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Bone Marrow Transplantation (2010) 45, 1352–1356 & 2010 Macmillan Publishers Limited All rights reserved 0268-3369/10
/bmt
ORIGINAL ARTICLE
Correspondence: Dr J Mehta, Department of Hematology/Oncology, Northwestern Memorial Hospital, 676 N St Clair Street, Suite 850, Chicago, IL 60611, USA. E-mail: j-mehta@ Received 17 August 2009; revised 12 October 2009; accepted 20 October 2009; published online 7 December 2009
Patients and methods
A retrospective cohort analysis was completed for patients receiving voriconazole and tacrolimus according to the
Voriconazole–tacrolimus interaction in HSCT SM Trifilio et al
Concomitant use of tacrolimus and voriconazole, both competitive inhibitors of the CYP450 3A4 isoenzyme, requires tacrolimus dose reduction. On the basis of clinical observations, we developed a preemptive dose-reduction strategy in allograft recipients who received voriconazole to maintain tacrolimus concentrations within a target range. A total of 27 patients started i.v. tacrolimus at an average daily dose of 0.022 mg/kg on day À1 (30% lesser than the usual starting dose). The dose was reduced by 30–40% if the 48-h steady-state concentration was 7–10 ng/ml, and by 40–50% if it was 10–15 ng/ml. No change was made if the concentration was o7 ng/ml. Subsequently, concentrations were generally monitored 2–3 times a week with dose adjustments as necessary. None of the 170 levels (3–12 per patient; median 5) obtained between days þ 1 and þ 16 were subtherapeutic (o5 ng/ml) and only 34 levels (20%) were 415 ng/ml. Each patient required dose reduction at least twice. The dose had to be increased in only two patients after the initial dose reduction. The median tacrolimus doses in mg/kg declined with time; being 0.022, 0.008 and 0.006 on days 0, 7 and 14, respectively. We conclude that a preemptive dose-reduction strategy is effective in maintaining tacrolimus concentrations within the desired therapeutic range, although serial monitoring remains prudent. Bone Marrow Transplantation (2010) 45, 1352–1356; doi:10.1038/bmt.2009.345; published online 7 December 2009 Keywords: voriconazole; tacrolimus; interaction; dosing scheme; hematopoietic SCT; therapeutic drug monitnically observed that multiple adjustments Pearson correlation coefficient was used to assess for a
Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring
Tacrolimus is primarily metabolized by the cytochrome P450 3A4 isoenzyme system. In addition, tacrolimus is also highly metabolized by CYP3A5.5 The peri-transplant period is characterized by the administration of numerous drugs that can affect the cytochrome P450 system and alter tacrolimus clearance. Population pharmacokinetic studies in HSCT recipients have shown that liver or kidney impairment can result in decreased tacrolimus clearance and increased blood tacrolimus concentrations.6
Introduction
Tacrolimus is widely used for the prevention of GVHD after allogeneic hematopoietic SCT(HSCT).1,2 Adverse events such as renal and hepatic toxicity have been associated with increased tacrolimus blood concentrations after HSCT.3,4 Such adverse reactions may be preventable with therapeutic drug monitoring and coordinated dose adjustments.
Invasive fungal infections are a source of considerable morbidity and mortality after HSCT. Voriconazole is a triazole drug with a broad spectrum of activity, and is one of the agents used for fungal prophylaxis after allogeneic HSCT.7,8 Voriconazole is a competitive inhibitor for the cytochrome P450 3A4, 2C9 and 2C19 isosenzyme systems.9,10 Predictably, numerous serious drug interactions have been described for voriconazole when combined with other drugs metabolized through these systems, including tacrolimus.11,12 As reported by others,12 we observed increased tacrolimus blood concentrations when this agent was administered concomitantly with voriconazole. Bringing the concentration back within the target range required significant dose reduction multiple times. From clinical observations, we empirically developed a preemptive, twostep dose-reduction strategy for clinical use. In this report, we evaluate the success of this preemptive dose-reduction strategy in adjusting serial tacrolimus blood concentration levels in 27 patients after HSCT.
