Table 6.

Physiologically based mathematical models to assess transporter induction or suppression ^a

Application (transporter/location)	Substrate	Inducer/suppressor	Advantages	Limitations	Reference
Empirical model
Intestinal P‐gp Hepatic OATP	Dabigatran Pravastatin Rosuvastatin Midazolam Tolbutamide Caffeine	Rifampin	Matrix of PXR compounds Simple (no additional model and physiology data are needed)	Each additional compound to the matrix brings it's own uncertainties, however, this limitation will change to an advantage the more compounds can be successfully estimated and therefore included in the matrix	108
Intestinal P‐gp Hepatic OATP	Sofosbuvir	Rifabutin Carbamazepine	Matrix of PXR compounds Simple (no additional model and physiology data are needed) The application of an established matrix. Any compound that is correctly predicted can be added to the initial matrix	Same as above	109
REF or RAF scaling within an IVIVE‐PBPK framework
Intestinal (and hepatic) P‐gp	Digoxin	Rifampin	Simple Use of apparent Km/Jmax from Caco‐2	An expected maximum fold‐change in vivo needs to be generated; in this case, the value was from in vivo biopsies. This is not a generally available parameter. However, there are some in vitro systems that reported comparable fold‐change (e.g., hepatocytes, LS180, and LS174T cells) The concentration‐dependent induction/suppression course is not included in the model	111
Intestinal P‐gp	Dabigatran etexilate Digoxin Quinidine Talinolol	Rifampin	Simple Used in vitro modeled transporter kinetic data (Km, Jmax and/or CL) values	Same as above	112
Intestinal P‐gp	Abemaciclib Acalabrutinib Bosutinib Crizotinib Dabigatran etexilate Digoxin Naldemedine Naloxegol Olaparib Quinidine Talinolol Verapamil	Rifampin	Simple Used in vitro modeled transporter kinetic data (Km, Jmax and/or CL) values	Same as above The more compounds that can be correctly estimated with the same REF, the higher the confidence in this system parameter	113
Hepatic OATP1B1	CP‐I	Rifampin; OATP1B1 521CC polymorphism	Use of sensitive biomarker levels in plasma and urine data Main route of elimination via OATP1B transport (> 85%) Circadian rhythm or food intake are not likely to cause interindividual variability in plasma CP‐I baseline	Endogenous factors like MRP2 mutations, hemogenesis triggered by anemia or hemolysis, may alter CP‐I baseline Reduced CP‐I synthesis in women has been reported Limited information on synthesis and turnover of CP‐I, factors influencing baseline	148, 149
Turnover model within an IVIVE‐PBPK model
Hepatic OATP1B, MRP2	Glibenclamide Repaglinide CP‐I	Rifampin	This PBPK model incorporated induction of OATP1B and CYP2C8 and inhibition of MRP2 CP‐I DDI used to obtain rifampin inhibition parameter data	Model not accessible to everyone due to program used ‐ low practicality	67
Hepatic OATP1B1	Repaglinide	Rifampin	Using the transporter induction turnover model, DDIs could be recovered reasonably well when an OATP1B1 induction Indmax value (2.3) and a kdeg for OATP1B1 of 0.0311/h was included for rifampin in simulations across a range of dosing regimens	Further investigations and data are required to assess the validity of the derived rifampin in vitro OATP1B1 Indmax value (i.e., using different rifampin doses and OATP1B1 substrates) and whether inclusion of an IndC50 value would reduce the overpredictions OATP1B1 is a polymorphic transporter and no genotype information was available from the clinical studies. Thus, understanding the effect of polymorphisms was not assessed in this investigation and may contribute to some of the variability observed due to the small sample size of the clinical studies	(SN, Personal communication)
Intestinal P‐gp	Digoxin Dabigatran etexilate	Rifampin	Measured values of P‐gp turnover were incorporated into a semi‐mechanistic physiological model to simulate the clinical impact of intestinal P‐gp induction by rifampin in humans The DDIs were best recovered across a range of rifampin doses using an IndC50 = 0.25 µM and Indmax = 5.6	Although these preliminary results are encouraging, the model needs to be verified against other clinical studies with different rifampin doses to confirm the utility of the model	(SN, Personal communication)
QSP
Hepatic OATP1B1 and P‐gp	Diclofenac Celecoxib	Rifampin	Changes in hepatic OATP1B1 and P‐gp can be included in the model	Transporter alterations have not been evaluated in the models for diclofenac and celecoxib	150

^a Caco‐2, human colorectal adenocarcinoma cell; CL, clearance; CP‐1, coproporphyrin I; CYP, cytochrome P450; DDI, drug‐drug interaction; IndC₅₀, test compound concentration that supports half‐maximal induction/suppression; Ind_max, maximum fold induction/suppression over vehicle control; IVIVE‐PBPK, in vitro‐to‐in vivo extrapolation linked physiologically based pharmacokinetics; J_max, maximum rate of transport; k_deg,, rate of degradation, defined by a first‐order rate constant; Km, Michaelis constant; MRP, multidrug resistance‐associated protein; OATP, organic anion transporting polypeptide; PBPK, physiologically based pharmacokinetics; P‐gp, MDR1 P‐glycoprotein; PXR, pregnane X receptor; QSP, quantitative systems pharmacology; RAF, relative activity factor; REF, relative expression factor.