4. Discussion
A review published in 202022 had reported nine PopPK
models of posaconazole (one could not be found online, and the full text
was not available even after contacting the author). Our review
incorporated five new published models into the scope of examination. We
focused only on the PopPK of posaconazole for the first time, providing
a simulation of posaconazole exposure at different covariates levels and
dosing regimens of 13 published models.
Without limiting the population, only three of our included studies
considered the pediatric population as the primary study
population29,32,33. During the literature screening,
there were few PK or clinical reports of posaconazole in the pediatric
population, which may be related to the limited use of posaconazole in
pediatrics. Posaconazole has not been approved for use in children under
13 years of age. Nevertheless, there have been some cases of
posaconazole being used off-label for the prevention of high-risk IFI in
children ≤12 years old36. This is not only due to the
satisfactory efficacy and safety of posaconazole in
adults37,38, but also because posaconazole is more
effective than other antifungal agents such as fluconazole and
itraconazole in pediatric patients with hematologic
malignancies39-42. Plasma concentrations of
posaconazole are highly variable in the younger pediatric
population43,44, which may lead to large fluctuations
in efficacy and safety. In pediatric patients treated with posaconazole,
TDM is necessary to ensure that the required drug exposure is achieved
and to minimize the occurrence of adverse events.
In this review, the structural model appears to be linked to the route
of administration, as demonstrated by the fact that the two
studies30,34 involving intravenous administration used
two-compartment models, while the studies of oral administration used
one-compartment models. Since most studies used sparse sampling lacking
absorption phase data or fixed ka to a specific value
according to the literature, inaccurate estimation of kamight have affected the judgment of structural models. In addition, two
models with absorption delays18,33 may have obscured
the initial distribution pattern30.
The sample size, evaluation method, inclusion and exclusion criteria of
covariates, pathological status, and concomitant medications were
different in different studies, which may lead to differences in the
influence of covariates in each study.
Diarrhea, a common symptom in
patients with graft-versus-host disease (GVHD), critically ill patients,
and patients after receiving chemotherapy, is associated with a
significant decrease in F45,46. Nearly half of the
studies in our review retained diarrhea in the final model. The F of
posaconazole was reduced by 59% and 45% in the adult models
M123 and M518, respectively. In
pediatric study models, M829 and
M1233, it was reduced by 33% for both. Additionally,
the presence of diarrhea in M224 and
M325 increased V and CL by a factor of 1.5.
M728 examined but did not retain diarrhea in the final
model. Unlike the six studies mentioned above, the formulation of
posaconazole used in M728 was a delayed-release tablet
rather than an oral suspension. Diarrhea was a risk factor for
sub-therapeutic concentration of posaconazole in patients using tablets,
but there was a decreasing trend observed in this
effect47,48. Metoclopramide, which was retained in
M518, similar to the diarrhea limited the absorption
and altered the exposure of posaconazole by increasing gastrointestinal
motility.
The use of PPI was considered an important covariate examined in six
models18,24,25,27,29,32,33, of which were retained
except M1132. The ultimate effect of the use PPI in
these models was manifested by reduced plasma exposure with the form of
raising V or CL, or decreasing F, which was consistent with the results
reported in other articles15,17,49. PPI can
effectively prevent stress mucositis in critically ill
patients50,51 by inhibiting the secretion of gastric
acid and increasing the pH of gastric juice. However, for posaconazole,
a weakly alkaline drug, its solubility and F may be altered by the
concomitant use of PPI13. M829 found
that PPI limited posaconazole absorption to a greater extent than
H2 receptor antagonists. This may be due to the stronger
and longer-lasting acid inhibitory effect of PPI than H2receptor antagonists52.
