Pharmacology of cyclosporine and tacrolimus

INTRODUCTION — Cyclosporine and tacrolimus selectively inhibit calcineurin, thereby impairing the transcription of interleukin (IL)-2 and several other cytokines in T lymphocytes. Calcineurin inhibitors have been mainstays of immunosuppression in solid organ transplantation for over three decades.

Cyclosporine and tacrolimus are occasionally used in the treatment of various immune-mediated diseases. However, concerns about their long-term toxicity (especially kidney function impairment and hypertension) and the availability of newer biologic agents have restricted the use of cyclosporine and tacrolimus to patients who have not responded to conventional treatment. The kidney toxicity of these agents is reviewed in detail separately. (See "Cyclosporine and tacrolimus nephrotoxicity".)

The pharmacology of cyclosporine and tacrolimus is reviewed here. The efficacy and use of these agents in specific conditions, including organ transplantation and immune-mediated diseases, are discussed separately in the topic reviews addressing the treatment of each disorder. (See appropriate topic reviews.)

MECHANISM OF ACTION — Cyclosporine is a lipophilic cyclic peptide of 11 amino acids, while tacrolimus is a macrolide antibiotic. Both drugs have been isolated from fungi and possess similar suppressive effects on cell-mediated and humoral immune responses.

Both drugs bind with high affinity to a family of cytoplasmic proteins present in most cells: cyclophilins for cyclosporine and FK-binding proteins for tacrolimus. The drug-receptor complex specifically and competitively binds to and inhibits calcineurin, a calcium- and calmodulin-dependent phosphatase [1-4]. This process inhibits the translocation of a family of transcription factors (NF-AT), leading to reduced transcriptional activation of cytokine genes for interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, IL-3, IL-4, CD40L, granulocyte-macrophage colony-stimulating factor, and interferon-gamma [1,2,5,6]. Ultimately, proliferation of T lymphocytes is reduced.

Cyclosporine and tacrolimus act primarily on T helper cells, although some inhibition of T suppressor and T cytotoxic cells may also occur. Cyclosporine also increases the expression of transforming growth factor (TGF)-beta, which may be an important mechanism by which it causes kidney fibrosis [7,8]. Unlike some other immunosuppressive agents, such as azathioprine and the alkylating agents, cyclosporine and tacrolimus do not cause clinically significant myelosuppression [9].

FORMULATIONS — Oral, intravenous, and ophthalmic formulations of cyclosporine are available (table 1). Oral, intravenous, and topical formulations of tacrolimus are available. The intravenous forms of both drugs should be used only if enteral administration is not possible, because there is the potential for greater toxicity with intravenous administration. Generic forms of cyclosporine and tacrolimus are available in many countries, including the United States. In general, patients stabilized on one preparation should not be switched to another, because there are concerns about differences in pharmacokinetics. If a conversion between preparations is necessary, monitoring trough concentrations should be performed until the results are stable [10]. (See 'Switching formulations' below.)

Cyclosporine — Oral, intravenous, and ophthalmic formulations of cyclosporine are available.

Cyclosporine is available in nonmodified and modified formulations. Nonmodified oral cyclosporine depends upon bile for absorption and has erratic gastrointestinal absorption patterns. Modified cyclosporine, a microemulsion formulation, does not depend upon bile salts for absorption and exhibits increased bioavailability and more consistent absorption.

Nonmodified — Liquid cyclosporine is available in capsules, oral solution, and concentrate for injection:

●Liquid-filled capsules of 25 mg and 100 mg are stored at less than 86°F (30°C) but not frozen.

●The oral solution of 100 mg/mL in 50 mL bottles remains stable for two months after opening if stored in the original container at less than 86°F (30°C) but does not require refrigeration and should not be frozen.

●Concentrate for injection of 50 mg/mL in 5 mL ampules should be stored at less than 86°F (30°C) and protected from light and freezing. Dilutions in 5 percent glucose or normal saline are stable for 24 hours. Substantial amounts of cyclosporine may be lost during intravenous administration through plastic tubing. Polyoxyethylated castor oil that is contained in the concentration for intravenous cyclosporine infusion can cause phthalate stripping from polyvinyl chloride (PVC)-containing intravenous tubing. Thus, when intravenous nonmodified cyclosporine is administered, PVC-free intravenous fluid containers and tubing should be used.

Modified — Capsules and solution are for oral use; no parenteral formulation is available. Patients who need an intravenous formulation should be prescribed cyclosporine nonmodified concentrate for injection. Cyclosporine modified capsules or the equivalent generic product are preferred due to superior pharmacokinetic profile compared with the nonmodified formulation:

●Capsules of 25 mg and 100 mg should be stored at 68 to 77°F (20 to 25°C); some generic formulations are available in a 50 mg capsule.

●The oral solution of 100 mg/mL is available in 50 mL bottles, which remains stable for two months after opening if stored in the original container at 68 to 77°F (20 to 25°C).

