Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.
IDENTIFICATION AND USE: Tacrolimus is white to off-white crystalline powder. It is a calcineurin-inhibitor immunosuppressant available in several preparations. Tacrolimus in both oral capsules and a solution for IV injection is used for prophylaxis of organ rejection in patients receiving liver, kidney or heart transplants. Tacrolimus topical ointment is used as a second-line therapy for the short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis in non-immunocompromised adults and children. HUMAN EXPOSURE AND TOXICITY: While most acute overdosages of tacrolimus at up to 30 times the intended dose have been asymptomatic and all patients recovered with no sequelae, some acute overdosages were followed by adverse reactions including tremors, abnormal renal function, hypertension, and peripheral edema. At therapeutic doses, patients receiving tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin, as well as an increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. While there are no adequate and well-controlled studies in pregnant women, the use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction. ANIMAL STUDIES: Both rats and baboons showed a similar toxicologic profile following oral or intravenous administration of tacrolimus. Toxicity following intravenous administration was evident at lower doses than after oral administration for both rats and baboons. Toxicity was seen at lower doses in rats than in baboons. The primary target organs were the kidneys, pancreatic islets of Langerhans and exocrine pancreas, spleen, thymus, gastrointestinal tract, and lymph nodes. In addition, decreases in erythrocyte parameters were seen. Tacrolimus also produced reproductive and developmental toxicity in both rats and rabbits. In rats, chronic oral administration of tacrolimus at high doses resulted in changes in sex organs, and glaucoma/eye changes. Oral doses of tacrolimus at 1 and 3.2 mg/kg/day produced overt signs of parental toxicity and changes in the fertility and general reproductive performance of rats. Effects on reproduction included some embryo lethality, reduced number of implantations, increased incidence of post-implantation loss, and reduced embryo and offspring viability. In a rabbit teratology study, signs of maternal toxicity including reduced body weight were produced at all oral doses of tacrolimus administered (0.1, 0.32, or 1 mg/kg/day). Doses of 0.32 and 1 mg/kg/day produced signs of developmental toxicity, such as increased incidence of post-implantation losses, reduced number of viable fetuses, and increased incidences of morphological variations. In a rat teratology study, increased post-implantation loss was observed at 3.2 mg/kg/day. Maternal doses of 1 mg/kg/day decreased the body weight of F1 offspring. Decreased body weight, reduced survival number, and some skeletal alterations were seen in F1 offspring at maternal doses of 3.2 mg/kg/day. Tacrolimus did not exhibit genotoxic activity in vitro in bacterial asaays in Salmonella typhimurium and Escherichia coli or mammalian assays in Chinese hamster lung-derived cells assays. No evidence of mutagenicity was observed in vitro in the CHO/HGPRT assay (the Chinese hamster ovary cell assay (CHO), which measures forward mutation of the HGPRT locus) or in vivo in clastogenicity assays performed in mice. Tacrolimus also did not cause unscheduled DNA synthesis in rodent hepatocytes.
◉ Summary of Use during Lactation:Limited data indicate that amounts of systemically administered tacrolimus are low in breastmilk and probably do not adversely affect the breastfed infant. United States and European experts and guidelines consider tacrolimus to be probably safe to use during breastfeeding. Exclusively breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern.
Topical tacrolimus presents a low risk to the nursing infant because it is poorly absorbed after topical application and peak blood concentrations are less than 2 mcg/L in most patients. Ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. If the breast is to be treated, an alternate drug is preferred; do not apply to the nipple area while nursing. A newer European guideline allows tacrolimus to be applied just after nursing, with the nipples cleaned gently and carefully before nursing.
◉ Effects in Breastfed Infants:One infant was exclusively breastfed during maternal tacrolimus therapy throughout gestation to at least 2.5 months of age at which time the infant was developing normally physically and neurologically. An ultrasound examination of the infant's thymus was normal.
The National Transplantation Pregnancy Registry reported data gathered from 1991 to 2011 on mothers who breastfed their infants following organ transplantation. A total of 68 mothers with transplants (mostly kidney or liver) used tacrolimus while breastfeeding a total of 83 infants. Duration of nursing ranged from 1 week to 1.5 years and follow-up of the children ranged from weeks to 16 years. There were no reports of problems in any of the infants or children. As of December 2013, a total of 92 mothers had breastfed 125 infants for as long as 26 months with no apparent adverse effects in infants.
The breastfed infants of six women who took tacrolimus during pregnancy for organ transplantation were breastfed (4 exclusive, 2 partial) for 45 to 180 days and followed for periods of 2 to 30 months. The mothers' mean daily tacrolimus dosage during breastfeeding was 9.6 mg daily (range 4.5 to 15 mg daily). Four mothers were also taking azathioprine 100 to 150 mg daily, one was taking diltiazem, and one was taking prednisolone 15 mg and aspirin 75 mg daily. None of the infants had any clear tacrolimus-related side effects, although one had transient thrombocytosis that resolved despite continued breastfeeding. Developmental milestones were normal and no pattern of infections was noted.
