Prophylactic administration of voriconazole with two different doses for invasive fungal infection in children and adolescents with acute myeloid leukemia

Sano, Hirozumi; Kobayashi, Ryōji; Hori, Daiki; Kishimoto, Kenji; Suzuki, Daisuke; Yasuda, Kazue; Kobayashi, Kunihiko

doi:10.1016/j.jmii.2016.05.002

Cited by 13 publications

(15 citation statements)

References 34 publications

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“…Total drug concentration of VRC in 932 plasma samples from 193 patients were determined by a HPLC-MS/MS method. The C max (1336 ± 676 ng/ml) in steady state of VRC reached therapeutic window (1,000-5,500 ng/ml) (Cabral-Galeano et al, 2015;Sano et al, 2018). However, there was still wide inter-individual variability in plasma concentration of VRC mostly associated with the diversity of metabolic types (CYP2C19) (Hamadeh et al, 2017).…”

Section: Discussionmentioning

confidence: 98%

The Impact of Plasma Protein Binding Characteristics and Unbound Concentration of Voriconazole on Its Adverse Drug Reactions

et al. 2020

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This study investigated voriconazole (VRC) unbound plasma concentration and its relationship with adverse drug reactions (ADRs) in patients with malignant hematologic disease. Plasma samples were collected from patients or spiked in vitro. A time-saving rapid equilibrium dialysis assay was used for the separation of unbound and bound VRC, following a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis method for drug concentration detection. Liver function and treatment details were collected from the electronic medical records of patients. Protein concentration was determined according to instructions. VRC plasma protein binding rate (PPB) in patient is significantly higher [69.5 ± 6.2%] than that in in-vitro samples, influenced by total drug concentration (C t), plasma protein concentration, and protein type. The a1-acid glycogen (AAG) has the highest affinity with VRC. Relationship between total PPB of VRC with PPB of individual protein is not a simple addition, but a compressive combination. Unbound drug concentration (C u) of VRC shows significant relationships with C t , protein concentration, AST level, metabolism type of CYP2C19 and coadministration of high PPB medicines. Unbound plasma concentration of VRC shows a more sensitive relationship with ADRs than C t .

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Section: Discussionmentioning

confidence: 98%

The Impact of Plasma Protein Binding Characteristics and Unbound Concentration of Voriconazole on Its Adverse Drug Reactions

et al. 2020

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“…They are also close to the loading dose of 7 mg/kg BID recommended by the Infectious Disease Society of America (IDSA) (Pappas et al, 2009), except for 12 mg/kg, which is the recommended dosage for 2-6-year-old NMs. Although the tolerance of higher dosage up to 10 mg/kg in children has been confirmed (Sano et al, 2016), further validation of this regimen's exposure and safety is needed before implementing it in clinical practice. In other subpopulations, dose adjustment is proposed based on several factors.…”

Section: Discussionmentioning

confidence: 99%

Application of a Physiologically Based Pharmacokinetic Model to Characterize Time-dependent Metabolism of Voriconazole in Children and Support Dose Optimization

et al. 2021

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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.

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“…Hence, we administered VRCZ as IFI prophylaxis for patients with AML. 15 However, the effectiveness of VRCZ for prophylaxis of IFI was inconsistent. This has prompted us to attempt dose adjustment of prophylactic VRCZ using blood concentration for patients with AML.…”

Section: Discussionmentioning

confidence: 99%

“…In these studies, we found AML, recurrent disease, and age over 9 years as risk factors for IFI. Hence, we administered VRCZ as IFI prophylaxis for patients with AML 15 . However, the effectiveness of VRCZ for prophylaxis of IFI was inconsistent.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of liposomal amphotericin against febrile neutropenia in pediatric patients receiving prophylactic voriconazole

Kobayashi

Matsushima

Hori

et al. 2021

Pediatrics International

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Background: The risk factors for invasive fungal infection have gradually become evident for pediatric patients with hematological diseases. Here we analyze the efficacy of liposomal amphotericin (L-AMB) for pediatric patients with febrile neutropenia using prophylactic voriconazole (VRCZ). Method: We administered L-AMB (2.5 mg/kg/day) in patients with febrile neutropenia who were receiving prophylactic VRCZ (10 mg/kg/day, orally) and were resistant to second-line antibiotics therapy. Thirteen patients (5 males, 8 females) with 19 febrile neutropenia episodes were targeted in this analysis. The median age of the patients was 14 years (range, 1-19 years). Eighteen out of 19 episodes occurred in patients with acute myeloid leukemia, with the remaining episode occurring in a patient with acute unclassified leukemia. Results: The median period from start of L-AMB administration to resolution of fever was 4 days (1-27 days). In 15 out of 19 episodes, fever resolved within 5 days from commencement of L-AMB administration. Using criteria proposed by T. J. Walsh et al., the success rate of L-AMB for febrile neutropenia was 89.5% in this study. Conclusions: Although the sample size of our study was small, the extremely high efficacy of L-AMB warrants its administration in patients with febrile neutropenia who are receiving VRCZ.

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Prophylactic administration of voriconazole with two different doses for invasive fungal infection in children and adolescents with acute myeloid leukemia

Abstract: More dose escalation is required based on this study. As VRCZ concentration is considerably influenced by genetic polymorphisms and drug-drug interactions, VRCZ should be used under therapeutic drug monitoring to keep effective drug concentrations.

Cited by 13 publications

References 34 publications

The Impact of Plasma Protein Binding Characteristics and Unbound Concentration of Voriconazole on Its Adverse Drug Reactions

The Impact of Plasma Protein Binding Characteristics and Unbound Concentration of Voriconazole on Its Adverse Drug Reactions

Application of a Physiologically Based Pharmacokinetic Model to Characterize Time-dependent Metabolism of Voriconazole in Children and Support Dose Optimization

Efficacy of liposomal amphotericin against febrile neutropenia in pediatric patients receiving prophylactic voriconazole

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