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.