Tacrolimus

Introduction Overview

Generic Name

Tacrolimus

Brand Name

Mylan Tacrolimus Capsules

Dosage Form

Oral capsules

Drug Class

Calcineurin inhibitors

Pharmacokinetics

Absorption:
Tacrolimus exhibits incomplete and variable gastrointestinal absorption after oral administration. Absolute bioavailability ranges from approximately 17% to 23% depending on the transplant population, with values of 17 ± 10% in adult kidney transplant recipients, 22 ± 6% in liver transplant recipients, 23 ± 9% in heart transplant recipients, and approximately 18 ± 5% in healthy volunteers. The absorption is dose proportional within clinical dosing ranges. Food presence markedly alters the rate and extent of absorption, with high-fat meals reducing AUC by ~27-37% and Cmax by up to 77%, necessitating consistent administration with regard to meals to maintain stable blood levels.

Distribution:
Tacrolimus is extensively bound (>99%) to plasma proteins, mainly albumin and alpha-1-acid glycoprotein, and strongly associates with erythrocytes resulting in a high blood to plasma concentration ratio (average ~35). The distribution is influenced by hematocrit and plasma protein concentrations. The volume of distribution (Vd) varies by patient population but generally remains between 0.8 to 2.6 L/kg, higher in pediatric patients. Protein binding and erythrocyte sequestration contribute to its extensive distribution.

Metabolism:
Tacrolimus is extensively metabolized in the liver by the cytochrome P450 system, particularly CYP3A4 and CYP3A5 isoenzymes, leading to the formation of at least eight metabolites primarily through demethylation and hydroxylation. The principal metabolite identified is 13-demethyl tacrolimus, which is less pharmacologically active. Tacrolimus metabolism is subject to interindividual variability influenced by genetic polymorphisms and drug interactions affecting CYP3A enzyme activity.

Elimination:
Following intravenous administration, tacrolimus has a clearance ranging from 0.040 to 0.083 L/hr/kg in healthy volunteers and transplant patients, with elimination half-life varying widely from approximately 11 to 48 hours depending on hepatic function and patient population. Excretion occurs mainly via biliary and fecal routes, accounting for approximately 92-95% of the administered dose, while urinary excretion of unchanged drug is less than 2%. Reduced clearance is observed in patients with severe hepatic impairment, requiring dose adjustment. Tacrolimus is not significantly dialyzable due to extensive protein and erythrocyte binding.

Dosage Forms

Available Dosage Forms:
Tacrolimus capsules are available for oral administration in hard-shell gelatin capsules containing an equivalent of 0.5 mg, 1 mg, or 5 mg of anhydrous tacrolimus. Each capsule dose is formulated with specific color coding and opacities for identification: 0.5 mg capsules have a light orange opaque cap and gray opaque body, 1 mg capsules have a light blue opaque cap and gray opaque body, and 5 mg capsules have a rubine red opaque cap with a gray opaque body. Each capsule contains white to off-white powder and is imprinted with unique black ink codes.

Dosages for Adults and Adolescents:
For prophylaxis of organ rejection in adult kidney transplant patients, the initial oral doses range from 0.075 to 0.2 mg/kg/day divided every 12 hours, adjusted according to concomitant immunosuppressants (e.g., azathioprine, mycophenolate mofetil, or corticosteroids). Therapeutic whole blood trough concentrations (ng/mL) vary over time post-transplant, e.g., kidney transplant patients on azathioprine have trough targets of 7–20 ng/mL for months 1–3 and 5–15 ng/mL for months 4–12. Similar dosing principles apply to liver and heart transplant adult patients, with dose variances based on co-therapy and transplant type.

Specific Patient Populations:
Pediatric liver transplant patients require higher initial dosages (0.15–0.2 mg/kg/day in two divided doses every 12 hours) to achieve similar trough concentrations as adults. Dosage adjustments are necessary in patients with renal impairment, where lower doses at the therapeutic range are recommended due to nephrotoxicity risk. Patients with severe hepatic impairment require dose reductions and close monitoring given decreased clearance and prolonged half-life of tacrolimus. African-American transplant recipients may require increased doses due to lower observed bioavailability and trough concentrations at standard dosing.

Consistent timing of administration every 12 hours is recommended, with or without food, but consistent with regard to meals to minimize pharmacokinetic variability. Grapefruit products must be avoided due to CYP3A4-mediated interaction causing increased drug concentrations.

Mechanism Of Action

Tacrolimus is a potent immunosuppressive agent acting as a calcineurin inhibitor. Mechanistically, tacrolimus binds intracellularly to the immunophilin FK506-binding protein 12 (FKBP-12). The tacrolimus-FKBP-12 complex inhibits calcineurin, a calcium/calmodulin-dependent serine/threonine phosphatase essential for T-cell activation. This inhibition prevents the dephosphorylation and nuclear translocation of the nuclear factor of activated T-cells (NF-AT), a critical transcription factor for interleukin-2 (IL-2) gene expression.

