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Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization.

ABSTRACT: Purpose: The aims of this study were to establish a joint population pharmacokinetic model for voriconazole and its N-oxide metabolite in immunocompromised patients, to determine the extent to which the CYP2C19 genetic polymorphisms influenced the pharmacokinetic parameters, and to evaluate and optimize the dosing regimens using a simulating approach. Methods: A population pharmacokinetic analysis was conducted using the Phoenix NLME software based on 427 plasma concentrations from 78 patients receiving multiple oral doses of voriconazole (200 mg twice daily). The final model was assessed by goodness of fit plots, non-parametric bootstrap method, and visual predictive check. Monte Carlo simulations were carried out to evaluate and optimize the dosing regimens. Results: A one-compartment model with first-order absorption and mixed linear and concentration-dependent-nonlinear elimination fitted well to concentration-time profile of voriconazole, while one-compartment model with first-order elimination well described the disposition of voriconazole N-oxide. Covariate analysis indicated that voriconazole pharmacokinetics was substantially influenced by the CYP2C19 genetic variations. Simulations showed that the recommended maintenance dose regimen would lead to subtherapeutic levels in patients with different CYP2C19 genotypes, and elevated daily doses of voriconazole might be required to attain the therapeutic range. Conclusions: The joint population pharmacokinetic model successfully characterized the pharmacokinetics of voriconazole and its N-oxide metabolite in immunocompromised patients. The proposed maintenance dose regimens could provide a rationale for dosage individualization to improve clinical outcomes and minimize drug-related toxicities.

SUBMITTER: Li S

PROVIDER: S-EPMC8762230 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Voriconazole is a potent antifungal drug with complex pharmacokinetics caused by time-dependent inhibition and polymorphisms of metabolizing enzymes. It also exhibits different pharmacokinetic characteristics between adults and children. An understanding of these alterations in pharmacokinetics is essential for pediatric dose optimization. Objective: To determine voriconazole plasma exposure in the pediatric population and further investigate optimal dosage regimens. Methods: An adult and pediatric physiologically based pharmacokinetic (PBPK) model of voriconazole, integrating auto-inhibition of cytochrome P450 3A4 (CYP3A4) and CYP2C19 gene polymorphisms, was developed. The model was evaluated with visual predictive checks and quantitative measures of the predicted/observed ratio of the area under the plasma concentration-time curve (AUC) and maximum concentration (Cmax). The validated pediatric PBPK model was used in simulations to optimize pediatric dosage regimens. The probability of reaching a ratio of free drug (unbound drug concentration) AUC during a 24-h period to minimum inhibitory concentration greater than or equal to 25 (fAUC24h/MIC ≥ 25) was assessed as the pharmacokinetic/pharmacodynamic index. Results: The developed PBPK model well represented voriconazole's pharmacokinetic characteristics in adults; 78% of predicted/observed AUC ratios and 85% of Cmax ratios were within the 1.25-fold range. The model maintained satisfactory prediction performance for intravenous administration in pediatric populations after incorporating developmental changes in anatomy/physiology and metabolic enzymes, with all predicted AUC values within 2-fold and 73% of the predicted Cmax within 1.25-fold of the observed values. The simulation results of the PBPK model suggested that different dosage regimens should be administered to children according to their age, CYP2C19 genotype, and infectious fungal genera. Conclusion: The PBPK model integrating CYP3A4 auto-inhibition and CYP2C19 gene polymorphisms successfully predicted voriconazole pharmacokinetics during intravenous administration in children and could further be used to optimize dose strategies. The infectious fungal genera should be considered in clinical settings, and further research with large sample sizes is required to confirm the current findings.

Project description:PurposeSYP-1018 is a lyophilized polymeric nanoparticle formulation of voriconazole that is under development for intravenous dosing. This study compared the pharmacokinetic and tolerability profiles of SYP-1018 with those of Vfend(®), the marketed formulation of voriconazole. The effect of CYP2C19 polymorphism on the voriconazole pharmacokinetics was also evaluated.MethodsAn open-label, two-treatment, two-period, two-sequence crossover study was conducted in 52 healthy male volunteers, who randomly received a single intravenous infusion of either of the two voriconazole formulations at 200 mg. Blood samples were collected up to 24 hours after drug administration for pharmacokinetic analysis. The plasma concentrations of voriconazole were determined using liquid chromatography with tandem mass spectrometry, and the pharmacokinetic parameters were estimated using a noncompartmental method. CYP2C19 genotype was identified in 51 subjects.ResultsThe geometric mean ratio (90% confidence interval) of SYP-1018 to Vfend(®) was 0.99 (0.93-1.04) for the maximum plasma concentrations (Cmax) and 0.97 (0.92-1.01) for the area under the concentration-time curve (AUC) from dosing to the last quantifiable concentration (AUClast). Nineteen homozygous extensive metabolizers (EMs, *1/*1), 19 intermediate metabolizers (IMs, *1/*2 or *1/*3), and ten poor metabolizers (PMs, *2/*2, *2/*3, or *3/*3) were identified, and the pharmacokinetic comparability between SYP-1018 and Vfend(®) was also noted when analyzed separately by genotype. The systemic exposure to voriconazole was greatest in the PM group, followed by the IM, and then the EM groups. Furthermore, the intrasubject variability for Cmax and AUClast was greater in IMs and PMs than in EMs. No serious adverse event occurred, and both treatments were well tolerated.ConclusionSYP-1018 had comparable pharmacokinetic and tolerability profiles to Vfend(®) after a single intravenous infusion. CYP2C19 genotype affected not only the pharmacokinetics of voriconazole, but its intrasubject variability. SYP-1018 can be further developed as a clinically effective alternative to Vfend(®).

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Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization.

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