Evaluation of Voriconazole CYP2C19 Phenotype-Guided Dose Adjustments by Physiologically Based Pharmacokinetic Modeling

Zubiaur, Pablo; Kneller, Lisa Alina; Ochoa, Dolores; Mejía, Gina; Saiz‐Rodríguez, Miriam; Borobia, Alberto M.; Koller, Dóra; García, Irene García; Navares‐Gómez, Marcos; Hempel, Georg; Abad‐Santos, Francisco

doi:10.1007/s40262-020-00941-8

Cited by 16 publications

(11 citation statements)

References 17 publications

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“…Furthermore, CYP2C19 phenotype is a clear predictor of drug metabolism ( Moriyama et al, 2017 ). Therefore, a reduction or increase in dose is not directly related to an increase in exposure or in the chances of achieving efficacy ( Theuretzbacher et al, 2006 ; Zubiaur et al, 2021 ). Studies such as the present one are important to confirm this pharmacokinetic characteristic, which enables more predictable dosage adjustments of the drug.…”

Section: Discussionmentioning

confidence: 99%

Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine

Calleja

Zubiaur²,

Ochoa³

et al. 2023

Front. Pharmacol.

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Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study was to evaluate the impact of 29 alleles in 12 candidate genes (e.g., CYP enzymes like CYP2D6, CYP3A4, or CYP2C19; ABC transporters like ABCB1; SLCO1B1; and UGT enzymes like UGT1A1) on desvenlafaxine pharmacokinetic variability and tolerability. Pharmacokinetic parameters and adverse drug reaction (ADR) incidence obtained from six bioequivalence clinical trials (n = 98) evaluating desvenlafaxine formulations (five with single dose administration and one with multiple-dose administration) were analyzed. No genetic polymorphism was related to pharmacokinetic variability or ADR incidence. Volunteers enrolled in the multiple-dose clinical trial also showed a higher incidence of ADRs, e.g., xerostomia or appetite disorders. Volunteers experiencing any ADR showed a significantly higher area under the time-concentration curve (AUC) than those not experiencing any ADR (5115.35 vs. 4279.04 ng*h/mL, respectively, p = 0.034). In conclusion, the strong dose-dependent relationship with the occurrence of ADRs confirms that the mechanism of action of desvenlafaxine is essentially dose-dependent.

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Section: Discussionmentioning

confidence: 99%

Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine

Calleja

Zubiaur²,

Ochoa³

et al. 2023

Front. Pharmacol.

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“…For slow metabolizers, the dose should be reduced by 50% and for fast metabolizers, increased by 50%. Similarly, Zubiaur et al 36 used a physiology-based pharmacokinetic model to analyze the dose adjustment of voriconazole in a study and suggested that the standard dosing regimen in the current guidelines may only be applicable to the normometabolic phenotype.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic drug monitoring and safety evaluation of voriconazole in the treatment of pulmonary fungal diseases