Ophthalmic emulsion — An ophthalmic emulsion of 0.05 percent is available in single vials of 0.4 mL and stored at 59 to 77°F (15 to 25°C).

Tacrolimus — Oral, intravenous, and topical formulations of tacrolimus are available.

●Tacrolimus immediate-release capsules of 0.5 mg, 1 mg, and 5 mg are stored at 59 to 86°F (15 to 30°C).

●Extended-release capsules (Astagraf XL/Advagraf) of 0.5 mg, 1 mg, and 5 mg are stored at 59 to 86°F (15 to 30°C). They should not be crushed or chewed.

●Extended-release tablets (Envarsus XR) of 0.75 mg, 1 mg, and 4 mg are stored at 59 to 86°F (15 to 30°C). They should not be crushed or chewed.

●Tacrolimus concentrate for injection of 5 mg/mL in 1 mL ampules is stored at 41 to 77°F (5 to 25°C) and is stable for 24 hours in plastic syringes at 75°F (24°C). When diluted in glucose or saline solutions, it remains stable for 24 hours in glass, but not PVC, containers.

●Tacrolimus ointment of 0.03 and 0.1% in 30 g and 60 g tubes are stored at 41 to 77°F (5 to 25°C).

●Tacrolimus granules (used to make a suspension) of 0.2 and 1 mg unit-dose packets are stored at 68 to 77°F (20 to 25°C). Tubing, syringes, and other equipment (cups) containing PVC should not be used to prepare or administer tacrolimus products. The suspension should be given immediately after preparation and not stored.

There are two extended-release formulations of tacrolimus designed for once-daily administration. Their mechanisms of prolonged release and pharmacokinetic profiles differ; therefore, the two are not interchangeable. The extended-release tacrolimus capsule (Astagraf XL/Advagraf) is a modified-release formulation that allows slow release of the drug by controlling water penetration and forming a protective polymer gel layer around tacrolimus [11]. The extended-release tacrolimus tablet (Envarsus XR) uses a drug-delivery technology that improves the bioavailability of drugs with low water solubility [12].

Extended-release tacrolimus capsules (Astagraf XL/Advagraf) are not approved in liver transplantation due to an increase in mortality in female liver transplant recipients [13].

Short courses of sublingual tacrolimus have been used as an alternative to intravenous tacrolimus when enteral administration is not possible [14].

DOSE AND ADMINISTRATION

Administration

●Cyclosporine – Cyclosporine should be administered at a consistent time of the day (at 12-hour intervals), and with a consistent relation to meals, in order to decrease the intra-individual blood concentration variations.

Cyclosporine nonmodified oral solution should be mixed with milk, chocolate milk, or orange juice at room temperature. Cyclosporine modified oral solution should be mixed with water, orange juice, or apple juice.

Both cyclosporine solutions may adhere to plastic and therefore should not be mixed in a plastic cup or with plastic utensils. If a dose is missed, patients should take it as soon as possible, ideally within four hours. They should not double the next dose.

●Tacrolimus – Tacrolimus immediate-release should be administered at a consistent time of the day (at 12-hour intervals) and preferably on an empty stomach. The extended-release products should be taken at the same time of the day, preferably in the morning. Patients should not chew, divide, or crush the tablets.

If an immediate-release tacrolimus dose is missed, patients should take it as soon as possible, ideally within four hours.

For the extended-release product, if a dose is missed, patients should take it as soon as possible within 14 to 15 hours after missing the dose. After the 14- to 15-hour timeframe, patients should wait until the usual scheduled time to take the next daily dose. Patients should not double the next dose. Patients should avoid alcoholic beverages while taking the extended-release product. Consumption of alcohol may increase the release rate of tacrolimus and/or adversely alter the pharmacokinetic properties and the effectiveness and safety of the extended-release product [15].

Tubing, syringes, and other equipment (cups) containing PVC should not be used when preparing or administering tacrolimus granule products [16]. To prepare the dose, patients should empty the entire contents of each granules packet into a glass cup. The granules should then be mixed with 1 to 2 tablespoons (15 to 30 mL) of room temperature drinking water. The granules will not completely dissolve. The suspension should be taken immediately after preparation. The cup or non-PVC syringe should be rinsed with the same quantity of water (15 to 30 mL) and given to the patient to ensure that all of the medication is taken. Wearing disposable gloves is recommended during dilution of the injection or when preparing the oral suspension in the hospital and when wiping any spills. Inhalation or direct contact with skin or mucous membranes of the powder or granules should be avoided. If such contact occurs, the skin should be washed thoroughly with soap and water; if ocular contact occurs, eyes should be rinsed with water. In case a spill occurs, the surface should be wiped with a wet paper towel. Granules should not be sprinkled on food.

Dose — The dose and target concentrations of cyclosporine and tacrolimus vary with the disease being treated. The doses used in patients with solid organ transplants are discussed below. Other diseases are discussed elsewhere in the appropriate topic reviews.

