High voriconazole target-site exposure after approved sequence dosing due to nonlinear pharmacokinetics assessed by long-term microdialysis

Kirbs, Claudia; Kluwe, Franziska; Drescher, Franziska; Lackner, Edith; Matzneller, Peter; Weiß, Johanna; Zeitlinger, Markus; Kloft, Charlotte

doi:10.1016/j.ejps.2019.02.001

Cited by 16 publications

(20 citation statements)

References 73 publications

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“…These results are consistent with those of our study. Those with phenotype of CYP2C19 poor metabolizers might have a higher risk of adverse events, in line with what has been previously observed 21,27–29 …”

Section: Discussionsupporting

confidence: 87%

“…Those with phenotype of CYP2C19 poor metabolizers might have a higher risk of adverse events, in line with what has been previously observed. 21,[27][28][29] The allele frequencies of CYP2C19 were consistent with the results in Asians reported by Mikus et al 24 That is why regulatory agencies include CYP2C19 as the only major pharmacogenetic biomarker in their dosing guidelines. 17 In addition, there are still many other genotypes, such as…”

Section: Discussionsupporting

confidence: 86%

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Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients

Zhao

Lin

Zhang

et al. 2020

Clinical Translational Sci

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Voriconazole is the mainstay for the treatment of invasive fungal infections in patients who underwent a kidney transplant. Variant CYP2C19 alleles, hepatic function, and concomitant medications are directly involved in the metabolism of voriconazole. However, the drug is also associated with numerous adverse events. The purpose of this study was to identify predictors of adverse events using binary logistic regression and to measure its trough concentration using multiple linear modeling. We conducted a prospective analysis of 93 kidney recipients cotreated with voriconazole and recorded 213 trough concentrations of it. Predictors of the adverse events were voriconazole trough concentration with the odds ratios (OR) of 2.614 (P = 0.016), cytochrome P450 2C19 (CYP2C19), and hemoglobin (OR 0.181, P = 0.005). The predictive power of these three factors was 91.30%. We also found that CYP2C19 phenotypes, hemoglobin, platelet count, and concomitant use of ilaprazole had quantitative relationships with voriconazole trough concentration. The fit coefficient of this regression equation was R 2 = 0.336, demonstrating that the model explained 33.60% of interindividual variability in the disposition of voriconazole. In conclusion, predictors of adverse events are CYP2C19 phenotypes, hemoglobin, and voriconazole trough concentration. Determinants of the voriconazole trough concentration were CYP2C19 phenotypes, platelet count, hemoglobin, concomitant use of ilaprazole. If we consider these factors during voriconazole use, we are likely to maximize the treatment effect and minimize adverse events. Invasive fungal infections are a feared complication in kidney transplant recipients, occurring in 0.1-3.5% of solid organ recipients. 1 Its 12-week survival rates were only 60.7%, and 22.1% of the survivors experienced graft loss because of invasive fungal infections. 2 Kidney transplantation, in conjunction with calcineurin inhibitors, is regarded as the best

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 86%

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients

Zhao

Lin

Zhang

et al. 2020

Clinical Translational Sci

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“…The performed IVIVE additionally confirmed the validity of the generated data. In clinical studies, VRC clearances of 244 mL/min (first dose, all genotypes) [ 24 ], 420 mL/min (first dose, normal metabolizers), 194 mL/min (first dose, heterozygous normal metabolizers), 149 mL/min (first dose, poor metabolizers) [ 23 ] and 272 mL/min (multiple dose, all genotypes) [ 77 ] have been reported. Thus, the estimated hepatic clearance of 127–266 mL/min, as derived from the IVIVE presented here, represents a good approximation, considering that only one metabolic pathway, VRC N -oxidation, was taken into account.…”

