Posaconazole meta-PK analysis upon oral suspension, delayed-release tablet, and intravenous infusion in patients versus healthy volunteers: impact of clinical characteristics and race
Lu Chen (1), Elke H.J. Krekels (1), Yalin Dong (2), Catherijne A.J. Knibbe (1,3), Roger J.M. Brüggemann (4,5)
(1) Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; (2) Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China; (3) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands; (4) Department of Pharmacy, Radboud University Medical Centre, Radboud University, Nijmegen, The Netherlands; (5) Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands
Objectives: We previously developed an integrated population PK model of posaconazole oral suspension (SUS), delayed-release tablet (DR-tablet), and intravenous injection (IV), in healthy volunteers (HV) [1]. Given the reported altered PK and high interindividual variability in patients versus HV [2,3], we extend that model to patients and investigated the potential impact of clinical characteristics and the Chinese race on posaconazole PK.
Methods: The population PK model was developed using NONMEM 7.5.0 supported by Pirana 3.0.0, and PsN 5.2.6. A total of 1046 concentrations from 105 prospectively studied Caucasian patients receiving either of the three formulations [4,5] were pooled with 3898 concentrations from 182 HV [1]. In the two-compartment model with respectively four and eight absorption transit compartments for SUS and DR-tablet from HV [1], adjustments in the number of absorption transit compartments were tested for the oral formulations in patients. Dose-nonlinearity on bioavailability (F) was incorporated for the SUS in patients using a sigmoidal function according to the model in HV [1], with re-estimated parameters. Binary covariates including diarrhea, mucositis, administration through a nasogastric tube, and comedication of proton pump inhibitors (PPIs), metoclopramide, or ranitidine, were investigated on both the absorption rate (ka) and F of the SUS (Fsus). Mucositis as a binary covariate and continuous citrulline levels were tested as covariates on both the ka and F of the DR-tablet (Ftab). Demographics, albumin, hematocrit levels and hypoalbuminemia with various cut-off values were investigated on the disposition parameters clearance, the central and peripheral volume of distribution (Vp), and intercompartmental clearance (Q). Being a patient was tested as a binary covariate on each PK parameter at the end of the covariate analysis. The covariate analysis followed a forward inclusion and backward deletion step, using an OFV difference of >3.84 (P <0.05) and >10.83 (P <0.001) for statistical significance, respectively. The predictive performance of the final model in Caucasian patients was assessed by an NPDE analysis based on 1000 simulations and stratified by formulation.
To evaluate the influence of the Chinese race, a total of 292 mainly trough concentrations from 80 Chinese patients receiving SUS were available. We first extrapolated the final model developed for Caucasian patients to the Chinese patients to inspect the fit in (stratified) GOF plots and NPDE plots. Second, the distribution of individual parameter values between the Chinese patients and Caucasian patients was visually assessed and the Chinese race was tested as a binary covariate on all parameters. Finally, the model fit was assessed upon the inclusion of a previously reported 25% CL reduction in Chinese patients [6].
Results: The model structure from HV described the PK data in patients well. In patients, Fsus decreases from 38% to 25% for doses increasing from 100 mg to 600 mg. Mucositis, diarrhea, administration through a nasogastric tube, and concomitant use of PPIs or metoclopramide, respectively reduced the Fsus by 61%, 36%, 44%, 48%, and 29%, putting patients with these clinical characteristics at increased risk of inadequate exposure. The Ftab in patients was 59% irrespective of dose. Patients with albumin <30 g/L showed a 28% reduction in CL. Additionally, an 84% larger Vp and 68% lower Q were found in patients compared with HV. The NPDE results indicate an accurate predictive performance of the final model in Caucasian patients for each formulation. No PK differences for Chinese patients could be identified.
Conclusions: Posaconazole PK is considerably different in patients compared to healthy volunteers, with altered Fsus that is also impacted by clinical covariates, a Ftab similar to fasted conditions in HV, and altered parameters for CL, Vp, and Q. Model performance was equal for Caucasian and Chinese patients. For patients, the DR-tablet is superior to SUS with a higher and more stable F, but is not equivalent to IV, as commonly assumed.
References:
1] Chen, et al. Drugs, 2023, 83 (1): 75-86.
[2] Dolton, et al. Antimicrob Agents Chemother, 2014, 58 (11): 6879-6885.
[3] Iwasa, et al. J Clin Pharmacol, 2022.
[4] Dolton, et al. Antimicrob Agents Chemother, 2012, 56 (11): 5503-5510.
[5] Jansen, et al. Clinical Microbiology and Infection, 2022, 28 (7): 1003-1009.
[6] EMA. Noxafil EPAR assessment report. https://www.ema.europa.eu/en/documents/variation-report/noxafil-h-c-610-ii-0062-epar-assessment-report-variation_en.pdf (March 17 2023, date last accessed).