protonix and Fk506 Interactions

Interactions between protonix(pantoprazole) and Fk506 (tacrolimus)

tacrolimus and pantoprazole (Moderate Drug-Drug)

MONITOR: Coadministration with lansoprazole has been reported to substantially increase the blood concentrations of tacrolimus in patients with CYP450 2C19 mutant alleles. The proposed mechanism is competitive inhibition of tacrolimus metabolism via intestinal and hepatic CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19, 3A4 is the major metabolic pathway in individuals who are 2C19-deficient, thereby increasing the risk of 3A4-mediated interactions. In a study of healthy volunteers, pretreatment with lansoprazole (30 mg daily for 4 days) increased the systemic exposure (AUC) of tacrolimus (2 mg single dose) by 81% in subjects with 2C19 mutant alleles and 29% in subjects without (i.e., 2C19 extensive metabolizers), whereas pretreatment with rabeprazole (10 mg daily for 4 days) had minimal effect in either group. There have also been several case reports of patients with such mutations who demonstrated significant increases in their tacrolimus trough levels shortly (within 1 to 3 days) after the addition of lansoprazole. Their levels normalized only after tacrolimus dosage was reduced and lansoprazole was discontinued and replaced with either famotidine or rabeprazole. Theoretically, other proton pump inhibitors (PPIs) with a similar metabolic profile such as esomeprazole, omeprazole, and pantoprazole can also cause this interaction.

MANAGEMENT: Approximately 16% to 25% of Caucasians and 36% to 47% of Asians have gene mutations that result in varying degrees of reduced 2C19 enzyme activity. It has been further estimated that approximately 2% of Caucasians and 16% of Asians are poor metabolizers with minimal 2C19 functional capacity. Since 2C19 genotype information is not frequently available for patients, caution is advised if tacrolimus must be prescribed with lansoprazole or other similar PPIs. Pharmacologic response to tacrolimus and blood concentrations should be monitored more closely whenever the PPI is added to or withdrawn from therapy, and the tacrolimus dosage adjusted as necessary to prevent concentration-dependent adverse effects such as nephrotoxicity, neurotoxicity, glucose disturbances, and infections. Clinicians should bear in mind that 2C19 deficiency can also be induced by drugs such as cimetidine, delavirdine, efavirenz, felbamate, fluconazole, fluoxetine, fluvoxamine, oxcarbazepine, ticlopidine, and voriconazole. To minimize the risk of interaction, alternatives such as famotidine, nizatidine, ranitidine, or rabeprazole should be considered for acid suppression therapy in patients receiving tacrolimus.