)
TemozolomidePD linked PBPK model for simulating the brain concentration of temozolomide and the levels DNA brain adductsNoPredictions were in close agreement with observed data and parameter estimates had low coefficients of variation(Ballesta et al., 2014)
ZidovudineModel intra-cellular concentrations of zidovudine in peripheral blood mononuclear cells and establish efficacy and toxicity following various dosing regimensNoPK features are well represented by the predictions100mg 4 times daily is predicted to be the safest and most efficacious dosing scheme(von Kleist and Huisinga, 2009)
Theoretical CompoundsProof of concept study to evaluate mechanisms for differences in unbound plasma and tissue concentrationsNoThis approach can be used to predict free tissue concentrations of various classes of drugs(Poulin, 2015)