Two mothers with systemic lupus erythematosus were reported who took tacrolimus 3 mg daily during pregnancy and lactation as well as prednisolone 30 or 40 mg daily. Three years after birth, both children were healthy. The durations of lactation were not stated.
In a case series of women who had liver transplants over a 25-year period, one woman breastfed (extent not stated) her infant while taking tacrolimus. No neonatal complications were noted.
A mother with a liver transplant was maintained on belatacept 10 mg/kg monthly, slow-release tacrolimus (Envarsus and Veloxis) 2 mg daily, azathioprine 25 mg daily, and prednisone 2.5 mg daily. She breastfed her infant for a year (extent not stated). The infant’s growth and cognitive milestones were normal.
An Australian case series reported 3 women with heart transplants who had a total of 5 infants, all of whom were breastfed (extent not stated) during maternal tacrolimus therapy. Daily dosages ranged from 3 to 13 mg daily. No adverse infant effects were reported up to the times of discharge.
A woman with rheumatoid arthritis refractory to etanercept took sarilumab 200 mg every two weeks during pregnancy until 37 weeks of gestation. She was also taking prednisolone 10 mg and tacrolimus 3 mg daily. She delivered a healthy infant at 38 weeks of gestation and breastfed her infant. Prednisolone was continued postpartum, tacrolimus was restarted at 7 days postpartum, and sarilumab was restarted at 28 days postpartum. The mother continued to breastfeed until 6 months postpartum. The infant was vaccinated with multiple live vaccines after reaching six months old, including the Bacille-Calmette-Guerin vaccine, with no adverse effects.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher with Prograf co-administration than with cyclosporine co-administration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to Prograf in patients concomitantly receiving MPA-containing products.
Grapefruit juice inhibits CYP3A-enzymes resulting in increased tacrolimus whole blood trough concentrations, and patients should avoid eating grapefruit or drinking grapefruit juice with tacrolimus.
Since tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes may increase tacrolimus whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations. Dose adjustments may be needed along with frequent monitoring of tacrolimus whole blood trough concentrations when Prograf is administered with CYP3A inhibitors or inducers. In addition, patients should be monitored for adverse reactions including changes in renal function and QT prolongation.
The aim of this study was to assess tacrolimus levels in breast milk and neonatal exposure during breastfeeding. An observational cohort study was performed in two tertiary referral high-risk obstetric medicine clinics. Fourteen women taking tacrolimus during pregnancy and lactation, and their 15 infants, 11 of whom were exclusively breast-fed, were assessed. Tacrolimus levels were analyzed by liquid chromatography-tandem mass spectrometry. Samples from mothers and cord blood were collected at delivery and from mothers, infants, and breast milk postnatally where possible. All infants with serial sampling had a decline in tacrolimus level, which was approximately 15% per day (ratio of geometric mean concentrations 0.85; 95% confidence interval, 0.82-0.88; P<0.001). Breast-fed infants did not have higher tacrolimus levels compared with bottle-fed infants (median 1.3 ug/L [range, 0.0-4.0] versus 1.0 ug/L (range, 0.0-2.3), respectively; P=0.91). Maximum estimated absorption from breast milk is 0.23% of maternal dose (weight-adjusted). Ingestion of tacrolimus by infants via breast milk is negligible. Breastfeeding does not appear to slow the decline of infant tacrolimus levels from higher levels present at birth.
Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject. Mean (+ or - SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 + or - 1.8 ng ml(-1)) were 71 + or - 18% (range 45-99%) of maternal concentrations (9.0 + or - 3.4 ng ml(-1)). The mean umbilical cord venous plasma (0.09 + or - 0.04 ng ml(-1)) and unbound drug concentrations (0.003 + or - 0.001 ng ml(-1)) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 + or - 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose. Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher haematocrit levels in venous cord blood.
Ten colostrum samples were obtained from six women in the immediate postpartum period (0-3 days) with a mean drug concentration of 0.79 ng/mL (range 0.3-1.9 ng/mL). The median milk:maternal plasma ratio was 0.5.
The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a US study, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67). There was no evidence based on blood concentrations that tacrolimus accumulates systemically upon intermittent topical application for periods of up to 1 year. As with other topical calcineurin inhibitors, it is not known whether tacrolimus is distributed into the lymphatic system.
The present invention provides amorphous tacrolimus in a free drug particulate form. Also provided are methods for preparing amorphous tacrolimus, and a tablet containing amorphous tacrolimus.
