Apixaban and Rosuvas­­tatin Pharmacokinetics in Nonalcoholic Fatty Liver Disease

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 ( = 22) and healthy control subjects ( = 12). The area under the concentration-time curve to the last sampling time (AUC) values for apixaban were not different between control and NAFLD subjects (671 and 545 ng/ml × hour, respectively; = 0.15). Similarly, the AUC values for rosuvastatin did not differ between the control and NAFLD groups (25.4 and 20.1 ng/ml × hour, respectively; = 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 ( < 0.001 and < 0.05, respectively). In multivariable linear regression analyses, only participant weight but not NAFLD, age, or // genotypes, was associated with apixaban and rosuvastatin AUC ( < 0.001 and = 0.06, respectively). NAFLD does not appear to affect the pharmacokinetics of apixaban or rosuvastatin.

Quantitative Proteomics and Mechanistic Modeling of Transporter‐Mediated Disposition in Nonalcoholic Fatty Liver Disease

“…It is possible that the complex interplay of uptake and efflux transporters across the multiple organs resulted in no apparent changes in rosuvastatin oral exposure. Renal clearance of rosuvastatin seems to be unaltered in NASH . On the other hand, various liver diseases, including NASH, are associated with intestinal dysbiosis and increased intestinal transit time .…”

“…In comparison, Tirona et al . reported no significant change in rosuvastatin oral plasma exposure between healthy and NAFLD subjects with no fibrosis or with fibrosis (i.e., presumed steatosis and NASH, respectively) …”

“…Observed and model‐based prediction of mean oral pharmacokinetics of rosuvastatin in heathy subjects (open triangles and green curves) and in NAFLD patients diagnosed without and with fibrosis (open circles and red curves). Observed data extracted from Tirona et al . Solid and dashed curves represent mean of 10 trials × 10 subjects and mean of individual trial, respectively, in healthy subjects, steatosis (blue curves) and NASH patients.…”

“…A similar assessment of the effect of NAFLD‐induced changes in protein expression on the oral PK of rosuvastatin suggest no effect in steatosis, which is consistent with the clinical observations in nonfibrotic NAFLD (assumed steatosis). However, the model‐based predictions presented a ~ 30% increase in rosuvastatin oral exposure in NASH, which is a marginal overprediction given that no statistically significant change was noted in fibrotic‐NAFLD patients (assumed NASH) in a clinical study . Rosuvastatin is a substrate of several transporters, including intestinal OATP2B1/BCRP, hepatic OATPs/NTCP/BCRP/MRP3, and renal OAT3/BCRP; and many of these transporters are known to influence its disposition and systemic PK .…”

Pharmacokinetics and Pharmacogenetics of Apixaban

“…Связывание с белками у субъектов с легким (класс A по классификации Чайлд-Пью) или умеренным (класс B по классификации Чайлд-Пью) нарушением функции печени было сопоставимо со связыванием с белками плазмы у здоровых субъектов. У пациентов с печеночной недостаточностью легкой или средней степени тяжести коррекции дозы не требуется [51]. Фармакокинетика апиксабана у пациентов с тяжелой печеночной недостаточностью (класс C по шкале Чайлд-Пью) не оценивалась.…”