Shen

Wang

et al. 2022

Therapeutic Advances in Drug Safety

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Aims: The gene polymorphism of voriconazole metabolism–related liver enzyme is notable in East Asia population. It casts a significant influence on the rational use of voriconazole. We conducted this study to investigate the relationship between steady-state voriconazole trough concentration (Ctrough) and adverse effects (AEs), especially hepatotoxicity. Methods: We conducted a real-world study in the Jinling Hospital from January 2015 to June 2020. A total of 140 patients receiving voriconazole were enrolled in this study. The determination and scoring of voriconazole-associated hepatotoxicity were performed according to the Roussel Uclaf Causality Assessment Method scoring scale and the severity of hepatotoxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE). Results: Elevated steady-state voriconazole Ctrough with concomitant AEs are the most common reason for dose adjustments during treatment. Compared with the group without any AEs, voriconazole Ctrough was significantly higher in the hepatotoxicity and neurotoxicity groups, and the incidence of both events showed an overall increasing trend with increasing voriconazole Ctrough. Hepatotoxicity occurred in 66.7% of patients within 7 days of the first dose of voriconazole and 94.4% within 15 days of the dose. Steady-state voriconazole Ctrough >3.61 mg/l was associated with an increased incidence of hepatotoxicity (area under the curve = 0.645, p = 0.047). Logistic regression analysis showed that timely voriconazole dose adjustment was a predictor of attenuated hepatotoxicity after adjustment for confounders, but hepatotoxicity was not associated with voriconazole Ctrough measured at a single time point. Conclusion: Hepatotoxicity and neurotoxicity correlate with voriconazole Ctrough, and dose reduction in patients with elevated steady-state voriconazole Ctrough may prevent hepatotoxicity. In patients with early occurrence of hepatotoxicity, initial therapeutic drug monitoring (TDM) might predict the risk of hepatotoxicity. Follow-up TDM may be necessary to predict late onset hepatotoxicity. Plain Language Summary Safety of voriconazole for the treatment of pulmonary fungal diseases Introduction: Several studies have suggested an association between the concentration of voriconazole in the blood and liver damage, but the evidence is weak. This study aimed to investigate relationships between voriconazole drug concentration and side effects and to analyze the factors affecting liver damage caused by voriconazole. Methods: We conducted a study at the Jinling Hospital from January 2015 to June 2020, in which a total of 140 patients were finally enrolled. Results: Voriconazole doses were adjusted in 44 patients due to abnormal voriconazole drug concentration or side effects, 32 patients reduced the dose and 8 patients increased the dose. An elevated liver enzyme level was the most common cause for dose adjustment. After the first dose adjustment, most patients achieved the target drug concentration. A total of 18 patients were determined as probable or highly probable to have drug-induced liver injury from voriconazole. Voriconazole drug concentration was significantly higher in the liver damage and nervous system damage groups as compared with the group without any side effects, and most liver damage events occurred within 14 days of the first dose. Voriconazole drug concentration >3.61 mg/l was associated with an increased incidence of liver damage. Conclusion: In this study, approximately one-third of patients with pulmonary fungal disease needed to adjust their dose after the standard dose of voriconazole treatment. The incidence of liver damage and nervous system damage showed an overall increasing trend with increasing voriconazole baseline concentrations. Initial therapeutic drug monitoring may be predictive of liver damage. Follow-up monitoring of liver enzymes may be needed.

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“…VCZ is rapidly absorbed, and its plasma levels depend on body weight, age, route of administration, presence of polymorphisms, and inflammation, among other factors [ 162 , 163 , 164 , 165 ]. After oral administration, the maximum plasma concentration occurs within 1 to 2 h, reaching about 96% [ 166 ].…”

Section: Voriconazolementioning

confidence: 99%

Nanotechnology-Based Approaches for Voriconazole Delivery Applied to Invasive Fungal Infections

et al. 2023

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Invasive fungal infections increase mortality and morbidity rates worldwide. The treatment of these infections is still limited due to the low bioavailability and toxicity, requiring therapeutic monitoring, especially in the most severe cases. Voriconazole is an azole widely used to treat invasive aspergillosis, other hyaline molds, many dematiaceous molds, Candida spp., including those resistant to fluconazole, and for infections caused by endemic mycoses, in addition to those that occur in the central nervous system. However, despite its broad activity, using voriconazole has limitations related to its non-linear pharmacokinetics, leading to supratherapeutic doses and increased toxicity according to individual polymorphisms during its metabolism. In this sense, nanotechnology-based drug delivery systems have successfully improved the physicochemical and biological aspects of different classes of drugs, including antifungals. In this review, we highlighted recent work that has applied nanotechnology to deliver voriconazole. These systems allowed increased permeation and deposition of voriconazole in target tissues from a controlled and sustained release in different routes of administration such as ocular, pulmonary, oral, topical, and parenteral. Thus, nanotechnology application aiming to delivery voriconazole becomes a more effective and safer therapeutic alternative in the treatment of fungal infections.

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Evaluation of Voriconazole CYP2C19 Phenotype-Guided Dose Adjustments by Physiologically Based Pharmacokinetic Modeling

Cited by 16 publications

References 17 publications

Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine

Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine

Therapeutic drug monitoring and safety evaluation of voriconazole in the treatment of pulmonary fungal diseases

Nanotechnology-Based Approaches for Voriconazole Delivery Applied to Invasive Fungal Infections

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