SM Trifilio1,2, MH Scheetz2,3, J Pi1,2 and J Mehta1,4
1Hematopoietic Stem Cell Transplant Program, Northwestern Memorial Hospital, Chicago, IL, USA; 2Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA; 3Department of Pharmacy Practice; Midwestern University Chicago College of Pharmacy, Chicago, IL, USA and 4The Feinberg School of Medicine; The Robert H. Lurie Comprehensive Cancer Center; Northwestern University, Chicago, IL, USA
1353
preemptive dose-reduction strategy. When voriconazole
Statistical analysis was performed using Intercooled Stata,
was initiated orally (200 mg twice daily from day 0 version 10.1 (Statacorp, College Station, TX, USA). The
/bmt
ORIGINAL ARTICLE
Correspondence: Dr J Mehta, Department of Hematology/Oncology, Northwestern Memorial Hospital, 676 N St Clair Street, Suite 850, Chicago, IL 60611, USA. E-mail: j-mehta@ Received 17 August 2009; revised 12 October 2009; accepted 20 October 2009; published online 7 December 2009
Patients and methods
A retrospective cohort analysis was completed for patients receiving voriconazole and tacrolimus according to the
Voriconazole–tacrolimus interaction in HSCT SM Trifilio et al
Concomitant use of tacrolimus and voriconazole, both competitive inhibitors of the CYP450 3A4 isoenzyme, requires tacrolimus dose reduction. On the basis of clinical observations, we developed a preemptive dose-reduction strategy in allograft recipients who received voriconazole to maintain tacrolimus concentrations within a target range. A total of 27 patients started i.v. tacrolimus at an average daily dose of 0.022 mg/kg on day À1 (30% lesser than the usual starting dose). The dose was reduced by 30–40% if the 48-h steady-state concentration was 7–10 ng/ml, and by 40–50% if it was 10–15 ng/ml. No change was made if the concentration was o7 ng/ml. Subsequently, concentrations were generally monitored 2–3 times a week with dose adjustments as necessary. None of the 170 levels (3–12 per patient; median 5) obtained between days þ 1 and þ 16 were subtherapeutic (o5 ng/ml) and only 34 levels (20%) were 415 ng/ml. Each patient required dose reduction at least twice. The dose had to be increased in only two patients after the initial dose reduction. The median tacrolimus doses in mg/kg declined with time; being 0.022, 0.008 and 0.006 on days 0, 7 and 14, respectively. We conclude that a preemptive dose-reduction strategy is effective in maintaining tacrolimus concentrations within the desired therapeutic range, although serial monitoring remains prudent. Bone Marrow Transplantation (2010) 45, 1352–1356; doi:10.1038/bmt.2009.345; published online 7 December 2009 Keywords: voriconazole; tacrolimus; interaction; dosing scheme; hematopoietic SCT; therapeutic drug monitnically observed that multiple adjustments Pearson correlation coefficient was used to assess for a
Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring
Tacrolimus is primarily metabolized by the cytochrome P450 3A4 isoenzyme system. In addition, tacrolimus is also highly metabolized by CYP3A5.5 The peri-transplant period is characterized by the administration of numerous drugs that can affect the cytochrome P450 system and alter tacrolimus clearance. Population pharmacokinetic studies in HSCT recipients have shown that liver or kidney impairment can result in decreased tacrolimus clearance and increased blood tacrolimus concentrations.6
Introduction
Tacrolimus is widely used for the prevention of GVHD after allogeneic hematopoietic SCT(HSCT).1,2 Adverse events such as renal and hepatic toxicity have been associated with increased tacrolimus blood concentrations after HSCT.3,4 Such adverse reactions may be preventable with therapeutic drug monitoring and coordinated dose adjustments.
Invasive fungal infections are a source of considerable morbidity and mortality after HSCT. Voriconazole is a triazole drug with a broad spectrum of activity, and is one of the agents used for fungal prophylaxis after allogeneic HSCT.7,8 Voriconazole is a competitive inhibitor for the cytochrome P450 3A4, 2C9 and 2C19 isosenzyme systems.9,10 Predictably, numerous serious drug interactions have been described for voriconazole when combined with other drugs metabolized through these systems, including tacrolimus.11,12 As reported by others,12 we observed increased tacrolimus blood concentrations when this agent was administered concomitantly with voriconazole. Bringing the concentration back within the target range required significant dose reduction multiple times. From clinical observations, we empirically developed a preemptive, twostep dose-reduction strategy for clinical use. In this report, we evaluate the success of this preemptive dose-reduction strategy in adjusting serial tacrolimus blood concentration levels in 27 patients after HSCT.
SM Trifilio1,2, MH Scheetz2,3, J Pi1,2 and J Mehta1,4
1Hematopoietic Stem Cell Transplant Program, Northwestern Memorial Hospital, Chicago, IL, USA; 2Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA; 3Department of Pharmacy Practice; Midwestern University Chicago College of Pharmacy, Chicago, IL, USA and 4The Feinberg School of Medicine; The Robert H. Lurie Comprehensive Cancer Center; Northwestern University, Chicago, IL, USA
1353
preemptive dose-reduction strategy. When voriconazole
Statistical analysis was performed using Intercooled Stata,
was initiated orally (200 mg twice daily from day 0 version 10.1 (Statacorp, College Station, TX, USA). The