3.3 Population pharmacokinetic analysis
A one-compartment pharmacokinetic model with first-order elimination
adequately describes the data. The inter-individual variability and
residual variability were all characterized by exponential model.
The analysis of the covariate model confirmed the ALB and EM were the
most significant covariates for the clearance (CL) and there were no
covariates that had a significant effect on volume of distribution (V).
The typical value of CL, V and oral bioavailability (F) of voriconazole
obtained in the final model are 1.52 L/h, 35.7 L and 0.909,
respectively. The oral absorption rate constant (KA) was fixed to a
value of 1.19h-1.22, 23 The
following formulations are included in the final model: CL (L/h) =
1.52×1.42(EM-1) × e0.911×(ALB/34.57)× e0.254; V (L) = 35.7; KA (h-1) =
1.19 (fixed); F = 0.909. The PPK parameter estimates of base model and
final model are summarized in Table 3.
The GOFs from the final model displayed that the individual-predicted
concentration
(IPRED)
and population-predicted concentration (PRDE) versus detection values
(DV) of the final model are close to Y=X (figure 1A and B). Besides, the
most conditional weighted residuals (CWRES) are symmetrical distribution
on both sides of the line Y=0 and most of points are within ±2(figure 1C
and D). The final model’s VPC results are presented in Figure 2. Most of
the measured values of voriconazole are covered within 90% of the
prediction interval (PI), and the predicted value is 5%-95%,
demonstrating that the final model possesses good predictive capacity.
The results of the final model NPDE statistical tests are as follows:
t-test P = 0.77, Fisher test P = 0.343, Shapiro-Wilks test P = 0.117,
comprehensive test P = 0.352. The statistical test results combined with
the diagnostic chart reveal that the final model exhibited a normal
distribution, with excellent stability and predictive performance
(Figure 3). In the final model bootstrap verification, 1000 resampled
bootstrap data sets were run successfully for 864 times. More
importantly, the PPK parameter estimates of the final model showed
similar results to the bootstrap results (Table 3), indicating the final
model with good robustness and stability.