Tacrolimus (FK506): Pulcoloft
Mechanism of action
The mechanism of action is similar to that of cyclosporine, but compared with cyclosporine, this product has the following characteristics: ① The immunosuppressive effect of this drug is tens to hundreds of times greater than that of cyclosporine in both in vitro and in vivo tests. The inhibitory effect on rejection that has occurred is also better than that of cyclosporine. (ii) The problem of irreversible chronic rejection in previous cyclosporine-based immunosuppression regimens remains the same, and this product is expected to reduce chronic rejection in liver and kidney transplant recipients. (iii) Patients treated with this product also have lower rates of bacterial and viral infections than those treated with cyclosporine.
Manufactured by Fujisawa, Japan, also known as Pulcoflora.
Drug absorption and metabolism
The oral bioavailability of this product decreases when it is administered after eating a moderately fatty meal. When taken with food, the absorption rate and extent of this product decreases.
Because the drug is extensively metabolized by the liver, patients with hepatic insufficiency have higher blood concentrations (relatively longer half-life and lower clearance) than patients with normal liver function. Patients with hepatic insufficiency need careful monitoring of whole blood concentrations and dose adjustment for use.
Side effects
1.Hepatotoxicity is much less than cyclosporine A (CsA); the incidence of renal impairment is 35%-42%.
2.The incidence of tremor is higher than that of CsA, and the incidence of glucose metabolism disorder after renal transplantation is significantly higher than that of CsA when combined with hormone application.
3, the incidence of infection and the effect on blood pressure and blood lipids is weaker than CsA, diarrhea 22% to 44%, constipation 31% to 35%, vomiting 13% to 29%, hypertension 37% to 50%, infection 72% to 76%, giant cell infection 14% to 20%.
Dosage
When combined, the general dose is 0.05-0.15mg/kg/d, divided into two doses. Administration of this product with a diet containing moderate fat will significantly reduce its bioavailability and oral absorption rate. Therefore, for maximum oral absorption, it should be taken on an empty stomach or at least one hour before or two to three hours after a meal.
In pediatric patients, 1.5 to 2 times the recommended adult dose is usually required to achieve the same blood levels as adults (except in cases of impaired hepatic and renal function). The dose for children is 0.3 mg/kg/day based on body weight.
Clinical data for elderly patients are scarce, but all suggest that the dose should be the same as other adults.
Precautions
1.Take the medication strictly according to the doctor’s prescription, do not adjust the dose by yourself.
2. Monitor the blood concentration as prescribed by the doctor.
3.Store at room temperature between 15 and 30 degrees, do not freeze.
4.Take medication regularly and develop a good habit of taking medication regularly.
5.When administered simultaneously with cyclosporine A, this product increases the half-life of cyclosporine A. In addition, synergistic/accumulative nephrotoxicity occurs. For these reasons, the combination of this product and cyclosporine is not recommended, and special attention should be paid when patients switch from the original cyclosporine to this product.
6. This product is contraindicated in pregnancy, and women patients should not breastfeed while using this product.
7.If severe tremor and motor (expressive) aphasia occur, the dose should be reconsidered under the guidance of a renal transplant specialist.
8. Patients taking this product and experiencing visual and neurological disturbances should not drive or operate dangerous machinery. Such effects may be aggravated by alcohol consumption.
Blood Concentration
The determination of FK506 blood concentration is generally taken as the reference value of the trough value, i.e. the plant measured by taking blood in the morning before taking the drug. The therapeutic range using fluorescence polarization immunoassay: about 12ng/ml within 1 month after surgery, 10-12ng/ml within 1 to 3 months, 8-10ng/ml within 3 to 6 months, 5-8ng/ml within 7 to 8 months, and maintained at about 5ng/ml after 12 months.
It is important to note: FK506 varies very much on an individual basis. Some patients with low concentrations experience toxicity; others with concentrations within the therapeutic range experience rejection, and even in the same patient, the same blood concentration at different times after surgery can produce different results. Therefore, the formulation of the effective concentration of FK506 must be individualized and must be performed under the guidance of a specialist.
Drugs that affect blood levels
Drugs that increase blood levels: estrogens, androgens, cimetidine, diltiazem, ipratropium, nicardipine, erythromycin, doxycycline, ketoconazole, fluconazole, itraconazole, norfloxacin, ciprofloxacin, methotrexate, tylenol, colchicine, danazol, clotrimazole.
Drugs that lower blood levels: phenobarbital, phenytoin, anandamide, rifampicin, isoniazid, aminoglutethimide, diphenhydramine, meperidine.
Follow-up
The therapeutic window (the ability to produce effective immunosuppression without side effects) for FK506 is very narrow, and its bioavailability varies greatly among individuals; it is not possible to establish a dose for all patients without both monitoring blood levels. Blood pressure, renal function, blood glucose, and blood concentration should be checked at each follow-up visit for patients treated with FK506. blood pressure, electrocardiogram, visual acuity, blood glucose concentration, blood potassium and other electrolyte concentrations, blood creatinine, urea nitrogen, hematological parameters, coagulation values and liver function. If clinically significant changes in the above parameters occur, the dosage of this product should be re-examined.
Blood concentrations should be measured more frequently in the early post-renal transplant period and should also be monitored frequently during growth and development in children when adjusting the dosage of drugs that can affect FK506 blood concentrations.