title: 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.
authors.affiliation: Pharmacokinetics & Metabolism Division, CSIR-Central Drug Research Institute , Lucknow , India .
authors.forename: Swati
authors.initials: S
authors.lastname: Jaiswal
authors.forename: Abhisheak
authors.initials: A
authors.lastname: Sharma
authors.forename: Mahendra
authors.initials: M
authors.lastname: Shukla
authors.forename: Kalpesh
authors.initials: K
authors.lastname: Vaghasiya
authors.forename: Nagarjun
authors.initials: N
authors.lastname: Rangaraj
authors.forename: Jawahar
authors.initials: J
authors.lastname: Lal
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D010599:Pharmacokinetics; D051381:Rats; D055647:Rats, Transgenic
keywords: Animal models; chimeric; drug metabolizing enzymes; knockout; transgenic; transporters