Genetic Variants, Other Medications Influence Optimal Dose of Prograf in MG Patients, Study Suggests

The therapeutic effects of Prograf (tacrolimus) in myasthenia gravis (MG) patients are influenced not only by dosage, but also by patients’ genetic profiles and other medications they may be taking for the disease, according to a study from China.

The findings point out factors that influence the portion of Prograf that actually enters the bloodstream and is able to have an impact (called  bioavailability) and that are important to consider when deciding on the medicine’s dose and to prevent adverse effects.

The study, “Dose optimization of tacrolimus with therapeutic drug monitoring and CYP3A5 polymorphism in myasthenia gravis patients,” appeared in the European Journal of Neurology.  

Prograf has a narrow therapeutic range and dose-dependent toxicity, so drug monitoring is important for optimizing the therapeutic dose for each patient.

Blood levels of the medicine are believed to depend on a number of factors, but this has never been explored in the context of myasthenia gravis.

Researchers investigated which variables influence the levels of Prograf in myasthenia gravis. The study included 171 MG patients who were treated with Prograf from 2013 to 2015 at Beijing Hospital in China.

Patients took the Prograf twice a day, every 12 hours. Blood concentrations were monitored before the morning dose, at a time when drug absorption and elimination reached a balance and the medicine concentration was expected to be stable.

Sex, age, and weight didn’t significantly affect Prograf’s blood levels. However, patients who carried the CYP3A5*3 genetic variation had significantly higher concentrations of the medicine in the blood. The CYP3A5 gene encodes a protein that is part of the cytochrome P450 family. These proteins are the major players in drug metabolism, contributing to the activation or excretion of drugs from the body. 

An effective concentration could be reached in patients positive for CYP3A5*3 that were taking 2-3 mg a day of the medicine. However, therapeutic levels of Prograf were not achieved by any, or only by a reduced number, of the patients with other CYP3A5 variants who were taking a similar dose.

The team also observed that other medications which can potentially interfere with Prograf influenced the concentration of the medicine in the blood.

Combined administration of a proton pump inhibitor and the antibiotic clarithromycin significantly increased the blood levels of Prograf, while corticosteroids, calcium channel blockers, or proton pump inhibitors by themselves did not have a significant effect.

Adverse reactions to treatment were observed in 61 patients (37.5%), requiring mean hospital stays of 28 days. The most common side effects were abnormal liver function (17.5%), high blood sugar (8.1%), high blood lipids (6.4%), and leukopenia, low white cells in the blood (6.4%).

Higher blood levels of Prograf were associated with a greater likelihood of side effects. Almost 30% of patients with concentrations lower than 5 ng/mL concentration experienced adverse events, which were increasingly more frequent with higher blood levels of Prograf. All patients with more than 20 ng/ml experienced some side effects.

The findings show that monitoring this medication in the blood was essential for optimizing the dose for myasthenia gravis patients.

The study reveals important factors to take into account, namely CYP3A5 genetic variants and the co-administration of other medications.

Prograf dosage should be tailored for each patient to reach the most effective therapeutic levels and to avoid side effects.

“The whole blood concentration of tacrolimus [Prograf] in MG patients is not entirely determined by the dosage … it is also influenced by many factors such as co-administration of PPI (proton pump inhibitors), CYP3A5*3 genetic polymorphism …” researchers wrote.

“Therefore, [therapeutic drug monitoring] and CYP3A5*3 genetic polymorphism is warranted for tacrolimus dosing adjustment to optimize the treatment for patients with MG,” they concluded.