Effect of cyclosporine A and polymorphisms in CYP2C19 and ABCC2 on the concentration of voriconazole in patients undergoing allogeneic hematopoietic stem cell transplantation
Xenobiotica; the fate of foreign compounds in biological systems. 2019;:1-19
1. Voriconazole is known to display highly variable pharmacokinetics affecting treatment efficacy and safety. This study aimed to identify the factors causing the variation of voriconazole concentration in patients with allogeneic hematopoietic stem cell transplantation. 2. The data of patients was collected, including clinical characteristics and voriconazole concentrations. A total of 5 single nucleotide polymorphisms of 3 candidate genes (CYP2C19, ABCC2, ABCG2) related to voriconazole metabolism were genotyped by MassArray method. The correlation between polymorphisms and voriconazole concentration was analyzed. 3. A total of 244 voriconazole concentrations of 43 patients were included in this study. The voriconazole concentration was significantly correlated with patients' total bile acid (P =0.001) and cyclosporin A (P < 0.001). The median concentration of the CYP2C19 normal metabolizers was remarkably lower than poor metabolizers (0.86 vs 2.27 mug/mL). The median concentration of ABCC2 rs2273697 GG genotype carriers was significantly higher than that of GA genotype carriers (P = 0.026). 4. The variability of voriconazole concentration is partially explained by total bile acid, metabolic types of CYP2C19. The voriconazole concentration of CYP2C19 normal metabolizers is likely to be lower than 1.0 mug/mL and thus at risk of infection due to inadequate treatment.
The impact of initiating posaconazole on tacrolimus pharmacokinetics in allogeneic stem cell transplantation
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2019;:1078155219833440
BACKGROUND Posaconazole reduces the risk of invasive Aspergillus in transplant patients, but significantly inhibits tacrolimus metabolism. One study demonstrated that a three-fold dose reduction of tacrolimus was required to obtain therapeutic concentrations when used with posaconazole. However, with empiric dose reduction, there is a risk of subtherapeutic tacrolimus levels and subsequent graft failure or graft-versus-host disease. Overall, the existing data on the impact of posaconazole on tacrolimus pharmacokinetics is limited. OBJECTIVE The purpose of this study is to determine whether tacrolimus doses should be decreased upon initiation of posaconazole in patients receiving an allogeneic stem cell transplant. METHODS This is a retrospective chart review at an academic medical center. All allogeneic stem cell transplant adults who received concomitant posaconazole and tacrolimus from February 2016 through December 2017 were included. RESULTS Seventy-nine patients identified using an internal electronic database were analyzed. The median time to therapeutic tacrolimus concentration was significantly longer in patients who did not receive an empiric dose reduction (0% DR, 10d; 1-30% DR, 4d; 31-65% DR, 5d; >65% DR, 4d; p = 0.0395). The rate of supratherapeutic levels was highest amongst patients who did not receive an empiric DR, and was noted to be significant compared to the group that had 31-65% DR ( p < 0.001). CONCLUSION This study validates our current practice of instituting an empiric 50% dose reduction of oral tacrolimus to 0.03 mg/kg/day when used concomitantly with posaconazole to achieve therapeutic levels in allogeneic stem cell transplant patients.
Tacrolimus blood concentration increase depends on administration route when combined with voriconazole in pediatric stem cell transplant recipients
Pediatric transplantation. 2019;:e13619
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.
High incidence of Pneumocystis jirovecii pneumonia in allogeneic hematopoietic cell transplant recipients in the modern era
BACKGROUND International guidelines for Pneumocystis jirovecii pneumonia (PJP) prevention recommend prophylaxis for ≥6 months following allogeneic hematopoietic cell transplantation, and longer in patients with graft-versus-host disease (GVHD) or on immunosuppressive therapy (IST). These recommendations are based on cohorts of patients who did not routinely receive anti-thymocyte globulin (ATG) for GVHD prophylaxis. METHODS We performed a retrospective chart review of 649 patients, all of whom received ATG as part of GVHD prophylaxis. RESULTS The cumulative incidence of definite PJP was 3.52% at both 3 and 5 years (median follow up, 1648 days for survivors). PJP occurred in 13 non-GVHD patients between days 207 and 508, due in part to low CD4 T-cell counts (<200 CD4 T cells/microL). PJP occurred in eight GVHD patients between days 389 and 792, due in part to non-adherence to PJP prophylaxis guidelines (discontinuation of PJP prophylaxis at <3 months after discontinuation of IST). Breakthrough PJP infection was not observed in patients receiving prophylaxis with cotrimoxazole, dapsone or atovaquone, whereas three cases were observed with inhaled pentamidine. DISCUSSION In conclusion, for non-GVHD patients receiving ATG-containing GVHD prophylaxis, 6 months of PJP prophylaxis is inadequate, particularly if the CD4 T-cell count is <200 cells/microL or if there is a high incidence of PJP in the community. For patients with GVHD receiving ATG-containing GVHD prophylaxis, continuing PJP prophylaxis until ≥3 months post-discontinuation of IST is important. Cotrimoxazole, dapsone and atovaquone are preferred over inhaled pentamidine.