Initial doses of calcineurin inhibitors should be determined by taking into account drug interactions, diet, time after transplantation, pharmacokinetics, presence of infection, drug toxicity, and/or rejection. Drug concentration monitoring should occur after the initial doses are given. (See 'Drug monitoring' below.)

Most centers start calcineurin inhibitor therapy just before transplantation or within the first 24 hours of transplantation (see "Kidney transplantation in adults: Induction immunosuppressive therapy"). Some centers delay the introduction of a calcineurin inhibitor until the serum creatinine has decreased by 50 percent from the pretransplant value or the patient has significant urine output. However, there is little evidence that delayed, rather than immediate, initiation of a calcineurin inhibitor results in lower rates of delayed graft function [17,18].

In addition, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that administration of calcineurin inhibitors should not be delayed until the onset of graft function [19].

●Cyclosporine modified – For nonautoimmune disease, cyclosporine modified is initially dosed at 4 to 10 mg/kg/day orally in two divided doses. Most clinicians start at the lower end of the dosing range and make adjustments based upon drug concentrations. The first dose may be administered within 24 hours of transplantation. In newly transplanted patients, the initial dose of cyclosporine modified is the same as the initial dose of cyclosporine nonmodified, although cyclosporine modified is preferred.

●Tacrolimus – Tacrolimus is typically dosed at 0.1 to 0.2 mg/kg/day orally in two divided doses. Most clinicians start at the lower end of the dosing range and make adjustments based upon drug concentrations. The product information recommends the following for tacrolimus initiation [16]:

•At 0.1 mg/kg/day in kidney transplant recipients who also receive mycophenolate mofetil plus an interleukin (IL)-2 receptor antagonist

•At 0.2 mg/kg/day in kidney transplant recipients treated with azathioprine rather than mycophenolate mofetil

•At 0.1 to 0.15 mg/kg/day in adult liver transplant recipients

•At 0.075 mg/kg/day in adult heart and lung transplant recipients

●Extended-release tacrolimus products – In patients receiving mycophenolate mofetil, glucocorticoids, and basiliximab induction, extended-release tacrolimus capsules (Astagraf XL/Advagraf) should be given at a dose of 0.15 to 0.2 mg/kg/day prior to reperfusion or within 48 hours of the completion of the transplant procedure. In patients treated with mycophenolate mofetil and glucocorticoids without basiliximab induction, extended-release tacrolimus capsules should be given as a single dose of 0.1 mg/kg within 12 hours prior to reperfusion, then 0.2 mg/kg at least 4 hours after the preoperative dose, and within 12 hours after reperfusion, then 0.2 mg/kg daily [13]. The recommended starting dose of extended-release tacrolimus tablets (Envarsus) in de novo kidney transplant patients is 0.14 mg/kg/day with antibody induction [20].

Drug monitoring — Therapeutic monitoring of cyclosporine and tacrolimus is complicated by the narrow margin between adequate immunosuppression and toxicity. Whole blood should be used as a sample for both drugs. A variety of assays are available, and clinicians should become familiar with the one used in their local laboratory.

Cyclosporine should be monitored using 12-hour trough (C0), two-hour post-dose (C2), or abbreviated area under the time concentration curve (AUC) [19]. Although monitoring of C0 is common practice, there is a poor correlation with safety, efficacy, and drug exposure using this strategy. Some centers use C2 monitoring among kidney transplant recipients since these concentrations may correlate more closely with exposure, and higher C2 concentrations have been associated with decreased acute rejection rates in the first year [21-23]. In one study of liver transplant patients, C2 was more closely associated with the first four-hour post-dose cyclosporine exposure (AUC0-4) than C0 [24]. C2 monitoring may be more accurate but is often more difficult and less convenient for the patient. Most centers monitor either C0 or C2 concentrations but not both. In rare circumstances, assessing both may be beneficial in a patient with absorption issues.

Tacrolimus should be monitored using 12- and 24-hour trough (C0) concentrations for the immediate-release and extended-release preparations, respectively [19].

Blood concentrations should be checked two to three days after starting cyclosporine or tacrolimus and after any dose change. Typically, after transplant, concentrations are measured every one or two days while hospitalized. After discharge, levels should be measured once or twice weekly for the first month, then weekly until three months posttransplantation, then every two weeks until six months posttransplant, and then monthly. Some stable, low-risk patients may have concentrations monitored every two to three months. However, if drugs that affect cyclosporine or tacrolimus metabolism are added or withdrawn, more frequent measurement of trough concentrations will be required (see 'Food and drug interactions' below). Tacrolimus and cyclosporine reach steady-state concentrations after four to six doses.

