3 Results
3.1 Overview of Studies
A total of 204 papers were initially retrieved from the databases. After
screening according to the predetermined inclusion and exclusion
criteria, 13 PopPK models (M1-M13) published between 2010 and 2022 were
retained in this review18,23-34. The screening process
of the study is shown in Figure 1. Table 1 summarizes the demographic
information of patients in the studies. The median number of subjects in
each study was 37 (range, 6 to 335) with 38.46 % of the studies having
numbers more than 50. With the exception of three studies that also
included healthy volunteers18,28,30, the other studies
included only patients with different pathological states such as
obesity, immune deficiency, hematological malignancies, and pulmonary
fibrosis. Nine18,23,25-28,30,31,34 studies included
adults, three29,32,33 included children, and one
included24 both. Of the 11 studies with oral
formulations of posaconazole, three18,23-26,33 were
with oral suspensions, four27,28,31,32 with
delayed-release tablets, and one29 was on both oral
suspension and delayed-release tablets. The two30,34remaining studies were conducted on intravenous formulations in the
obese population and in critically ill patients treated with
extracorporeal membrane oxygenation.
3.2 Model Building and
Evaluation
Table 2 summarizes the information about model building and evaluation.
The median number of the plasma samples used for modeling was 226 (55 to
5756). About half of the studies used sparsely sampled data from
clinical TDM, with the rest of the rich data obtained mostly from PK
studies. NONMEM software was used in all studies for modeling except in
one study that used Monolix27. The deviation,
reliability, and accuracy of the models were internally evaluated by
goodness-of-fit (GOF), Jackknife technique, visual predictive check
(VPC), and normalized prediction distribution errors (NPDE) or
bootstrap. Almost all models exhibited satisfactory predictive
performance and robustness in internal validation. Few studies had
simulated dosing regimens based on the model and had proposed
recommended doses for different conditions. Detailed recommended
programs and target definitions are shown in Table 2.
3.3 Structural Model
Table 3 summarizes the characteristics of the final model, such as the
type of structural model used, estimated pharmacokinetic parameters,
model variability, and excluded and retained covariates. The PK
characteristics of studies comprising oral suspensions and tablets were
well described by the one-compartment model, while the two studies
involving intravenous administration30,34 were better
suited to the two-compartment model. With reference to absorption,
six18,23,25,27,29,33 models were described in terms of
first-order absorption and two18,33 with a lag time
characterizing the absorption delay18,33. Out of the
five27-29,31,32 studies using delayed-release tablets,
two28,31 studies were described with sequential zero
first-order absorption. The mode of absorption for the remaining
five24,26,30,32,34 studies was not mentioned. The
absorption rate constant (ka) was estimated from 11 oral
administration studies with a median(range) of 0.494
h−1 (0.0396-1.26 h−1), five of
which23,25,27,29,31 fixed it to a certain value
according to the published literature. With the exception of
four24,26,29,32 studies not mentioned the elimination
of posaconazole, the remaining studies was best described by first-order
elimination kinetics. Clearance (CL) and volume of distribution (V)
varied considerably in the different models, with a median (range) for
clearance of 14.95 L/h (7.3–195 L/h). The median (range) of V in the
one-compartment model was found to be 1100 L (186–5280 L). In the
two30,34 studies adopting the two-compartment model, V
for the central compartment (V1) and peripheral
compartment (V2) were estimated to be in the range of
26.2-150 L and 96.2-396 L, respectively.
The median (range) of inter-individual variability (IIV) of CL and V (or
V1) was found to be 37.9% (21.8-87.8%) and 29.9 %
(15.6-52.4%) respectively. Only four18,26-28 studies
reported the inter-occasion variability (IOV) of related PK
parameters18,26-28. The proportional, additive, or
combined residual error was applied to the final models. The median
(range) of the most widely used proportional residual error (coefficient
of variation, % CV) was found to be 14.8% (1.79–53.8%).
3.4 Covariates
The stepwise covariate model (SCM) building exercise with forward
inclusion, and backward elimination was the most commonly used method
for building covariate models. The statistical criteria used in each
study were slightly different. Multiple factors that potentially
influenced the exposure of posaconazole were tested during modeling, and
covariates such as weight, sex, age, total protein, incidence of
diarrhea, use of drugs such as PPI, phenytoin, rifampin, fosamprenavir,
nutritional supplements, and chemotherapeutic agents were retained in
the final model of different studies to account for changes in PK
parameters such as CL, V, and F.
In our review, the incidence of diarrhea and the use of PPI were the
most common covariates included in the final model of
six18,23-25,29,33 and
five18,24,25,29,33 studies, respectively, with a
negative effect on the bioavailability of posaconazole. Body weight
appeared as a final covariate in 31% of the studies and also negatively
correlated with posaconazole exposure. In addition, each of the other
covariates such as the sex, age, total protein, and use of phenytoin
were found in only one study.
To characterize the manner and extent of influence of the covariates on
the corresponding models, we performed simulations of steady-state
24-hour plasma concentrations at different covariate levels. Since no
covariates were included for model M627,
M1132 and M1334, and incomplete
information was available for M728, no simulation was
performed for these models. According to the type of formulation, the
models were divided into two groups for simulation: (a) oral suspension,
(b) tablet or intravenous infusion. Tablets and intravenous formulations
were placed together because they have similar plasma exposure. The
simulation results have been shown in Figure 2. For most of the models,
the effect of different covariate levels on the steady-state plasma
concentration of posaconazole was clearly observable. Nevertheless, the
effects of age in M123, gamma-glutamyl transferase
(GGT) in M224, and weight and chemotherapy in
M325 on the exposure of posaconazole seemed to be
inconspicuous.
3.5 Dose Simulation
The therapeutic target and model-based dosing regimen adjustments are
shown in Table 2. The simulation endpoint concentration of the final
model in most studies was set as the minimum concentration of 0.7 mg/L
for prophylaxis and 1.0 mg/L for treatment. To intuitively compare the
exposure levels and attainment of posaconazole, we simulated the
steady-state plasma concentration-time profiles at different dosing
regimens for each model except M728, because there was
not enough information to reproduce the model, and the results are shown
in Figure 3. In the adult population using oral suspensions, only
M518 could achieve the target concentration of 0.7
mg/L for prophylaxis at a dose of 200 mg thrice daily. On increasing the
dose of posaconazole to 300 mg thrice daily or 400 mg thrice daily, more
models were able to achieve posaconazole exposure for the prophylaxis or
treatment. Nevertheless, M426 failed to meet the
target exposure at three simulated doses. The pediatric population
receiving 200 mg of oral suspension thrice daily could already reach the
target concentration. At doses of 200, 300, and 400 mg daily, all models
using tablet and intravenous formulations achieved the target
concentrations.