1. Introduction

Posaconazole is a second-generation triazole antifungal agent derived from the structure of itraconazole1. Similar in action to itraconazole, posaconazole blocks the synthesis of ergosterol, a major sterol found on the membrane of fungal pathogens, by inhibiting the activity of the enzyme, lanosterol 14α-demethylase. The properties and function of fungal cell membranes get altered due to the accumulation of 14α-methyl sterol precursors, obstructing cell growth and division and resulting in an antifungal effect2,3. Posaconazole is a broad-spectrum antifungal agent active against various fungi, including common pathogens such as Candida species andAspergillus species, as well as novel pathogens such asCryptococcus neoformans, Fusarium species, and Zygomycetesspecies4.
Posaconazole is available in three types of formulations: oral suspension, delayed-release tablet, and intravenous injection5. In 2006, posaconazole suspension was approved by the United States (US) Food and Drug Administration (FDA) for the prevention of invasive Candida and Aspergillusinfections in patients ≥ 13 years of age with severe immunodeficiency conditions, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It was also approved by the US FDA for treating patients with other neutropenic hematological malignancies and those who had undergone hematopoietic stem cell transplantation6,7. Posaconazole delayed-release tablet and intravenous injection were approved by the FDA in 2013 and 2014, respectively8.
Up to now, a large number of literature have studied the pharmacokinetic characteristics and influencing factors of posaconazole. The pharmacokinetics (PK) of posaconazole vary significantly among individuals9-12. The absorption of posaconazole oral suspension is saturable, resulting in high variability in bioavailability (F) and serum exposure levels8. In addition, gastric acid, the presence of food, and gastrointestinal movement also affect bioavailability13-15. The absorption of posaconazole is reduced, thus decreasing its F on administration with drugs that inhibit gastric acid secretion such as proton pump inhibitors (PPI) and histamine (H2) receptor antagonists and drugs that alter gastrointestinal motility such as metoclopramide16-18. The development of delayed-release tablets and intravenous injections has effectively improved the PK of posaconazole and increased drug exposure19. However, regardless of the formulation, the therapeutic effect of posaconazole on invasive aspergillosis was closely related to its serum concentration level16,20. In addition, the metabolism of posaconazole almost does not depend on the cytochrome P450 (CYP450) enzyme system but achieves limited metabolism under the action of uridine diphosphate glucuronic acid transferase (UDP-glucuronosyltransferases, UGTs). Drugs that can interact with the UGT enzyme, such as phenytoin, rifampicin, and fosamprenavir may affect the plasma concentration of posaconazole21,22. Therefore, considering the inter- and intra-individual differences of posaconazole, the interactions between drugs, and the effect of serum drug concentration on efficacy, routine therapeutic drug monitoring (TDM) of posaconazole is recommended to ensure the adequate exposure required to achieve maximum efficacy for prophylaxis or treatment19.
Some population pharmacokinetics (PopPK) models18,23-34 of posaconazole have been developed to better describe the PK characteristics of posaconazole in different target populations and to assist in adjusting the dosing regimen35. A review published in 202022 has summarized the PK parameters of eight of these models. This review aims to comprehensively compare the PK characteristics of these models and examine the effects of covariates and dosing regimens on the PK of posaconazole.