Target concentrations — Target concentrations for cyclosporine and tacrolimus vary depending upon which disease is being treated. These recommendations are presented elsewhere:

●In kidney transplant recipients (see "Kidney transplantation in adults: Maintenance immunosuppressive therapy")

●In lung transplant recipients (see "Maintenance immunosuppression following lung transplantation", section on 'Calcineurin inhibitors')

●In liver transplant recipients (see "Liver transplantation in adults: Initial and maintenance immunosuppression", section on 'Calcineurin inhibitors')

●In heart transplant recipients (see "Heart transplantation in adults: Induction and maintenance of immunosuppressive therapy", section on 'Calcineurin inhibitors')

●In hematopoietic cell transplant recipients (see "Prevention of graft-versus-host disease", section on 'Calcineurin inhibitors (CNI)' and "Treatment of acute graft-versus-host disease")

●In glomerular diseases (see "Membranous nephropathy: Treatment and prognosis", section on 'Calcineurin inhibitors' and "Treatment of idiopathic nephrotic syndrome in children" and "Minimal change disease: Treatment in adults", section on 'Glucocorticoid-sparing regimens' and "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Calcineurin inhibitors as alternative initial therapy' and "Steroid-resistant nephrotic syndrome in children: Management", section on 'Immunosuppressive therapy')

●In inflammatory bowel diseases (see "Management of the hospitalized adult patient with severe ulcerative colitis")

●In autoimmune diseases (see "Chronic immunotherapy for myasthenia gravis", section on 'Glucocorticoid-sparing therapy')

Dose adjustments — In clinical practice, dose adjustments are made in small increments with subsequent drug concentration monitoring. If a cyclosporine concentration is high, then the dose of cyclosporine may be lowered by 25 to 50 mg per dose. If the concentration is low, then the dose may be increased by 25 to 50 mg per dose. For tacrolimus, dose adjustments are typically 0.5 to 1 mg per dose. If a drug concentration is supratherapeutic (eg, C0 >400 ng/mL for cyclosporine or >20 ng/mL for tacrolimus), then the dose may be held until the concentration returns to the therapeutic range. It is important to determine whether the concentration was obtained correctly before making any dose adjustments. Tacrolimus and cyclosporine reach steady-state concentrations after four to six doses, and therefore, dose adjustments can be assessed via drug concentration monitoring two to three days after an adjustment. In addition, safety and efficacy should be monitored after adjustments.

Optimal dosing and concentrations may be affected by several factors including pharmacokinetic factors, presence of infection, drug toxicity, and/or rejection (table 2) (see "Kidney transplantation in adults: Maintenance immunosuppressive therapy" and "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection"). Testing for polymorphisms of the multidrug resistance-1 (P-glycoprotein) and CYP3A5 genes may aid in the dosing of calcineurin inhibitors [25-30], but large, well-designed trials are needed to determine if testing improves outcomes and is cost effective.

Switching formulations — When switching formulations of products, drug concentrations should be closely monitored for several weeks. The frequency of monitoring should depend upon several factors (table 2), as well as how far the patient is from transplant. In a stable patient who is more than six months posttransplant, we monitor drug concentrations weekly for two to three weeks. The dose should subsequently be adjusted to attain the preconversion blood concentration. In addition, safety and efficacy should be monitored after conversion.

●Cyclosporine

•Oral to intravenous administration – For patients unable to take oral cyclosporine, the intravenous dose should equal one-third of the oral dose. Intravenous administration should occur over at least two to six hours twice daily in a well-hydrated patient to avoid nephrotoxicity.

•Nonmodified to modified formulation – In general, modified formulations of cyclosporine lead to higher area under the time concentration curve (AUC) than nonmodified preparations. Thus, patients stabilized on either form should generally not be switched from one to the other. If patients are switched, a 1:1 ratio is recommended when converting from the nonmodified to the modified formulation.

•Cyclosporine to tacrolimus – Clinicians use a 40:1 ratio when converting from cyclosporine to tacrolimus. As an example, if a patient takes 125 mg of modified cyclosporine twice daily (250 mg/day), then a tacrolimus dose of 3 mg twice daily (6 mg/day) would be appropriate.

●Tacrolimus

•Oral to intravenous administration – For patients unable to take oral tacrolimus, the intravenous dose should equal one-third to one-fifth of the oral daily dose and should be given as a continuous 24-hour infusion.

•Immediate-release to extended-release capsules – A 1:1 conversion from immediate-release tacrolimus to extended-release tacrolimus capsules (Astagraf XL/Advagraf) has been proven equivalent. The ratio of exposure (AUC0-24) of extended-release tacrolimus capsules to immediate-release tacrolimus twice daily is approximately 90 percent across various conversion studies in kidney, liver, and heart transplant recipients; however, in liver transplant patients, the extended-release tacrolimus capsule AUC was significantly lower in the early posttransplant period compared with that of tacrolimus twice daily [29,31-36].

•Immediate-release to extended-release tablets – Eighty percent of the total daily dose of immediate-release tacrolimus should be used when converting to extended-release tablets (Envarsus XR) [37].

•Oral immediate-release to sublingual immediate-release tacrolimus – To convert from oral tacrolimus to sublingual tacrolimus, the oral tacrolimus dose should be decreased by 50 percent [14,38].

