Establishment of a mathematical prediction model for voriconazole stable maintenance dose: a prospective study

Abstract

Background: In patients with invasive fungal infection (IFI), the steady-state serum trough concentration (C _min) of voriconazole (VCZ) is highly variable and can lead to treatment failure (C _min < 0.5 mg/L) and toxicity (C _min ≥ 5.0 mg/L). However, It remains challenging to determine the ideal maintenance dose to achieve the desired C _min level quickly.

Aims: This randomized, prospective observational single-center study aimed to identify factors affecting VCZ-C _min and maintenance dose and create an algorithmic model to predict the necessary maintenance dose. MeThe study enrolled 306 adult IFI patients, split into two groups: non-gene-directed (A) (where CYP2C19 phenotype is not involved in determining VCZ dose) and gene-directed (B) (where CYP2C19 phenotype is involved in determining VCZ dose).

Results: Results indicated that CYP2C19 genetic polymorphisms might significantly impact VCZ loading and maintenance dose selection. CYP2C19 phenotype, C-reaction protein (CRP), and average daily dose/body weight were significant influencers on VCZ-C _min, while CYP2C19 phenotype, CRP, and body weight significantly impacted VCZ maintenance dose. A feasible predictive formula for VCZ stable maintenance dose was derived from the regression equation as a maintenance dose (mg) =282.774-0.735×age (year)+2.946×body weight(Kg)-19.402×CYP2C19 phenotype (UM/RM/NM:0, IM:1, PM:2)-0.316×CRP (mg/L) (p < 0.001).

Discussion: DiThis formula may serve as a valuable supplement to the Clinical Pharmacogenetics Implementation Consortium (CPIC^®) guideline for CYP2C19 and VCZ therapy, especially for IFI patients with highly variable inflammatory cytokines during VCZ therapy.

Keywords: CYP2C19; prediction model; proinflammatory cytokines; security; voriconazole.

Figure 1

Study flow diagram. VCZ, voriconazole; C _min, serum trough concentration. UM, Ultrarapid metabolizer; RM, rapid metabolizer; NM, normal metabolizer; IM, intermediate metabolizer; PM, poor metabolizer.

Figure 2

(A) The difference of VCZ-C _min between groups (A, B). (B) The difference of VCZ-C _min among subgroups (group C1, C2, D1, D2, E1, and E2). (C) The percentage of patients obtaining C _min levels of < 0.5 mg/L, 0.5 mg/L ≤ C _min < 5.0 mg/L, and C _min > 5.0mg/L between groups (A, B). (D) The percentage of patients achieving C _min level of < 0.5 mg/L, 0.5 mg/L ≤ C _min < 5.0 mg/L and C _min > 5.0 mg/L among subgroups (group C1, C2, D1, D2, E1, and E2). Data were expressed as mean ± SD and were analyzed using Student’s t-test. *p<0.05; **p<0.01.VCZ-C _min, voriconazole serum trough concentration; UM, Ultrarapid metabolizer; RM, rapid metabolizer; NM, normal metabolizer; IM, intermediate metabolizer; PM, poor metabolizer.

Figure 3

(A–C) The linear correlation between VCZ-C _min (mg/L) and CRP (mg/L), PCT (ng/mL), and IL-6 (pg/mL), respectively. (A) VCZ-C _min vs. CRP; (B) VCZ-C _min vs. PCT; (C) VCZ-C _min vs. IL-6. (D–F) Comparison of CRP, PCT, and IL-6 among C _min < 0.5 mg/L, 0.5 mg/L ≤ C _min < 5.0 mg/L, and C _min ≥ 5.0 mg/L. (D) CRP; (E) PCT; (F) IL-6. Data were expressed as the median values (range) and interquartile range (IQR) and were analyzed by Mann-Whitney U-test and Kruskal-Wallis test. ***p<0.001. VCZ-C _min, voriconazole serum trough concentration; CRP, C-reactive protein; PCT, procalcitonin; IL-6, interleukin-6.

Figure 4

(A) Comparison of dose-normalized VCZ-C _min among control, esomeprazole, omeprazole, rabeprazole and pantoprazole groups. (B) The percentage of patients obtaining C _min < 0.5 mg/L, 0.5 mg/L ≤ C _min <5.0 mg/L, and C _min ≥ 5.0 mg/L among different groups. Data were expressed as mean ± SD and were analyzed by Student’s t-test. ***p<0.001. Dose-normalized VCZ-C _min=[VCZ-C _min (mg/L)×body weight (Kg)]/average daily dose (mg); VCZ-C _min,voriconazole serum trough concentration.

Figure 5

The frequency of hepatotoxicity among groups. (A) The frequency of hepatotoxicity among different VCZ-C _min (< 0.5, 0.5-5.0, ≥ 0.5 mg/L); (B) The frequency of hepatotoxicity between group A and group (B, C) The frequency of hepatotoxicity among subgroups (UM/RM/NM (C1), UM/RM/NM (C2), IM (D1), IM (D2), PM (E1), and PM (E2)). Data were described as their number for categorical variables and were analyzed by a Chi-squared test or Fisher’s exact test. *p<0.05; ****p<0.0001. VCZ-C _min, voriconazole serum trough concentration; UM, Ultrarapid metabolizer; RM, rapid metabolizer; NM, normal metabolizer; IM, intermediate metabolizer; PM, poor metabolizer.