2. Methods

2.1 Search Strategy

PopPK studies of posaconazole from inception to May 2022 were searched from PubMed and EMBASE databases using the following keywords: ‘posaconazole’ in title or abstract, ‘population pharmacokinetic’, ‘popPK’, ‘pop PK’, ‘PPK’, ‘population pk model’, ‘compartmental pharmacokinetic’, ‘pharmacokinetic model’, ‘population model’, ‘NONMEM’, ‘nonlinear mixed effects modeling’, ‘NLME’, ‘mixed effect’, ‘WinNonmix’, and ‘Monolix’.

2.2 Inclusion/Exclusion Criteria

All literature articles describing the PopPK models of posaconazole were included according to the retrieval results. Studies that met the following criteria were included in this review: (1) the study population was human, whether adult or pediatric patients or healthy volunteers; (2) posaconazole was used as the research drug, with no limitation on the type of formulation; and (3) the PK analysis was carried out and a PopPK model was established. The following studies were excluded: (1) reviews, case reports, methodological articles, and in vitro studies; (2) non-English language publications; (3) papers that lack a source for details of methods or results; (4) studies using non-compartmental or non-parametric methods.

2.3 Data Extraction

The following information was extracted from the PopPK models that met inclusion and exclusion criteria: (1) population characteristics, such as country, sex, weight, age, disease, administration route, dose and posaconazole concentration; (2) model characteristics, such as the number of samples collected, the method of modeling, evaluation, and dose simulation; (3) Results of PopPK analysis, such as structural models, statistical models (inter-individual and residual variation), parameter estimates, and covariates examined and retained.

2.4 Comparison of Studies

The population characteristics, modeling strategies, and model information for each study have been summarized in tabular form. The steady-state concentration-time profiles of posaconazole at different covariate levels were simulated. The daily dose of 300-600 mg was set as the instructions. For categorical covariates, 0 and 1 represented the absence or presence, respectively. Continuous covariates were simulated with three levels: adult weight (60, 120, and 180 kg), child weight (10, 20, and 30 kg); age (20, 40, and 60 years); and total protein (4.8, 6.5, and 7.8 g/dL).
The effect of different dosing regimens on posaconazole steady-state concentration profile was also simulated. The dosage for oral suspensions was set at 200, 300, and 400 mg thrice daily. A loading dose of 200, 300, and 400 mg twice on the first day and a maintenance dose of 200, 300, and 400 mg once daily was set for tablets and intravenous formulations. The infusion time of the intravenous formulations was set at 90 min.