•Granules – To convert from granules to capsules or from capsules to granules, the total daily dose should remain the same [16].

PHARMACOKINETICS

Absorption — Oral cyclosporine and tacrolimus are only partially absorbed with large inter- and intra-individual variability. Cyclosporine and tacrolimus are absorbed in the small intestine, and peak blood concentrations occur after one to eight hours. The oral bioavailability is limited for both drugs (roughly 20 percent for tacrolimus) as a result of poor absorption, partial metabolism by enzymes in the bowel mucosa, intestinal P-glycoprotein (P-gp) efflux, and first-pass hepatic metabolism [39-42]. In general, modified formulations of cyclosporine lead to higher area under the time concentration curve (AUC) than the nonmodified preparations.

In healthy volunteers, the oral bioavailability of extended-release tacrolimus tablets was approximately 50 percent higher as compared with tacrolimus immediate-release at steady state [37]. Both extended-release tacrolimus products exhibit chronopharmacokinetic effects; evening administration, compared with morning dosing, results in a 15 percent lower AUC for extended-release tacrolimus tablets and a 35 percent lower AUC for extended-release tacrolimus capsules [13,37]. Thus, both products should be taken consistently every morning.

Pharmacokinetic trials comparing extended-release tacrolimus formulations with immediate-release tacrolimus have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration with extended-release formulations. However, extended-release tacrolimus tablets have an AUC0-24 (area under the time concentration curve from 0 to 24 hours) that is comparable with that of immediate-release tacrolimus; extended-release tacrolimus capsules have an AUC0-24 that is higher than that of immediate-release tacrolimus [13,37].

The absorption and metabolism of calcineurin inhibitors may vary with race and ethnicity. As an example, the mean tacrolimus exposure after a single 5 mg oral dose in healthy Hispanic and African American individuals was 18 and 39 percent less, respectively, than in White individuals [43]. Similar results have been seen with the extended-release products [13,37]. Such variation may be related to differences in the frequency of polymorphisms in the CYP3A5 gene among African American, Hispanic, and White transplant recipients [44-46].

The absorption of cyclosporine, but not tacrolimus, is dependent upon bile salts. Thus, cyclosporine modified or tacrolimus may be preferable in patients with biliary diversion or cholestasis. Cyclosporine modified absorption is decreased modestly when ingested with a fatty meal (table 3). Similarly, tacrolimus absorption is decreased if administered after a fatty meal and should be taken on an empty stomach, if possible [47].

Patients receiving long-term cyclosporine ophthalmic emulsion of 0.05 percent had no detectable blood cyclosporine concentrations, indicating no significant systemic absorption [48].

Topical tacrolimus is minimally absorbed in patients with normal skin, but clinically significant absorption has been reported when used in patients with skin disease [49].

Distribution — Cyclosporine and tacrolimus are lipophilic and undergo extensive body distribution. In the blood, most of the absorbed amount of each drug is taken up by erythrocytes. In the plasma, cyclosporine binds mainly to lipoproteins, whereas tacrolimus binds to proteins, primarily albumin and alpha-1-acid glycoprotein. The plasma protein binding of tacrolimus is approximately 99 percent and is independent of concentration over a range of 5 to 50 ng/mL.

The highest tissue cyclosporine concentration is achieved in the thymus, spleen, lymph nodes, bone marrow, liver, pancreas, kidney, adrenal glands, lung, and skin. Tacrolimus accumulates mainly in the lung, spleen, heart, kidney, and pancreas.

Cyclosporine penetrates well into synovial fluid but does not cross the blood-brain barrier. Both drugs cross the placenta and appear to some extent in breast milk, but actual toxicity in breastfed infants appears to be rare [50]. Some centers measure cyclosporine and/or tacrolimus blood concentrations in breastfed infants to confirm that these are low.

Metabolism — Cyclosporine and tacrolimus are extensively metabolized by cytochrome P-450 CYP3A enzymes in the liver. There is also some metabolism in the gut mucosa. Cyclosporine metabolism is age dependent, with a 1.5- to 2.5-fold increase in half-life in adults compared with children. Liver dysfunction also prolongs the half-life of both cyclosporine and tacrolimus. The most active cyclosporine metabolites have only 10 to 20 percent of the drug's immunosuppressive activity. By comparison, one of the metabolites of tacrolimus possesses equal immunosuppressive potency to the parent drug.

Elimination — Cyclosporine and tacrolimus are excreted in the bile. The elimination half-life can vary significantly among patients, especially with cyclosporine nonmodified, but is approximately 19 hours for cyclosporine modified and 12 hours for immediate-release tacrolimus. The elimination half-life of extended-release tacrolimus tablets after oral administration of 2 mg once daily for 10 days was 31±8 hours in healthy subjects [37]. The elimination half-life of extended-release tacrolimus capsules after oral administration of 4 mg capsules daily for 10 days was 38±3 hours in healthy subjects [13].

