Tacrolimus increased

Ketoconazole/Rifampin/Tacrolimus Increased metabolism of other agents Avoid... 

The significance of the reported increases in mycophenolic acid levels with concurrent tacrolimus is not clear, and the manufacturers note that the benefit of concurrent use with tacrolimus has not been established. There are also inherent problems in interpretation of the results of studies comparing ciclosporin or tacrolimus with mycophenolate. It has been suggested that the changes in mycophenolic acid trough levels are because tacrolimus increases mycophenolic acid levels however, another interpretation may be that the differences in mycophenolic acid trough levels and AUCs seen are because ciclosporin decreases mycophenolic acid exposure. ... 

An increase in the bioavailability of tacrolimus was observed in healthy volunteers orally administered three capsules schisandra extract (each containing 11.25 mg deoxyschizandrin) twice daily for 13 days. The maximum plasma concentration of tacrolimus increased by 227% as compared to tacrolimus administered prior to treatment with schisandra. Tacrolimus is metabolized by CYP3A4 and CYP3A5, and P-gp is important in the absorption metabolism of this drug. The authors suggested that inhibition of CYP3A and P-gp by schisandra were likely responsible for the observed interaction (Xin et al. 2007). 

MMF is metabolized by the liver, and enterohepatic recirculation occurs. It is excreted in the urine, and dose reduction is required in moderate-to-severe renal disease. Tacrolimus increases MMF levels, while cyclosporine does not (180). Administration of metronidazole and some fluoroquinolones will reduce levels of mycophenolate by 10% to 20%. This reduction appears due to the effect of the antibiotics on GI flora and thus the elimination of the enterohepatic recirculation of the drug (181). 

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Most pharmacokinetic interactions in transplantation occur due to interactions with the CYP enzyme system however, several interactions have been shown to occur via alternative mechanisms. One of the most notable is that seen between tacrolimus and some of the prokinetic agents. Cisapride and metoclopramide have been shown to increase the absorption of tacrolimus by enhancing gastric emptying.41... 

Substrates of the CYP3A4 isozyme will compete with cyclosporine, tacrolimus, and sirolimus for metabolism therefore, concentrations of both medications may be increased (usually by less than or equal to 20%). bnducers of the CYP3A4 isozyme will enhance the metabolism of cyclosporine, tacrolimus, and sirolimus therefore, concentrations of these medications may be decreased. 

Although tacrolimus therapy is associated with increasing blood pressure, studies have found that tacrolimus has less dramatic effects on GFR and RBF than cyclosporine. In some clinical trials, tacrolimus caused less severe HTN and required significantly fewer antihypertensive medications at both 24 and 60 months after transplantation than cyclosporine.61-63 Thus conversion from cyclosporine-based immunosuppression to tacrolimus-based immunosuppression may be one way to minimize blood pressure increases in transplant recipients. Conversion to sirolimus also may be an alternative to the calcineurin inhibitors in patients with difficult-to-treat HTN because sirolimus therapy is less associated with increased blood pressure. Additionally, withdrawal or tapering of steroid therapy may be an effective strategy for lowering blood pressure. 

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

Tacrolimus, an immunosuppressant that inhibits T-cell activation, is a useful alternative in severe recalcitrant psoriasis. Although it is not FDA approved for this indication, patients have received oral doses of 0.05 mg/kg daily, with increases up to 0.15 mg/kg daily, depending on results. Adverse effects include diarrhea, nausea, paresthesias, hypertension, tremor, and insomnia. 

Rifampin Azoles, cyclosporine, methadone propranolol, Pis, oral contraceptives, tacrolimus, warfarin Increased metabolism of other agent Avoid if possible... 

Although ciclosporin and tacrolimus applied systemically improve psoriatic lesions, they are clearly less active when applied topically. Therefore, liposomal preparations have been developed. Indeed, ciclosporin penetrates deeper strata of rodent and human cadaver skin more efficiently when incorporated into liposomes [51], Moreover, tacrolimus concentrations in murine skin have increased ninefold, and skin graft survival prolonged, if the drug is liposome encapsulated [52]. This indicates that topical psoriasis therapy with tacrolimus may become possible. At present, topical tacrolimus is confined to the less recalcitrant forms of mild eczema. 

Insulin-dependent posttransplant diabetes mellitus (PTDMj. lnsulin-dependent PTDM was reported in 20% of tacrolimus-treated kidney patients without pretransplant history of diabetes mellitus in the Phase 3 study. The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at 1 year and in 50% at 2 years posttransplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM. 

Lymphomas As with other immunosuppressants, patients receiving tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin. 

Myocardial hypertrophy Myocardial hypertrophy has been reported in association with the administration of tacrolimus and generally is manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been observed in infants, children, and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. 

Renal/Hepatic function impairment The use of tacrolimus in liver transplant recipients experiencing posttransplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood levels of tacrolimus. 

Because tacrolimus is metabolized mainly by the cytochrome P450 3A enzyme systems, substances known to inhibit or induce these enzymes may affect the metabolism of tacrolimus with resultant increases or decreases in whole blood or plasma levels. 

Drug/Food interactions The presence of food reduced the absorption of tacrolimus (decrease in AUC and C ax > 1 increase in Tmax)- The relative oral bioavailability... 

Coadministered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. 

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information needed for the follow-up of the patient. Liver transplantation-excess mortality, graft loss, and hepatic artery thrombosis (HAT) The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant recipients. Many of these patients had evidence of infection at or near the time of death. 

In this and another study in de novo liver transplant recipients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death. 

WraZ/nfecf/on. Treatment with tacrolimus ointment may be associated with an increased risk of varicella zoster virus infection (chicken pox or shingles), herpes simplex virus infection, or eczema herpeticum. 

Other skin disorders The use of tacrolimus ointment in patients with Netherton syndrome is not recommended because of the potential for increased systemic absorption of tacrolimus. The safety of tacrolimus ointment has not been established in patients with generalized erythroderma. 

The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, whereas that of fluvastatin and rosuvastatin is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include the macrolide antibiotics, cyclosporine, ketoconazole and its congeners, HIVprotease inhibitors, tacrolimus, nefazodone, fibrates, and others (see Chapter 4). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy. 

Posaconazole is the newest triazole to be licensed in the USA. It is available only in a liquid oral formulation and is used at a dosage of 800 mg/d, divided into two or three doses. Absorption is improved when taken with meals high in fat. Posaconazole is rapidly distributed to the tissues, resulting in high tissue levels but relatively low blood levels. Visual changes have not been reported, but drug interactions with increased levels of CYP3A4 substrates such as tacrolimus and cyclosporine have been documented. 

Toxicities of the PSIs can include profound myelosuppression (especially thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and headache. Because nephrotoxicity is of major concern when administering calcineurin inhibitors, there is interest in increased early use of PSIs since renal toxicity is less common with these agents. However, increased use in stem cell transplantation regimens as graft-versus-host disease prophylaxis, particularly when combined with tacrolimus, has revealed an increased incidence of hemolytic-uremic syndrome. 

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