We previously developed an integrated population pharmacokinetic model for posaconazole oral suspension (SUS), delayed-release tablet (DR-tablet), and intravenous (IV) infusion in healthy volunteers (HV). Here we extended that model to patients and investigated the potential impact of clinical characteristics and the Chinese race on posaconazole pharmacokinetics.
1046 concentrations from 105 prospectively studied Caucasian patients receiving either of the three formulations were pooled with 3898 concentrations from 182 HV. Clinical characteristics were tested for significance. The Chinese racial impact was assessed using 292 opportunistic samples from 80 Chinese patients receiving SUS.
Bioavailability of the SUS (F) in patients decreases from 38.2% to 24.6% when the dose increases from 100 mg to 600 mg. The bioavailability of DR-tablet (F) was 59% regardless of dose. Mucositis, diarrhea, administration through a nasogastric tube, and concomitant use of proton pump inhibitors or metoclopramide, respectively reduced F by 61%, 36%, 44%, 48%, and 29%, putting patients with these characteristics at increased risk of inadequate exposure. Clearance decreases from 7.0 to 5.1 L/h once patient’s albumin is <30 g/L. Patients showed an 84.4% larger peripheral volume of distribution (V) and 67.5% lower intercompartmental clearance (Q) compared to HV. No racial difference could be identified.
Posaconazole pharmacokinetics is considerably different in patients versus HV, with altered F that is also impacted by clinical covariates, a F similar to fasted conditions in HV, and altered parameters for clearance, V, and Q. No evidence suggests that Chinese patients require a different dose compared to Caucasian patients.
Copyright © 2023. Published by Elsevier Ltd.