Food and drug interactions

●Food interactions – The presence, composition, and timing of food may affect the absorption of many of the immunosuppressive drugs (table 3). Because the avoidance of food at the time of medication administration is not always practical, many clinicians recommend that patients be consistent and always take their medication in the same manner, whether it is with or without food.

A group of active chemical compounds in grapefruit, known as the furanocoumarins, are potent inhibitors of cytochrome P-450 3A4 enzyme. Grapefruit or grapefruit juice can result in an increase in systemic exposure to cyclosporine or tacrolimus. It is important to educate patients about the interaction between grapefruit/grapefruit juice and their immunosuppressive agents. Patients should be counseled to completely avoid grapefruit and grapefruit juice when being treated with cyclosporine or tacrolimus. In patients who refuse to avoid grapefruit and grapefruit juice, more frequent monitoring of blood cyclosporine or tacrolimus concentrations is required.

●Drug interactions – There are multiple interactions between calcineurin inhibitors and commonly used medications. General principles of these drug interactions are reviewed here. More detailed discussions of drug interactions are found elsewhere.

•Since cyclosporine and tacrolimus are substrates of cytochrome P-450 3A4/5 (CYP3A4/5) drug metabolism and P-glycoprotein (P-gp) transport, and cyclosporine also inhibits P-gp, any drug that affects CYP3A4 metabolism or P-gp transport, including other substrates, can potentially interact with calcineurin inhibitors (table 4 and table 5 and table 6). A common example is the prescribing of macrolides for respiratory tract infections: acute cyclosporine and tacrolimus toxicity may occur due to CYP3A4/5 and/or P-gp inhibition. In addition, carvedilol inhibits P-gp and may increase the blood concentrations of cyclosporine and tacrolimus [51].

If a patient cannot avoid a strong or moderate inhibitor/inducer of CYP3A4/5 or P-gp, then drug concentrations and toxicities must be closely monitored. Limited data are available regarding precise dose adjustments when interacting medications are coadministered with cyclosporine and tacrolimus. Specific drug interactions may be determined using the drug interactions program embedded in UpToDate.

•Clinicians may take advantage of drug interactions to lower the dose of the calcineurin inhibitor or to enhance the drug concentration. The effects of diltiazem and ketoconazole on cyclosporine and tacrolimus metabolism have led to their use in transplant recipients as a method of lowering the total dose and cost of cyclosporine or tacrolimus therapy [52,53]. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)

•Drugs that affect gastrointestinal motility or emptying (eg, prokinetic agents) may affect absorption of calcineurin inhibitors. Metoclopramide, for example, may reduce oral cyclosporine and tacrolimus absorption by accelerating their passage through the intestine. By contrast, narcotics may prolong transit time in the intestine, increasing the time for absorption.

•Concomitant administration of cyclosporine or tacrolimus with other potentially nephrotoxic drugs (eg, nonsteroidal antiinflammatory drugs) should be avoided because increased toxicity may result. Since calcineurin inhibitors may produce or worsen hyperkalemia, serum potassium levels should be monitored closely in patients concomitantly taking drugs that may increase potassium (eg, amiloride, triamterene, and spironolactone). (See "Cyclosporine and tacrolimus nephrotoxicity".)

•Divalent cations may influence the absorption of tacrolimus. In a single-dose, crossover study in healthy volunteers, coadministration of tacrolimus and aluminum hydroxide-magnesium hydroxide resulted in a 21 percent increase in the mean tacrolimus area under the curve (AUC) and a 10 percent decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone [16]. However, in another study, patients did not require tacrolimus dose adjustment when magnesium/aluminum was prescribed with tacrolimus therapy [54]. To minimize these potential interactions, magnesium- and aluminum-containing products should not be administered within two hours of tacrolimus products, and tacrolimus drug concentrations should be closely monitored.

•Several antiviral medications are being evaluated or have already been approved for treatment of coronavirus disease 2019 (COVID-19). Clinicians should be aware that these medications could interact with cyclosporine or tacrolimus, and if these immunosuppressants are continued during COVID-19 infection, their levels should be frequently monitored. Nirmatrelvir-ritonavir, for example, can dramatically increase cyclosporine and tacrolimus concentrations and associated toxicity. (See "COVID-19: Issues related to solid organ transplantation", section on 'Drug-drug interactions'.)

For additional information on drug interactions, use the drug interactions program provided by UpToDate.

SIDE EFFECTS — The side effects of cyclosporine and tacrolimus are generally similar. When used for the treatment of autoimmune disorders, the frequency and severity of side effects are lower compared with those seen in transplant recipients. This observation is explained by the lower doses used and the option to decrease the dose or discontinue the medication when toxicity appears in patients with autoimmune disorders; these options may not be available in transplant recipients.

