Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply.

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate-release tacrolimus (IR-TAC) is not available. Alternative options explored include extended-release tacrolimus (ER-TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER-TAC formulations are of non-inferior efficacy compared to IR-TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy-proven rejection, but improved tolerance from classic adverse effects of IR-TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third-party payors is an obstacle in non-KTRs. In the setting of IR-TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.

Safety and efficacy of topical calcineurin inhibitors in the treatment of childhood atopic dermatitis.

Approximately 10-20% of infants in industrialized countries experience atopic dermatitis. In recent decades topical corticosteroids have been the first-choice therapy for treatment of flares. However, this form of therapy may induce skin atrophy, especially after application to facial lesions or with long-term use. Thus, development of new anti-inflammatory topical agents for the treatment of childhood atopic dermatitis was needed. The topical calcineurin inhibitors tacrolimus and pimecrolimus have an effect on various cells of the cutaneous immune system, specifically on T cells, by inhibiting the phosphatase calcineurin and preventing the transcription of proinflammatory cytokines. In several clinical studies of children and adults with atopic dermatitis, topical calcineurin inhibitors were found to be effective both on the face and the trunk and extremities, in both short- and long-term treatment regimens. Tachyphylaxis or rebound were not observed. In most patients an improvement of their eczema occurred during the first week of treatment, as measured by subjective and objective clinical signs of atopic dermatitis. Treatment significantly reduced the incidence of flares and the need for corticosteroids in children and adults. Treatment success, commonly defined as 'excellent improvement' or 'clearing of all lesions', was observed in more than one-third of all children treated with 0.03% or 0.1% tacrolimus or 1% pimecrolimus. Topical application of pimecrolimus and tacrolimus does not lead to significant blood concentrations of these agents in the majority of children with atopic dermatitis, and any increase in blood concentrations decreases after a few days of therapy. No changes in laboratory parameters were observed in short- and long-term studies in patients with atopic dermatitis. The most common adverse effect following the application of topical calcineurin inhibitors is mild to moderate symptoms of irritation such as burning, erythema and pruritus, which occurred in up to 20% of all children treated with tacrolimus and 10% of children treated with pimecrolimus, and usually faded after a few days. In contrast to topical corticosteroids, calcineurin inhibitors do not induce skin atrophy, even after long-term use. Topical calcineurin inhibitors have been proven to be effective and have a good safety profile during short-term and long-term use for up to 1 year with pimecrolimus and up to 4 years with tacrolimus. Given the lack of extensive experience with use of topical calcineurin inhibitors over longer periods, regular use of these agents, particularly in children, should be undertaken only after careful consideration of individual cases. Sun protection should also be advised.