Demographic characteristics such as weight, age, and sex were also
examined. The influence of body weight on V, CL, and F of posaconazole
are described in several models25,28-30. The high
lipophilicity of posaconazole may be responsible for extensive lipid
tissue distribution53, which may account for the
greater V in individuals with high body weight. Sex and age were tested
in most studies but were retained only in M1031 and
M123, respectively. M1031 showed
lower CL in women than in men, consistent with the finding that males
were associated with reduced posaconazole trough concentrations as
mentioned in three reports47,54,55. On the contrary,
some studies have found that men have higher plasma exposure than women
(P = 0.028)56,57. Jia et al.54speculated that differences in sex hormones and fat content between men
and women contributed to the varied PK of posaconazole. Despite the fact
that age was considered to be relevant to the decrease of V in
M123, the effect of age on posaconazole concentration
was not noticeable in our simulations, which may be explained by the low
plasma exposure caused by the large V in M1.
Some studies have also considered the effect of biochemical indicators
on the PK of posaconazole. Posaconazole has a plasma protein binding
rate of 98% and is primarily bound to albumin58.
Restricted transmembrane transport caused by protein binding results in
a reduction in metabolism and excretion and an elevation of plasma
concentrations, which fits with the findings of M1031.
However, this study did not find a relationship between albumin and PK
parameters, indicating that the CL/F of posaconazole may be influenced
by other plasma-binding proteins such as
lipoprotein59,60 and C-reactive protein
(CRP)54. M224 found that
posaconazole exposure decreased with the baseline bilirubin ≥ 2 × the
upper limit of normal (ULN) or GGT ≥ 2 × ULN24. This
may be an indirect effect caused by metabolic disorders due to liver
impairment, although liver function is not an absolute condition for
changes in bilirubin61 and GGT62-65levels. Other biochemical markers such as alanine aminotransferase
(ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALK)
were also tested in some models but were not retained.
The effect of concomitant
medications on posaconazole exposure was mainly reflected in
M518. Phenytoin and rifampin presented a remarkable
effect on CL/F (621% increase). This effect may arise from enzymatic
interactions; phenytoin and rifampin, inducers of the UGT
enzyme66,67, increase the metabolism of posaconazole,
which is metabolized by UGT1A4 by approximately
17%22. These two drugs were also tested by
M829 and M1132 but were not
retained, possibly because the populations in both studies were
pediatric with immature expression of drug-metabolizing enzymes or
because of the low proportion of patients with concomitant use of these
two drugs. Fosamprenavir also increased CL/F, although this effect was
much less than that of phenytoin and rifampin. M518reported that nutritional supplements increased the F of posaconazole by
129%, in agreement with the findings of published
studies15,68,69. PK studies have demonstrated that
food, especially a high-fat diet, can greatly increase the rate and
extent of posaconazole absorption70-72. However, for
patients with eating disorders due to severe IFI, liquid nutritional
supplements are often used as a substitute of food for enteral
nutrition69. Furthermore, M325revealed a 0.6-fold decrease in V as a result of the co-administration
of chemotherapy. In conclusion, TDM is advisable when used in
combination with drugs that may alter the PK of posaconazole.
Regardless of the covariate or dose simulations, there were observable
differences in posaconazole steady-state concentrations between models,
even at the same dose. Such differences may derive from variation in the
race, age, or disease state of the population, the formulation of
posaconazole, and the assay conditions of the plasma samples among
studies. Nevertheless, the pattern of covariate or dose effects on the
exposure of posaconazole was mostly consistent. According to the
simulated PK profile, posaconazole tablets and intravenous formulations
showed higher concentrations than oral suspensions, which was consistent
with the reported finding73. This might be because
delayed-release tablets with drug-polymer combinations prevent drug
recrystallization in the intestinal fluid and therefore exhibit higher F
than suspensions74.
Since only a small number of studies used non-parametric modeling
methods75,76, we only retained studies using
parametric modeling methods, which also ensured the comparability among
models. Further discussion is needed if more non-parametric studies are
conducted in the future. The other limitation is that the models in this
review were evaluated using internal data. Thus, the good predictive
performance of the models is only reflected in their own centers and is
difficult to apply when extrapolated to other centers. A more rigorous
external evaluation of these models is recommended to verify their
predictive performance and robustness after extrapolation to other
scenarios.