1.
Effects of voriconazole on population pharmacokinetics and optimization of the initial dose of tacrolimus in children with chronic granulomatous disease undergoing hematopoietic stem cell transplantation
Chen, X., Wang, D., Lan, J., Wang, G., Zhu, L., Xu, X., Zhai, X., Xu, H., Li, Z.
Annals of translational medicine. 2021;9(18):1477
Abstract
BACKGROUND This study aimed to explore the effects of voriconazole on population pharmacokinetics and optimization of the initial dose of tacrolimus in children with chronic granulomatous disease (CGD) undergoing hematopoietic stem cell transplantation (HSCT). METHODS Thirty-four children with CGD undergoing HSCT were assessed to establish a population pharmacokinetic model (PPM) using the non-linear mixed effect. Tacrolimus concentrations were simulated by the Monte Carlo method in children weighing <25 kg at different doses. RESULTS In the final model, weight and concomitant use of voriconazole were included as covariates. With the same weight, the relative value of tacrolimus clearance was 1:0.388 in children not taking voriconazole: children taking voriconazole. Compared with children not taking voriconazole, the measured tacrolimus concentrations were all higher in children taking voriconazole (P<0.01); however, these were not corrected by dose or body weight for concentration differences. Thus, we simulated the tacrolimus concentrations using different body weights (5-25 kg) and different dose regimens (0.1-0.8 mg/kg/day) for the same body weight and dose. Tacrolimus concentrations in children taking voriconazole were higher than those in children not taking voriconazole (P<0.01). Also, in children with CGD undergoing HSCT who were not taking voriconazole, the initial dose regimen of 0.5 mg/kg/day was recommended for body weights of 5-10 kg, and 0.4 mg/kg/day was recommended for body weights of 10-25 kg. In children with CGD undergoing HSCT who were taking voriconazole, an initial dose regimen of 0.3 mg/kg/day was recommended for body weights of 5-25 kg. CONCLUSIONS We established, for the first time, a PPM of tacrolimus in children with CGD undergoing HSCT in which voriconazole significantly increased tacrolimus concentrations. In addition, the initial dose of tacrolimus in children with CGD undergoing HSCT was recommended.
2.
Tacrolimus blood concentration increase depends on administration route when combined with voriconazole in pediatric stem cell transplant recipients
Utano, T., Kato, M., Osumi, T., Shioda, Y., Kiyotani, C., Terashima, K., Tomizawa, D., Matsumoto, K., Yamatani, A.
Pediatric transplantation. 2019;:e13619
Abstract
BACKGROUND Understanding of TAC pharmacokinetics is required to avoid both overdosing and underdosing. VRCZ is known to increase the TAC blood concentration by inhibiting CYP3A4; however, detailed, practical information on pediatric cases is still scarce. Herein, we investigated the association between the TAC blood concentration and dosage focusing on the administration route and concomitant use of VRCZ in children. METHODS In total, 38 children who received TAC during stem cell transplantation at our hospital between January 2013 and April 2018 were included. The ratio of the TAC blood concentration (ng/mL) to dosage (mg/kg/day) (C/D) was calculated at the last continuous intravenous infusion (C/Div) and after switching to oral administration (C/Dpo). RESULTS Patients with VRCZ (n = 14) showed a higher C/D regardless of administration route (median C/Div: with VRCZ/without VRCZ = 832/643, median C/Dpo: with VRCZ/without VRCZ = 339/45). Additionally, the (C/Div)/(C/Dpo) was about one-fourth in cases with VRCZ; the median (C/Div)/(C/Dpo) was 3.3 for cases with VRCZ and 13.5 for cases without VRCZ. Interestingly, the increase in the TAC blood concentration due to VRCZ was higher when TAC was administered orally, especially in adolescent patients. CONCLUSIONS To obtain an optimal TAC blood concentration, dose adjustment based on multiple factors, such as administration route, concomitant use of VRCZ, and age, is required.