Section: Discussionmentioning

confidence: 99%

Towards the Elucidation of the Pharmacokinetics of Voriconazole: A Quantitative Characterization of Its Metabolism

et al. 2022

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The small-molecule drug voriconazole (VRC) shows a complex and not yet fully understood metabolism. Consequently, its in vivo pharmacokinetics are challenging to predict, leading to therapy failures or adverse events. Thus, a quantitative in vitro characterization of the metabolism and inhibition properties of VRC for human CYP enzymes was aimed for. The Michaelis–Menten kinetics of voriconazole N-oxide (NO) formation, the major circulating metabolite, by CYP2C19, CYP2C9 and CYP3A4, was determined in incubations of human recombinant CYP enzymes and liver and intestine microsomes. The contribution of the individual enzymes to NO formation was 63.1% CYP2C19, 13.4% CYP2C9 and 29.5% CYP3A4 as determined by specific CYP inhibition in microsomes and intersystem extrapolation factors. The type of inhibition and inhibitory potential of VRC, NO and hydroxyvoriconazole (OH–VRC), emerging to be formed independently of CYP enzymes, were evaluated by their effects on CYP marker reactions. Time-independent inhibition by VRC, NO and OH–VRC was observed on all three enzymes with NO being the weakest and VRC and OH–VRC being comparably strong inhibitors of CYP2C9 and CYP3A4. CYP2C19 was significantly inhibited by VRC only. Overall, the quantitative in vitro evaluations of the metabolism contributed to the elucidation of the pharmacokinetics of VRC and provided a basis for physiologically-based pharmacokinetic modeling and thus VRC treatment optimization.

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“…While results are very promising, when evaluating drug concentrations in tissues, there are considerations. Protein binding was not measured in the tissue homogenates, however it is expected to be comparable to the 31.68 ± 1.92% reported in plasma for horses [31][32][33]. Even though we could not determine the voriconazole distribution on a cellular level, the various compartments from the tissue samples are potential targets of fungal invasion [34].…”

Section: Discussionmentioning

confidence: 71%

Sustained-release voriconazole-thermogel for subconjunctival injection in horses: ocular toxicity and in-vivo studies

et al. 2020

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Background: Keratomycosis is a relatively common, sight threatening condition in horses, where treatment is often prolonged and costly. Subconjunctival (SCo) injections offer less resistance to drug diffusion than the topical route, resulting in better penetration to the ocular anterior segment. Voriconazole, a second generation triazole antifungal, is effective against common fungal organisms causing keratomycosis. If combined with a thermogel biomaterial, voriconazole can be easily injected in the SCo space to provide sustained drug release. The purpose of this study was to evaluate the drug concentrations in the anterior segment and clinical effects after SCo injections of voriconazole-containing thermogel: poly (DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) in healthy equine eyes. Results: Voriconazole aqueous humor (AH) and tear concentrations were compared between 6 horses, receiving 1% voriconazole applied topically (0.2 mL, q4h) (Vori-Top) or 1.7% voriconazole-thermogel (0.3 mL) injected SCo (Vori-Gel). For the Vori-Gel group, voriconazole concentrations were measured in AH and tears at day 2 and then weekly for 23 days, and at day 2 only for the Vori-Top group. Ocular inflammation was assessed weekly (Vori-Gel) using the modified Hackett-McDonald scoring system. Ocular tissue concentrations of voriconazole following SCo 1.7% voriconazole-thermogel (0.3 mL) injections were evaluated post euthanasia in 6 additional horses at 3 different time points. Three horses received bilateral injections at 2 h (n = 3, right eye (OD)) and 48 h (n = 3, left eye (OS)) prior to euthanasia, and 3 horses were injected unilaterally (OS), 7 days prior to euthanasia. Voriconazole-thermogel was easily injected and well tolerated in all cases, with no major adverse effects. On day 2, drug concentrations in tears were higher in the Vori-Top, but not statistically different from Vori-Gel groups. For the Vori-Gel group, voriconazole was non-quantifiable in the AH at any time point. Total voriconazole concentrations in the cornea were above 0.5 μg/g (the target minimum inhibitory concentration (MIC) for Aspergillus sp.) for up to 48 h; however, concentrations were below this MIC at 7 days post treatment. Conclusions: Voriconazole-thermogel was easily and safely administered to horses, and provided 48 h of sustained release of voriconazole into the cornea. This drug delivery system warrants further clinical evaluation.

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High voriconazole target-site exposure after approved sequence dosing due to nonlinear pharmacokinetics assessed by long-term microdialysis

Cited by 16 publications

References 73 publications

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients

Towards the Elucidation of the Pharmacokinetics of Voriconazole: A Quantitative Characterization of Its Metabolism

Sustained-release voriconazole-thermogel for subconjunctival injection in horses: ocular toxicity and in-vivo studies

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