Xiao-Bin Lin1,2,3, Zi-Wei Li1,2,4, Miao Yan1,2, Bi-Kui Zhang1,2, Wu Liang5, Feng Wang1,2, Ping Xu1,2, Da-Xiong Xiang1,2, Xu-Biao Xie6, Shao-Jie Yu6, Gong-Bin Lan6, Feng-Hua Peng6. 1. Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China. 2. Institute of Clinical Pharmacy, Central South University, Changsha, Hunan, 410011, China. 3. Department of Pharmacy, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. 4. Department of Pharmacy, Ruijin Hospital Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. 5. Beijing Dryas Pharma-Tech Co. LTD., Beijing, 100085, China. 6. Department of Urological Organ Transplantation, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Abstract
AIMS: The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections. METHODS: A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed-effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model. RESULTS: A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l·h-1 , 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily. CONCLUSIONS: Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.
AIMS: The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections. METHODS: A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed-effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model. RESULTS: A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l·h-1 , 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily. CONCLUSIONS: Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.
Authors: F López-Medrano; M Fernández-Ruiz; J T Silva; P L Carver; C van Delden; E Merino; M J Pérez-Saez; M Montero; J Coussement; M de Abreu Mazzolin; C Cervera; L Santos; N Sabé; A Scemla; E Cordero; L Cruzado-Vega; P L Martín-Moreno; Ó Len; E Rudas; A P de León; M Arriola; R Lauzurica; M David; C González-Rico; F Henríquez-Palop; J Fortún; M Nucci; O Manuel; J R Paño-Pardo; M Montejo; P Muñoz; B Sánchez-Sobrino; A Mazuecos; J Pascual; J P Horcajada; T Lecompte; A Moreno; J Carratalà; M Blanes; D Hernández; M C Fariñas; A Andrés; J M Aguado Journal: Am J Transplant Date: 2016-05-31 Impact factor: 8.086
Authors: Andreas H Groll; Robert Townsend; Amit Desai; Nkechi Azie; Mark Jones; Marc Engelhardt; Anne-Hortense Schmitt-Hoffman; Roger J M Brüggemann Journal: Transpl Infect Dis Date: 2017-09-28 Impact factor: 2.228
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