Inhibition of IL-2 synthesis suppresses T-lymphocyte activation and proliferation, disrupting both cellular- and humoral-mediated immune responses. Tacrolimus also downregulates the expression of other pro-inflammatory cytokines such as IL-1 beta, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony-stimulating factor. Additionally, tacrolimus reduces IL-2 receptor expression and nitric oxide release, induces apoptosis in immune cells, and promotes transforming growth factor beta production, further contributing to its immunosuppressive effects.

This multifaceted inhibition of T-cell function translates clinically into effective prevention of organ transplant rejection by inhibiting the host immune response against allogeneic tissue. Tacrolimus shares a similar mechanism with cyclosporine, another calcineurin inhibitor, but exhibits higher potency and distinct binding affinity profiles. Clinical studies have demonstrated tacrolimus’s superiority or non-inferiority compared to cyclosporine with respect to graft survival and rejection episode rates. Research evidence supports its use in various solid organ transplantations, including kidney, liver, and heart, as part of combination immunosuppressive regimens.

Pharmacological Actions

Immunosuppressive activity via calcineurin inhibition
Inhibition of T-lymphocyte activation and proliferation
Suppression of interleukin-2 and additional cytokine expression
Reduction of IL-2 receptor expression on immune cells
Inhibition of nitric oxide release
Induction of apoptosis in immune cells
Modulation of transforming growth factor beta production leading to immune regulation
Prevention of allograft rejection in organ transplantation
Alteration of both cellular and humoral immune responses
High binding affinity to FKBP-12 immunophilin

Therapeutic Or Clinical Uses

Prophylaxis of organ rejection in adult patients receiving kidney transplants
Prophylaxis of organ rejection in adult patients receiving liver transplants
Prophylaxis of organ rejection in adult patients receiving heart transplants
Prophylaxis of organ rejection in pediatric patients receiving liver transplants
Use in combination with corticosteroids and other immunosuppressants to enhance efficacy
Management of transplant patients at increased risk for rejection requiring potent immunosuppression
Off-label use may include autoimmune conditions requiring immunosuppression (not included in product labeling)
Prevention of graft-versus-host disease in allogeneic hematopoietic stem cell transplants (use documented elsewhere)
Utilized in patients intolerant or refractory to other calcineurin inhibitors
Part of immunosuppressive regimens with mycophenolate mofetil or azathioprine for transplant prognosis improvement

Side Or Adverse Effects

Abnormal renal function including nephrotoxicity (acute and chronic)
Hypertension requiring antihypertensive therapy
New onset diabetes mellitus post-transplant (NODAT)
Tremor and neurologic disturbances including tremors, headache, paresthesia
Neurotoxicity including risk of posterior reversible encephalopathy syndrome (PRES), seizures, and altered mental status
Infections, both common and opportunistic, including cytomegalovirus infection
Hyperkalemia requiring monitoring and management
Gastrointestinal disturbances such as diarrhea, nausea, constipation, abdominal pain
Hepatotoxicity and liver function abnormalities
Hyperglycemia
Leukopenia and anemia
Peripheral edema and fluid retention
Blood clotting disorders including thrombotic microangiopathy
Myocardial hypertrophy including ventricular wall thickening
Pure red cell aplasia and hematological abnormalities
Skin reactions including rash and pruritus

Precautions

Avoid concurrent use with tacrolimus extended-release formulations due to non-equivalent absorption
Monitor blood glucose closely due to risk of new onset diabetes after transplant
Regular monitoring of renal function to detect nephrotoxicity early
Close neurologic monitoring to identify early signs of neurotoxicity and PRES
Avoid grapefruit products to prevent elevated tacrolimus levels
Conduct therapeutic drug monitoring to individualize dosing and minimize toxicity
Adjust doses carefully in patients with hepatic or renal impairment
Advise contraception for men and women of reproductive potential due to fetal risk
Avoid live vaccinations during therapy due to immunosuppressive effect
Educate patients and caregivers on recognizing medication errors and capsule identification
Monitor potassium levels regularly to prevent and manage hyperkalemia
Exercise caution with concomitant nephrotoxic agents and CYP3A4 modulators
Monitor blood pressure and treat hypertension as necessary
Educate on signs of infection and malignancy risk
Consider dose modifications or discontinuation in cases of thrombotic microangiopathy

