Tacrolimus dosing

Voriconazole is started in the patient along with 1 mg/kg per day of methylprednisolone to control the graft-versus-host disease. Her tacrolimus dose was also decreased by 70% with the addition of voriconazole and a recent tacrolimus blood level of 1 0 ng/mL. Unfortunately, the patient remains febrile with worsening respiratory pain. A repeat CT scan of the lung demonstrates new nodules, and pleural effusion in the right lung. 

Alleles predict higher tacrolimus doses and lower dosage... 

Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Bowman P, Boyle G, Law Y, Miller S, Lamba J, Burckart GJ. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant 2003 3 477 183. 

Fredericks S, Moreton M, Reboux S, et al. Multidrag resistance gene-1 (MDR-1) haplotypes have a minor influence on tacrolimus dose requirements. Transplantation 2006 82(5) 705-708. 

Bekersky, L Dressier, D. Mekki, O. Effect of time of meal consumption on bioavailability of a single oral 5 mg tacrolimus dose. J. Clin. Pharmacol. 2001, 41 (3), 289-297. 

The incidence of adverse effects (for example neurotoxicity, nephrotoxicity, and hyperglycemia), particularly those requiring drug withdrawal, was initially found to be higher in tacroUmus-treated Uver transplant patients, but subsequently fell after the initial tacrolimus dose was reduced. This was in accordance with the results of very early trials, which showed that the initially proposed dose of tacrolimus was too high (3). In subsequent studies, tacrolimus and ciclosporin had a similar spectrum of adverse effects for nephrotoxicity, infectious complications, and lymphoproliferative disorders, and long-term adverse effects occurred at comparable rates, that is less than 2% (SED-13,1130) (SEDA-21, 390). 

Senior PA, Paty BW, Cockfield SM, Ryan EA, Shapiro AM. Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing. Am J Transplant 2005 5 2318-2323. 

Thervet, E., Anglicheau, D., King, B., Schlageter, M.-H., Cassinat, B., Beaune, P., Legendre, C., and Daly, A. K. (2003) Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. 

The effect of CYP3A5 and MDRl (ABCBl) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics 2004 14(3) 147-154. 

One study in patients with leukaemia who had undergone stem cell transplantation found that the levels of tacrolimus were increased by 25 to 33% within 72 hours of starting imatinib. An empiric tacrolimus dose reduction of 25% at the start of imatinib treatment was found to prevent further serum level fluctuations. The manufacturers suggest that ciclosporin levels may also be increased by imatinib, via its effects on the cytochrome P450 isoenzyme CYP3A4. ... 

The authors of this report advise that, because of the long half-life of sirolimus, and the difficulty in reducing elevated levels quickly, prescrib-ers should consider reducing the sirolimus and tacrolimus doses before starting amiodarone rather than waiting for the interaction to occur. They also advise more frequent monitoring of sirolimus and tacrolimus levels if amiodarone is also given. This appears to be the only published report of this interaction at present. 

However, a study in 18 renal transplant patients found that the concurrent use of Maalox (aluminium/magnesium hydroxide) or sodium bicarbonate did not reduce tacrolimus blood levels and no patients required a tacrolimus dose increase. ... 

When tacrolimus is given orally, its serum levels are considerably increased by oral fluconazole, and tacrolimus dose reductions may be needed. Itraconazole, ketoconazole, posaconazole, voriconazole, and oral clotrimazole, also raise tacrolimus levels. There is some evidence that the levels of intravenous tacrolimus are minimally affected by fluconazole and ketoconazole. In theory it is possible that miconazole oral gel may also interact with tacrolimus. 

The interaction between tacrolimus and fluconazole is established, clinically important and can develop rapidly (within 3 days). The authors of one of the reports say that up to 200 mg of oral fluconazole daily can be used safely and effectively provided that the tacrolimus dosage is reduced by half One study specifically examining dose adjustments suggests that fluconazole can be safely used if 60% of the original tacrolimus dose is given. If tacrolimus is given intravenously, no clinically important interaction appears to occur. ... 

The interactions of tacrolimus with itraconazole and ketoconazole also appear to be established, and the manufacturer states that nearly all patients will require tacrolimus dose reductions when given these drugs. Information about clotrimazole is limited, but on the basis of the case report and study it would be prudent to monitor tacrolimus levels, and adjust the dose as necessary. 

The manufacturers of posaconazole recommend that the tacrolimus dose is reduced by about two-thirds in patients given posaconazole. Tacrolimus levels should be closely monitored and further dose adjustments... 

The manufacturers of voriconazole advise reducing the tacrolimus dose to one-third when starting voriconazole, closely monitoring tacrolimus levels throughout, and increasing the tacrolimus dose in response to levels obtained when voriconazole is stopped. However, greater reductions in tacrolimus dose may be needed in some patients, and raised tacrolimus levels requiring a total 90% tacrolimus dose reduction were reported in one patient. ... 

A retrospective study identified 3 patients taking tacrolimus who had received a total of 5 courses of intravenous chloramphenicol, each lasting for at least 12 days. Tacrolimus trough blood levels were doubled by day 2, and had risen by 207% at their peak, on day 6. The tacrolimus dose had been decreased by about one-third by day 12, and the tacrolimus levels returned to around the baseline value. ... 

Direct information seems to be limited to these case reports. However, it would be prudent to closely monitor the effects of adding clarithromycin or erythromycin in any patient, being alert for the need to reduce the tacrolimus dosage to avoid nephrotoxicity. The manufaeturers prediet that josamycin and troleandomycin will internet similarly and so the same precautions would also be appropriate. The manufaeturers of telithromy-cin also recommend close monitoring of tacrolimus levels and reducing the tacrolimus dose as required. Most other maerolides would also be expected to interact although they do not all behave identically. 

A study in 12 liver transplant patients taking tacrolimus with orlistat 120 mg three times daily for 6 months found that concurrent use was well tolerated. However, 4 patients required a reduction and 2 required an increase in their tacrolimus dose, although these adjustments were only minor dose changes. No diarrhoea was reported by the patients in this study, concurrent use was well tolerated and no episodes of rejection occurred. The authors concluded that orlistat could be safely used in patients taking tacrolimus provided that tacrolimus levels are carefully monitored. ... 

A retrospective study in 10 HIV-positive kidney transplant patients found that all of the patients taking a protease inhibitor (not specified) required a tacrolimus dose reduction, and 3 of them needed to be changed from a protease inhibitor to an alternative antiretroviral. ... 

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