Table 5.

Summary of remaining technical challenges and knowledge gaps for applying PBPK modeling and simulation in drug development

Area of PBPK application	Specific purpose	PK characterization	Knowledge gaps
DDI involving enzymes	Drug as victim	For enzymes expressed in multiple sites (liver, intestine, kidney), difficult to assess in vivo contribution of each site to metabolism. For example, in the absence of i.v. PK data for poorly soluble compounds, Fg cannot be estimated. When multiple enzymes metabolize a compound, mass balance studies may not differentiate between the enzymes. The requirement of in vivo DDI studies for each enzyme is difficult to justify.	Abundance data for non‐ CYP mechanisms Sufficient clinical datasets for qualification of non‐CYP3A mechanisms
	Drug as perpetrator	The selection of an appropriate range for sensitivity analysis to cover the uncertainty in the in vitro data (Ki, KI, kinact, EC50 and Emax) is key to ensuring a realistic assessment of DDI.	Sufficient clinical datasets for qualification of non‐CYP3A mechanisms IVIVE for non‐CYP mechanisms
DDI involving transporters	Drug as victim	Similar to those presented above for ‘Drug as victim’ of enzyme inhibition. In addition, it is difficult to determine the relative contribution of transporter in vivo vs. enzyme to elimination of the drug.	IVIVE and scaling factors
	Drug as perpetrator	Similar to those presented above for ‘Drug as perpetrator’ of enzyme inhibition.	Sufficient clinical datasets for qualification
Extrapolation from healthy to other populations	Pediatrics, Elderly, Obese Ethnic bridging/ pharmacogenetics Organ impairment	Mechanistic understanding of PK in base population may be challenged by lack of i.v. data. When multiple enzymes/transporters are involved in the elimination of drug, it is difficult to determine the relative contribution of each protein to elimination of the drug.	Knowledge of any additional pathways or compensatory mechanisms, not observed in base population. Difficult to verify in vivo relevance of enzyme and transporter abundance, ISEFs and pharmacogenetic data for different enzymes.
Absorption/ formulation related	Food‐drug interactions	Quantitative assessment of fraction absorbed and contributing mechanisms non‐identifiable, in the absence of i.v. data for poorly soluble compounds, when Fg and Fh cannot be estimated.	IVIVE and IVIVC for BCS II and IV drugs