Impact of Albumin and Omeprazole on Steady-State Population Pharmacokinetics of Voriconazole and Development of a Voriconazole Dosing Optimization Model in Thai Patients with Hematologic Diseases

Abstract

This study aimed to identify factors that significantly influence the pharmacokinetics of voriconazole in Thai adults with hematologic diseases, and to determine optimal voriconazole dosing regimens. Blood samples were collected at steady state in 65 patients (237 concentrations) who were taking voriconazole to prevent or treat invasive aspergillosis. The data were analyzed using a nonlinear mixed-effects modeling approach. Monte Carlo simulation was applied to optimize dosage regimens. Data were fitted with the one-compartment model with first-order absorption and elimination. The apparent oral clearance (CL/F) was 3.43 L/h, the apparent volume of distribution (V/F) was 47.6 L, and the absorption rate constant (Ka) was fixed at 1.1 h^-1. Albumin and omeprazole ≥ 40 mg/day were found to significantly influence CL/F. The simulation produced the following recommended maintenance doses of voriconazole: 50, 100, and 200 mg every 12 h for albumin levels of 1.5-3, 3.01-4, and 4.01-4.5 g/dL, respectively, in patients who receive omeprazole ≤ 20 mg/day. Patients who receive omeprazole ≥ 40 mg/day and who have serum albumin level 1.5-3 and 3.01-4.5 g/dL should receive voriconazole 50 and 100 mg, every 12 h, respectively. Albumin level and omeprazole dosage should be carefully considered when determining the appropriate dosage of voriconazole in Thai patients.

Keywords: Thai patients; albumin; omeprazole; population pharmacokinetics; voriconazole.

Figure 1

Goodness-of-fit (GOF) plots for the final model. (a) Population-predicted concentration (PRED) versus observed concentration; (b) Individual predicted concentration (PRED) versus observed concentration; (c) Conditional weighted residuals (CWRES) versus PRED; (d) CWRES versus time after dose; The red lines in (a) and (b) show regression lines, and in (c) and (d) they show the positive where CWRES equals 0.

Figure 2

Prediction-corrected visual predictive check (pcVPC) plot of the final model. Open circles show observed plasma voriconazole concentrations. The red line is 50th percentile, and blue lines are the 5th and 95th percentiles, of the observed concentrations. Shaded areas are the 95% CIs of the corresponding model-predicted percentiles.

Figure 3

Simulated steady-state trough or minimal concentrations (C_{min, ss}) in the non-omeprazole group or omeprazole 20 mg/day group stratified by plasma albumin (Alb) and a maintenance dose of voriconazole administration (50, 100, 150, 200, 250, 300, 350, and 400 mg orally every 12 h of voriconazole). The round, square, and triangle lines show the percentage that achieved a therapeutic range (C_{min, ss} = 1–5 mg/L), a toxic range (C_{min, ss} > 5 mg/L), and a sub-therapeutic range (C_{min, ss} < 1 mg/L), respectively.

Figure 4

Simulated steady-state trough or minimal concentrations (C_{min, ss}) in the omeprazole ≥ 40 mg/day group stratified by plasma albumin (Alb) and voriconazole dose administration (50, 100, 150, 200, 250, 300, 350, and 400 mg orally every 12 h of voriconazole). The round, square, and triangle lines show the percentage that achieved a therapeutic range (C_{min, ss} = 1–5 mg/L), a toxic range (C_{min, ss} > 5 mg/L), and a sub-therapeutic range (C_{min, ss} < 1 mg/L), respectively.