Population Pharmacokinetics of Morphine in Patients with Nonalcoholic Steatohepatitis (NASH) and Healthy Adults

Abstract

Altered expression and function of transporters in nonalcoholic steatohepatitis (NASH) patients may affect the pharmacokinetics (PK), efficacy, and safety of substrate drugs. A population pharmacokinetic (PopPK) analysis was performed to assess differences in morphine and morphine-3-glucuronide (M3G) disposition in NASH and healthy subjects. A total of 315 serum and 42 urine samples from 21 subjects (14 healthy; 7 NASH) were analyzed using NONMEM. Morphine and M3G PK were described by three-and one-compartment models, respectively. After accounting for the effect of total body weight on all clearance and volume of distribution parameters using an allometric scaling approach, NASH severity score (NASF; combination of fibrosis and nonalcoholic fatty liver disease activity scores) was the most significant predictor of differences in M3G exposure. The model predicted a linear decrease in the clearance of M3G with increasing NASF scores on a natural logarithmic scale. These results may provide some insight into the potential effect of NASH on the disposition of hepatic transporter substrates.