Influence of azole antifungal drugs on blood tacrolimus levels after switching from intravenous tacrolimus to once-daily modified release tacrolimus in patients receiving allogeneic hematopoietic stem cell transplantation
Journal of clinical pharmacy and therapeutics. 2019
WHAT IS KNOWN AND OBJECTIVE Azole antifungal drugs are often co-administered with tacrolimus after allogeneic hematopoietic stem cell transplantation (HSCT). However, the influence of azole antifungal drugs on variation in tacrolimus pharmacokinetics when switching from intravenous tacrolimus (Tac-iv) to once-daily modified release tacrolimus (Tac-MR) remains to be elucidated. This study was performed to evaluate the effects of oral azole antifungal drugs on variation in tacrolimus pharmacokinetics after conversion to Tac-MR in HSCT patients. METHODS Patients concomitantly receiving fluconazole (FLCZ) or voriconazole (VRCZ) along with tacrolimus were evaluated retrospectively. Blood tacrolimus concentrations before and after changing to oral administration were compared between FLCZ and VRCZ groups. RESULTS AND DISCUSSION A total of 52 patients (34 FLCZ and 18 VRCZ) were included in the analysis. There were no significant differences in the most recent daily dose (Div ) and blood level (Civ ) of Tac-iv, Civ /Div , and ratio of daily dose of tacrolimus on the first to second day after changing to Tac-MR (Dpo1-2 ) to Div between FLCZ and VRCZ groups (P > 0.2). The trough levels of tacrolimus on the first to second day after switching to Tac-MR (Cpo1-2 ) and on the third to fifth day after the switch (Cpo3-5 ) were significantly higher in the VRCZ group than the FLCZ group (P < 0.05). The values of (Civ /Div )/(Cpo1-2 /Dpo1-2 ) and (Civ /Div )/(Cpo3-5 /Dpo3-5 ) in the VRCZ group were significantly lower compared with those in the FLCZ group (P < 0.05). Furthermore, individual values of (Civ /Div )/(Cpo3-5 /Dpo3-5 ) in the FLCZ group varied widely. WHAT IS NEW AND CONCLUSION Voriconazole increased blood tacrolimus level more markedly than FLCZ after switching to Tac-MR, whereas FLCZ caused a large variation in tacrolimus blood level. These results suggest that therapeutic monitoring of tacrolimus after the switch may need to be performed carefully considering that orally co-administered VRCZ and FLCZ exhibit different change in blood tacrolimus level just after the switch.
Effect of Isavuconazole on Tacrolimus and Sirolimus Serum Concentrations in Allogeneic Hematopoietic Stem Cell Transplant Patients: A Drug-Drug Interaction Study
Transplant infectious disease : an official journal of the Transplantation Society. 2018;:e13007
INTRODUCTION Isavuconazole, a triazole antifungal, is an inhibitor of cytochrome P450 3A4, which also metabolizes tacrolimus and sirolimus. In previous studies, isavuconazole administration increased tacrolimus and sirolimus area under the curve values by 2.3-fold and 1.8-fold, respectively, in healthy adults and tacrolimus concentration/dose (C/D) ratio by 1.3-fold in solid organ transplant patients. We aimed to determine the magnitude of effect of isavuconazole administration on tacrolimus and sirolimus C/D ratios in allogeneic hematopoietic stem cell transplant (alloHSCT) patients. METHODS A retrospective, single-center, single-arm study in adult alloHSCT patients who received at least ten days of combination therapy with isavuconazole and tacrolimus and/or sirolimus as inpatients or outpatients was conducted. Tacrolimus and sirolimus trough serum concentrations were measured up to twice weekly for up to four weeks. RESULTS Twenty-two patients receiving tacrolimus and twenty patients receiving sirolimus met the inclusion criteria. The mean C/D ratio increased from baseline by 1.42-fold for tacrolimus during week 1 (p = 0.002) and up to 1.56-fold for sirolimus during week 2 (p = 0.02). For the remaining timepoints, tacrolimus and sirolimus C/D ratios were not statistically significantly different from baseline. CONCLUSION In alloHSCT patients, modest increases in tacrolimus and sirolimus C/D ratios from baseline were observed within the first 2 weeks after initiation of isavuconazole. This article is protected by copyright. All rights reserved.
Dose adjustment of immunosuppressants during co-administration of posaconazole: a systematic review
Clinical and investigative medicine. Medecine clinique et experimentale. 2018;41(1):E5-e15
PURPOSE The purpose of this retrospective study was to analyze the dose adjustment of immunosuppressants (cyclosporine, tacrolimus and sirolimus) for the patients with allogeneic hematopoietic stem cell and solid-organ (heart/lung) transplantation during co-administration of posaconazole. METHODS MEDLINE, EMBASE and Cochrane Library were searched from January 1, 2000 to June 30, 2017 for clinical reports of patients who received allogeneic hematopoietic stem cell and organ transplantation and were co-administered posaconazole and immunosuppressants (cyclosporine, tacrolimus or sirolimus). RESULTS Seven studies were included in the systematic review with a total of 215 patients. Five studies involved hematopoietic stem cell transplant, one heart transplant and one lung transplant. In general, the co-administration of posaconazole with sirolimus, tacrolimus or cyclosporine necessitated immunosuppressant dose reductions to maintain the levels of the drug in the optimal therapeutic range. Reported dose reductions were 50%-68% for sirolimus, 75% for tacrolimus and 14%-49% for cyclosporine. The findings were similar for hematopoietic stem cell, heart or lung transplantation studies. CONCLUSION Our findings indicate that, when posaconazole is co-administered, the dosage of sirolimus and tacrolimus should be reduced by 60%-70% and for cyclosporine and by 30%-40% following allogeneic hematopoietic stem cell and solid-organ transplantation.