Nephrotoxicity — Nephrotoxicity is a significant adverse effect of both drugs. Cyclosporine and tacrolimus nephrotoxicity is manifested as an acute increase in plasma creatinine, which is largely reversible after reducing the dose, or as chronic occasionally progressive kidney disease, which is usually irreversible. Other kidney effects of cyclosporine include tubular dysfunction and, rarely, a thrombotic microangiopathy (TMA). (See "Cyclosporine and tacrolimus nephrotoxicity".)

Hypertension — Hypertension, caused by renal vasoconstriction and sodium retention, generally develops within the first few weeks of therapy. Stimulation of the renal sodium chloride cotransporter is a potential mechanism by which calcineurin inhibitors may mediate this effect [55]. The blood pressure elevation usually responds to dose reduction, but antihypertensive medications may be required. (See "Cyclosporine and tacrolimus nephrotoxicity" and "Hypertension after kidney transplantation", section on 'Approach to pharmacologic therapy'.)

Calcium channel blockers are usually considered the drugs of choice if antihypertensive therapy is needed in the setting of cyclosporine therapy. As noted above, diltiazem also impairs cyclosporine metabolism, thereby allowing a lower dose to be given. Initiation of diltiazem should prompt immediate reduction in the dose of cyclosporine or tacrolimus and careful monitoring of blood concentrations. Diltiazem also reverses the acute vasoconstriction induced by cyclosporine; there is, however, no convincing evidence that this prevents chronic cyclosporine nephrotoxicity. (See "Cyclosporine and tacrolimus nephrotoxicity", section on 'Prevention of chronic calcineurin inhibitor nephrotoxicity'.)

Neurotoxicity — Neurotoxicity associated with cyclosporine and tacrolimus may manifest as follows [56-61]:

●Mild tremor is common with both cyclosporine and tacrolimus use, occurring in 35 to 55 percent of patients [58,59]. It may improve despite continued therapy.

●Rarely, patients develop severe headache, visual abnormalities, and seizures. This syndrome is associated with acute hypertension and resembles hypertensive encephalopathy [56]. Posterior leukoencephalopathy is usually seen on brain imaging [61]. (See "Reversible posterior leukoencephalopathy syndrome".)

●Akinetic mutism, encephalopathy, seizures, focal neurologic abnormalities, and even coma have been reported with intravenous tacrolimus [57].

●A calcineurin-inhibitor pain syndrome has been reported with both cyclosporine and tacrolimus [62]. This syndrome is characterized by symmetrical pain in the lower limbs, usually involving the bones of the feet, ankles, and knees. Magnetic resonance imaging (MRI) may show marrow edema. Symptoms usually improve with cessation of the drug and/or use of calcium channel blockers.

The neurologic side effects are usually reversible following a change from intravenous to an oral preparation, lowering of the drug dose, or drug discontinuation [56,57,60]. They are generally more common with tacrolimus than with cyclosporine [58,59].

Metabolic abnormalities — Cyclosporine and tacrolimus have been associated with the following metabolic abnormalities:

●Glucose intolerance and diabetes mellitus (see "Kidney transplantation in adults: Posttransplantation diabetes mellitus")

●Hyperlipidemia (see "Heart transplantation: Hyperlipidemia after transplantation" and "Lipid abnormalities after kidney transplantation")

●Hyperuricemia and gout (see "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients")

●Hyperkalemia (see "Cyclosporine and tacrolimus nephrotoxicity", section on 'Hyperkalemia')

●Hypomagnesemia (see "Cyclosporine and tacrolimus nephrotoxicity", section on 'Hypomagnesemia')

Cyclosporine may also contribute to bone loss after organ transplantation [63]; this effect may be due to the induction of high bone turnover. (See "Drugs that affect bone metabolism" and "Kidney transplantation in adults: Bone disease after kidney transplantation", section on 'Pathogenesis and risk factors'.)

Infections — Bacterial, viral (most often, cytomegalovirus [CMV]), and fungal infections often develop in transplant recipients receiving combined immunosuppressive therapy. In a large trial of liver transplant recipients comparing the efficacy and safety of cyclosporine- and tacrolimus-based immunosuppressive regimens, infection, sepsis, and CMV disease occurred in approximately 40, 20, and 15 to 25 percent of patients, respectively [58].

Infection in the solid organ transplant recipient is discussed in more detail elsewhere. (See "Infection in the solid organ transplant recipient".)

Risk of malignancy — Both cyclosporine and tacrolimus are associated with an increased risk of squamous cell skin cancer and benign or malignant lymphoproliferative disorders. Spontaneous regression of lymphoma may occur if the drug is discontinued early. (See "Malignancy after solid organ transplantation".)

The overall level of immunosuppression appears to be the principal factor that increases the risk of posttransplant malignancy. However, evidence from animal models suggests that cyclosporine itself may promote cancer progression, principally via the production of transforming growth factor (TGF)-beta. In vitro, cyclosporine treatment of a normally noninvasive adenocarcinoma cell line induced an invasive phenotype; in addition, cyclosporine promoted tumor growth in immunodeficient animals [64]. Both the in vitro and in vivo changes were prevented by the administration of anti-TGF-beta antibodies.

