Fk506

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Contents 1 Introduction 2 Indications 3 Contraindications 4 Dosage 5 Pharmacokinetics 6 Adverse-effects 7 Drug-interactions 8 Mechanism-of-action 9 Origin 10 More General Terms 11 Additional Terms 12 Internet Database 13 References

Introduction

• Also tacrolimus. Tradename Prograf.

Indications

• prophylaxis of organ rejection in patients receiving allogeneic liver transplants
• used concomitantly with glucocorticoids
• immunosuppressive agent used for maintenance of immunosuppression after cardiac transplantation & for treatment of refractory rejection
• lichen sclerosis (topical) [4]

Contraindications

• concurrent use of cyclosporine; separate use by at least 24 hours
  

• pregnancy category = c

Dosage

• IV continuous infusion: 0.05-1 mg/kg/day until oral dose is tolerated starting no sooner than 6 hours after transplantation
• oral: 0.15-0.3 mg/kg/day divided every 12 hours

• Tabs: 1 mg, 5 mg.
• Injection: 5 mg/mL (1 mL).
• Topical: 0.1%

Pharmacokinetics

• absorption is highly variable; food decreases absorption
• volume of distribution (Vd) = 17 L/kg [6]
• extensively metabolized in the liver by cyt P450 3A4
• eliminated primarily via the bile
• protein binding 75-99%
  

• elimination via liver
• protein binding = 75-99 %
• elimination by hemodialysis = -
• 1/2life = 4-40 hours

Adverse-effects

• not common (1-10%)

• nephrotoxicity with hyperkalemia, elevated serum creatinine & hypertension
• neurotoxicity including insomnia, mild tremors, headache, photophobia, hyperesthesia, confusion, seizures, dysarthria, persistent coma
• infections & malignant complications including post- transplant lymphoproliferative disorder, bacterial, viral, & fungal infections
• hyperglycemia including new onset diabetes
• gastrointestinal symptoms including nausea/vomiting, abdominal pain
• peripheral edema at high to toxic levels
• BK virus-associated nephropathy in renal transplant patients [5]
  
• drug adverse effects of immunosuppressive agents

Drug-interactions

• separate antacids from tacrolimus by at least 2 hours
• agents which may increase plasma tacrolimus

• erythromycin, clotrimazole, flucanozole, methylprednisolone, ketoconazole, itraconazole, diltiazem, verapamil, nicardipine, cimetidine, clarithromycin, danazol, metoclopramide, bromocryptine

• cyclosporine is associated with synergistic immunosuppression & increased nephrotoxicity
• nephrotoxic antibiotics & amphotericin B increase nephrotoxicity
• agents which may decrease plasma tacrolimus

• rifampin, rifabutin, carbamazepine, phenytoin, phenobarbital

• any drug that inhibits cyt P450 3A4 may increase levels of tacrolimus
• any drug that induces cyt P450 3A4 may diminish levels of tacrolimus

Mechanism-of-action

• inhibits calcineurin [4]
• inhibits formation of interleukin-2

Origin

• Produced by Streptomyces tsukubaensis

More General Terms

• heterocyclic compound, 3 rings
• lactone
• immunosuppressive agent
• prokaryote-specific molecule
• calcineurin inhibitor

Additional Terms

• cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)
• FK506-binding protein 1A (12 kD FK506-binding protein, immunophilin FKBP12, FKBP1A)
• FK506-binding protein 2 (13 kD FK506-binding protein, FKBP2)
• FK506-binding protein 3, 25 kD FK506-binding protein or rapamycin-selective 25 kD immunophilin
• sirolimus; rapamycin (Rapamune)
• tacrolimus in blood
• tacrolimus toxicity

Internet Database

PubChem: 445643
PubChem: 439492
PubChem: 64779

References

1. Kaiser Permanente Northern California Regional Drug Formulary, 1998
2. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
3. Department of Veterans Affairs, VA National Formulary
4. Hengge UR et al, Multicentre, phase II trial on the safety and efficacy of topical tacrolimus ointment for the treatment of lichen sclerosus. Br J Dermatol 2006, 155:1021 PMID: [1]
5. FDA Medwatch [2]
6. The Drug Monitor Tacrolimus [3]

tacrolimus; FK506 (Prograf)