Novel pre-clinical methodologies for pharmacokinetic drug–drug interaction studies: spotlight on “humanized” animal models

Abstract

Poly-therapy is common due to co-occurrence of several ailments in patients, leading to the elevated possibility of drug-drug interactions (DDI). Pharmacokinetic DDI often accounts for severe adverse drug reactions in patients resulting in withdrawal of drug from the market. Hence, the prediction of DDI is necessary at pre-clinical stage of drug development. Several human tissue and cell line-based in vitro systems are routinely used for screening metabolic and transporter pathways of investigational drugs and for predicting their clinical DDI potentials. However, ample constraints are associated with the in vitro systems and sometimes in vitro-in vivo extrapolation (IVIVE) fail to assess the risk of DDI in clinic. In vitro-in vivo correlation model in animals combined with human in vitro studies may be helpful in better prediction of clinical outcome. Native animal models vary remarkably from humans in drug metabolizing enzymes and transporters, hence, the interpretation of results from animal DDI studies is difficult. With the advent of modern molecular biology and engineering tools, novel pre-clinical animal models, namely, knockout rat/mouse, transgenic rat/mouse with humanized drug metabolizing enzymes and/or transporters and chimeric rat/mouse with humanized liver are developed. These models nearly simulate human-like drug metabolism and help to validate the in vivo relevance of the in vitro human DDI data. This review briefly discusses the application of such novel pre-clinical models for screening various type of DDI along with their advantages and limitations.

Comparative Pharmacokinetics of Mitragynine after Oral Administration of Mitragyna speciosa (Kratom) Leaf Extracts in Rats

“…The absolute oral bioavailability of mitragynine was 17.0, 25.1, and 31.2 % for mitragynine hydrochloride, LKT, and the LKT organic fraction, respectively. Multiple factors might be responsible for the increased mitragynine exposure when the animals were dosed with the LKT and the LKT organic fraction compared to the mitragynine hydrochloride dose alone, including the possible presence of permeability/solubility enhancers, cytochrome P450 (CYP450) enzyme inhibitors, and/or gastrointestinal motility inhibitors in LKT and the LKT organic fraction [22]. Based on the results listed above, we found that the LKT organic fraction (methanol : ethyl acetate, 50 : 50, %v/v) or the LKT itself provided significantly better oral exposure of mitragynine than mitragynine hydrochloride alone.…”

“…However, this study was able to provide significant insight into the differences in the bioavailability of the traditional preparations, specifically the brewed tea, and the formulated preparations that are available commercially. Even though rats and humans have significantly different expressions of drug metabolizing enzymes and transporters, there are similarities in the gastrointestinal tract and absorption [22]. Pharmacokinetic studies in rats can provide baseline data, which can be allometrically scaled for clinical predictions.…”

Functional Integrity of the Chimeric (Humanized) Mouse Liver: Enzyme Zonation, Physiologic Spaces, and Hepatic Enzymes and Transporters

“…For human drug metabolism, the model facilitates the administration of metabolites that are identified as culprits of toxicity/activity, as required in new drugdiscovery processes. The preparation serves as useful preclinical tools for drug-drug interactions (Jaiswal et al, 2014), and for drug-induced liver injury (DILI) studies on troglitazone (Barnes et al, 2014;Samuelsson et al, 2014), bosentin (Xu et al, 2015), and fialuridine (Xu et al, 2014).…”

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

“…These mice respond to selective induction of ligands for humanspecific nuclear receptors (Katoh et al, 2005a;Emoto et al, 2008;Sanoh and Ohta, 2014). In addition, h-chimeric liver mouse models have been used to study preclinical drugdrug interactions (Jaiswal et al, 2014) and drug-induced liver injury stemming from troglitazone (Barnes et al, 2014;Samuelsson et al, 2014), bosentan (Xu et al, 2015), and fialuridine (Xu et al, 2014), and have provided an essential in vivo safety testing tool for potential human toxic metabolites (Strom et al, 2010;Cohen, 2014;Kitamura and Sugihara, 2014;Xu et al, 2015).…”