Pregnancy and lactation — The effects of cyclosporine and tacrolimus on pregnancy and lactation are discussed in more detail elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclosporine' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tacrolimus' and "Sexual and reproductive health after kidney transplantation", section on 'Management of immunosuppression'.)

Other side effects — Other side effects associated with the use of cyclosporine and tacrolimus include the following:

●Gastrointestinal – Gastrointestinal side effects include anorexia, nausea, vomiting, diarrhea, and abdominal discomfort. These symptoms are more frequent with tacrolimus (72 versus 47 percent for cyclosporine in one report) [59]. Elevated serum aminotransferase levels with mild hyperbilirubinemia may also occur; if present, this abnormality is reversible with dose reduction or discontinuation of the drug [65].

●Cosmetic – Gingival hyperplasia and hirsutism occur with cyclosporine therapy [66,67] but not with tacrolimus. Poor dental hygiene, higher doses of cyclosporine, and concomitant use of nifedipine appear to be the principal risks [68]. Case reports suggest that the gingival hyperplasia can be effectively treated with a two-week course of metronidazole (750 mg three times daily) while cyclosporine is continued [69,70]. It is not clear whether metronidazole acts in this setting via its antibacterial activity or via another mechanism. Treatment with azithromycin (500 mg/day for three consecutive days) may also be effective, particularly among those with mild or early disease [71]. In the transplant setting, the substitution of cyclosporine with tacrolimus was found to significantly ameliorate gingival hyperplasia without increasing the risk of kidney allograft dysfunction or rejection [72].

An increasingly recognized complication of immunosuppressive therapy in transplant recipients is alopecia, a finding attributed, in one study, to the use of tacrolimus [73]. At one transplant center, alopecia was noted in 3 to 6 percent of recipients receiving this agent [74]. Higher doses were associated with an increased risk. Another study reported an incidence of 30 percent among kidney-pancreas recipients who received tacrolimus [75].

CONTRAINDICATIONS — Hypersensitivity to cyclosporine, tacrolimus, or polyoxyl castor oil products (used as solvents for injection preparation of both drugs) is a contraindication to their use. The following conditions are generally accepted contraindications to the use of cyclosporine or tacrolimus:

●Concurrent malignancy (except for nonmelanoma skin carcinoma)

●Uncontrolled hypertension

●Uncontrolled infections

●Hypersensitivity

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the Basics)" and "Patient education: Heart transplantation (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Formulations – Cyclosporine and tacrolimus are immunosuppressive agents occasionally used in the treatment of various immune-mediated diseases and more commonly used to prevent rejection in solid organ transplantation; the drugs are available in oral, intravenous, ophthalmic, and topical formulations (table 1). (See 'Formulations' above.)

●Mechanism of action – Cyclosporine and tacrolimus reduce T cell activation through the inhibition of calcineurin after forming complexes in the cytoplasm with cyclophilins and FK-binding proteins, respectively. Calcineurin inhibition results in reduced transcription of early cytokine genes, including those for interleukin (IL)-2, tumor necrosis factor (TNF), and several others. (See 'Mechanism of action' above.)

●Dose and administration – The dose, route, formulation, and drug concentrations of calcineurin inhibitors depend upon several factors. Routine blood monitoring is recommended. Many factors should be considered when making dose adjustments to calcineurin inhibitors. (See 'Dose and administration' above.)

●Pharmacokinetics

•Oral cyclosporine and tacrolimus are only partially absorbed, with large inter- and intra-individual variability. The oral bioavailability is limited for both drugs due to poor absorption, partial metabolism by enzymes in the bowel mucosa, and first-pass hepatic metabolism. The drugs are lipophilic and undergo extensive body distribution. Cyclosporine does not cross the blood-brain barrier. (See 'Absorption' above and 'Distribution' above.)

•Cyclosporine and tacrolimus are metabolized by hepatic cytochrome P-450 3A enzymes in the liver and are excreted into the bile. Liver dysfunction prolongs the half-life of both agents. A variety of important drug interactions with drugs that either affect or are metabolized by these enzymes can occur (table 4 and table 5 and table 6). Details about specific interactions are available by using the drug interaction program included with UpToDate. (See 'Metabolism' above and 'Elimination' above and 'Food and drug interactions' above.)

●Side effects – The side effects of cyclosporine and tacrolimus are similar. Nephrotoxicity is the most common and clinically significant adverse effect of both drugs. Hypertension, caused by renal vasoconstriction and sodium retention, is also common and generally develops within the first few weeks of therapy. Other potential adverse effects include neurotoxicity, metabolic abnormalities, infections, and an increased risk of malignancy. Contraindications to use depend upon the presence of various comorbidities or hypersensitivity to the agents. (See 'Side effects' above and "Cyclosporine and tacrolimus nephrotoxicity" and 'Contraindications' above.)