Pharmaceutical researchers and regulators are increasingly aware of the influence that transporters have on the pharmacokinetics of drugs. These transporter mediated drug-drug interactions (DDIs) can precipitate adverse reactions in patients and as a result, safety guidelines across the United States, Europe and Japan have been updated to require safety assessments of DDIs in large scale clinical trials of pharmaceuticals.
Patient drug interactions related to hepatic organic anion-transporting polypeptides (OATPs) are of particular concern when evaluating statins. According to a recent article by Uchida, et al published in Drug Metabolism and Disposition, the systemic exposure of rosuvastatin, a drug widely used to treat elevated cholesterol levels, was “significantly increased by concomitant dosing with cyclosporine A, and commonly lower dosage of rosuvastatin is therefore required when administered with cyclosporine A” in a clinical environment.
Previously, in vivo animal model studies have been conducted to predict DDIs in humans, but the reality is that often times little correlation exists between preclinical murine outcomes and actual clinical outcomes in patients. To combat this, “knockout models lacking murine oatp isoforms and OATP-humanized transgenic mice have been developed” notes Uchida, et al; however, the pharmacokinetics may still be affected by other inherent murine transporters.
As such the researchers in this study examined the effectiveness of using PXB-mice (chimeric mice with humanized livers and high levels of human hepatocytes) to predict human DDIs between rosuvastatin and cyclosporine A. The “observed DDIs in vivo were considered to be reasonable,” according to Uchida, et al, and suggest that humanized liver mice such as PXB and TK-NOG mice could play an important role in drug discovery and the evaluation of DDIs in a preclinical setting.