Warnings

Boxed warning for increased risk of serious infections and malignancies
Not interchangeable with tacrolimus extended-release formulations; switching requires physician supervision
High potential for nephrotoxicity necessitating dose reductions and closely monitored renal function
Risk of neurotoxicity including serious neurologic events such as PRES and seizures
Induction of new onset diabetes mellitus particularly in African-American and Hispanic populations
Potential for anaphylactic reactions with intravenous formulation containing castor oil derivatives
Increased risk of thrombotic microangiopathy, especially when combined with mTOR inhibitors or infections
Avoid use in combination with sirolimus due to increased morbidity and mortality in liver and heart transplants
QT interval prolongation and risk of Torsade de Pointes necessitate caution in susceptible patients
Risk of myocardial hypertrophy, requiring echocardiographic monitoring in symptomatic patients
Avoid live vaccines during therapy due to impaired immune responses
Pregnancy use is associated with fetal risk including prematurity and congenital anomalies
Consider dose adjustments and monitoring for drug interactions with CYP3A4 inhibitors and inducers
Potential for pure red cell aplasia, with discontinuation indicated if this condition develops
Counsel patients extensively to prevent medication errors, as dosing errors have led to graft rejection

Contraindication

Known hypersensitivity to tacrolimus or any component of the formulation
Hypersensitivity to polyoxyl 60 hydrogenated castor oil (in injectable formulations)
Concurrent use with sirolimus in liver and heart transplantation due to increased risk of serious adverse events
Use of tacrolimus extended-release formulations as a substitute for immediate-release capsules without physician supervision
Patients with a history of severe allergic reactions to calcineurin inhibitors
Situations where immunosuppression is contraindicated due to infection or malignancy risk
Use in patients with known unstable or uncontrolled hypertension without proper medical management
Patients with unresolved or uncontrolled neurological disorders exacerbated by immunosuppressants
Pregnant women when potential fetal risks outweigh benefits and alternatives exist
Administration with tacrolimus and cyclosporine simultaneously due to enhanced toxicity risk
Lack of supervision by physicians experienced in immunosuppressive therapy

Drug Interactions

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, ritonavir) increase tacrolimus blood concentrations dramatically; require dose reduction and frequent monitoring
Strong CYP3A4 inducers (e.g., rifampin, rifabutin, phenytoin, carbamazepine, St John's wort) decrease tacrolimus levels; require dose increase and monitoring
Mycophenolic acid exposure is higher with tacrolimus co-administration compared to cyclosporine; warrants monitoring and possible dose adjustment of mycophenolate products
Grapefruit and grapefruit juice increase tacrolimus levels via CYP3A inhibition and should be avoided
Cannabidiol increases tacrolimus levels and risk of toxicity; dose reduction and therapeutic drug monitoring recommended on co-administration
Magnesium and aluminum hydroxide antacids increase tacrolimus exposure; monitor levels and adjust dosing as needed
Calcium channel blockers (e.g., verapamil, diltiazem) increase tacrolimus blood concentrations necessitating dose adjustments
Antiviral agents such as telaprevir and boceprevir markedly increase tacrolimus levels; require substantial dose reduction and monitoring
Immunosuppressants like sirolimus increase adverse effect risks and are not recommended in combination
Amiodarone may elevate tacrolimus concentrations and prolong QT interval requiring monitoring
Caspofungin decreases tacrolimus exposure modestly; monitor tacrolimus levels and adjust dose accordingly
Rifampin lowers tacrolimus exposure via induction; monitor blood concentrations and adjust dosing
Other drugs affecting CYP3A (e.g., erythromycin, fluconazole, cimetidine, lansoprazole) may alter tacrolimus levels; monitor and adjust doses
Tacrolimus should not be co-administered with cyclosporine due to additive toxicity and interaction
Drug interactions affecting tacrolimus metabolism may impact efficacy and toxicity; therapeutic drug monitoring is critical

Preparations Of The Drug

Tacrolimus Capsules, USP available in doses of 0.5 mg, 1 mg, and 5 mg
Capsules are hard-shell gelatin capsules filled with white to off-white powder
0.5 mg capsule: light orange opaque cap and gray opaque body, printed with 'MYLAN 2045' in black ink
1 mg capsule: light blue opaque cap and gray opaque body, printed with 'MYLAN 2046' in black ink
5 mg capsule: rubine red opaque cap and gray opaque body, printed with 'MYLAN 2047' in black ink
Inactive ingredients include anhydrous lactose, various iron oxides and dyes, colloidal silicon dioxide, croscarmellose sodium, gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, titanium dioxide, propylene glycol, and shellac glaze
Capsules are supplied in unit dose blister packages of 100 capsules (10 cards of 10 capsules each)
Store capsules at controlled room temperature of 20° to 25°C (68° to 77°F) and protect from light
Handling precautions include avoiding opening or crushing capsules due to occupational exposure risk; in case of contact with skin or mucous membranes, wash thoroughly
Tacrolimus injection is available but contains castor oil derivatives and reserved for patients unable to take oral therapy
Packaging designed with patient safety in mind to prevent dosing errors and ensure identification