1521-009X/46/5/485–492$35.00 https://doi.org/10.1124/dmd.117.079624 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 46:485–492, May 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Apixaban and Rosuvastatin Pharmacokinetics in Nonalcoholic Fatty Liver Disease Rommel G. Tirona, Zahra Kassam, Ruth Strapp, Mala Ramu, Catherine Zhu, Melissa Liu, Ute I. Schwarz, Richard B. Kim, Bandar Al-Judaibi, and Melanie D. Beaton Department of Physiology and Pharmacology (R.G.T., C.Z., U.I.S, R.B.K.), Division of Clinical Pharmacology, Department of Medicine (R.G.T., C.Z., M.L., U.I.S., R.B.K.), Department of Medical Imaging (Z.K.), Division of Gastroenterology, Department of Medicine (B.A.-J., M.D.B.), and Lawson Health Research Institute (R.G.T., Z.K., R.S., M.R., U.I.S., R.B.K., M.D.B.), University of Western Ontario, London, Ontario, Canada; and Department of Medicine, University of Rochester, Rochester, New York (B.A.-J.) Received November 23, 2017; accepted February 19, 2018 ABSTRACT There is little known about the impact of nonalcoholic fatty liver disease (NAFLD) on drug metabolism and transport. We examined the pharmacokinetics of oral apixaban (2.5 mg) and rosuvastatin (5 mg) when administered simultaneously in subjects with magnetic resonance imaging–confirmed NAFLD (N = 22) and healthy control subjects (N = 12). The area under the concentration-time curve to the last sampling time (AUC 0–12 ) values for apixaban were not different between control and NAFLD subjects (671 and 545 ng/ml 3 hour, respectively; P = 0.15). Similarly, the AUC 0–12 values for rosuvastatin did not differ between the control and NAFLD groups (25.4 and 20.1 ng/ml 3 hour, respectively; P = 0.28). Furthermore, hepatic fibrosis in NAFLD subjects was not associated with differences in apixaban or rosuvastatin pharmacokinetics. Decreased systemic exposures for both apixaban and rosuvastatin were associated with increased body weight (P < 0.001 and P < 0.05, respectively). In multivariable linear regression analyses, only participant weight but not NAFLD, age, or SLCO1B1/ABCG2/CYP3A5 genotypes, was associated with apixaban and rosuvastatin AUC 0–12 (P < 0.001 and P = 0.06, respectively). NAFLD does not appear to affect the pharmacokinetics of apixaban or rosuvastatin. Introduction Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, affecting approximately 30% of adult North Americans (Sayiner et al., 2016). It is defined by hepatic steatosis, in the absence of significant alcohol consumption and other causes of hepatic fat accumulation (Ludwig et al., 1980). NAFLD encompasses both simple steatosis and nonalcoholic steatohepatitis (NASH), the latter being a more advanced stage of the disease involving liver inflammation, hepatocyte ballooning, and ultimately progressing to fibrosis (Brunt et al., 2011). NASH fibrosis is of particular concern as it is associated with increased liver-related and overall mortality (Dulai et al., 2017). There are no currently approved medications to treat NASH. Current disease management involves lifestyle modification and pharmacother- apies for common comorbidities such as hypertension, diabetes, and dyslipidemia (Rinella and Sanyal, 2016). A number of pharmacologic agents for NASH are being studied in clinical trials that aim to reverse the histologic features of the disease, particularly fibrosis (Rotman and Sanyal, 2017). Despite the wide prevalence of NAFLD, it is remarkable that relatively little is known regarding how this disease influences drug disposition in humans. Few studies have evaluated the pharmacokinetics of drugs in NAFLD. In one study, antipyrine metabolic clearance was found to be reduced in NASH (Fiatarone et al., 1991), indicating lower overall cytochrome P450 (P450) activity for the drug that is metabolized by multiple P450 isoenzymes (Engel et al., 1996). With respect to changes to particular P450 enzymes, it has been compellingly estab- lished that in vivo hepatic CYP2E1 activity is increased in NASH, as revealed by chlorzoxazone phenotyping (Emery et al., 2003; Orellana et al., 2006). In addition, we demonstrated that CYP3A activity is decreased in NAFLD using a combination of oral midazolam phenotyp- ing and measurement of plasma 4b-hydroxycholesterol (4bHC), an endogenous metabolic biomarker (Woolsey et al., 2015). This reduced in vivo CYP3A activity in NAFLD was recently confirmed using a translational systems pharmacology approach (Krauss et al., 2017). Last, there are now several studies demonstrating that the systemic exposure of glucuronide metabolites of drugs, namely acetaminophen and morphine, are increased in NASH (Barshop et al., 2011; Canet et al., 2015; Ferslew et al., 2015). These findings were attributed to increased hepatocyte basolateral membrane expression of multidrug resistance protein (MRP) 3 and hepatocellular internalization of canalicular MRP2 (Hardwick et al., 2011; Canet et al., 2015). Taken together, there remains This work was supported by the Canadian Institutes of Health Research [Grant MOP-136909]. https://doi.org/10.1124/dmd.117.079624. ABBREVIATIONS: A, apical; AUC, area under the plasma concentration-time curve; AUC 0–‘ , area under the concentration-time curve to infinity; AUC 0–12 , area under the plasma concentration-time curve to the last sampling time; B, basolateral; BCRP, breast cancer resistance protein; CL renal , renal clearance; 4bHC, 4b-hydroxycholesterol; KHB, Krebs-Henseleit bicarbonate buffer; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MR, magnetic resonance; MRI, magnetic resonance imaging; MRP, multidrug resistance protein; m/z, mass/charge ratio; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OATP, organic anion-transporting polypeptide; P450, cytochrome P450; P-gp, P-glycoprotein; PNPLA3, patatin-like phosphatase domain containing 3; ROI, region of interest; t 1/2 , half-life; T max , time to maximum plasma concentration; X urine,0–12 , amount excreted in urine. 485 at ASPET Journals on June 4, 2020 dmd.aspetjournals.org Downloaded from