Chronopharmacokinetics of ciclosporin and tacrolimus

Abstract

The correct use of immunosuppressive drugs has a considerable influence on the prognosis of patients with organ transplants. The appropriate utilisation of the drugs involves the administration of an adequate dosage to reach the blood concentrations that will suppress the alloimmune response, while avoiding secondary toxicities. However, transplanted patients exhibit heterogeneous immunological responses and high inter- and intraindividual pharmacokinetic variabilities. One cause of these variabilities that is rarely considered is circadian rhythms. In vitro and in vivo experiments have clearly demonstrated that all organisms are highly organised according to an internal biological clock that influences various physiological functions. Considering that the absorption, distribution, metabolism and elimination of drugs is influenced by the physiological functions of the body, it is not surprising that the pharmacokinetic, and consequently the pharmacodynamic, profiles of drugs can be influenced by circadian rhythms. Ciclosporin, a mainstay immunosuppressive drug used following organ transplantation, displays minimum blood concentration (C(min)), maximum blood concentration (C(max)) and area under the blood concentration-time curve (AUC) in the morning that are generally higher than the corresponding parameters in the evening. These observations are supported by the ciclosporin total body clearance and elimination half-life in the morning, which are, on average, higher and shorter, respectively, than those in the evening. In addition, the disposition of tacrolimus is determined by the time of administration. The tacrolimus C(max) and AUC after the morning dose are significantly higher than those after the evening dose. Finally, the results reported in this review suggest considering more carefully the chronopharmacokinetics of tacrolimus and ciclosporin in order to obtain better results with fewer adverse effects. Significantly, the morning appears to be the best time for therapeutic monitoring using the C(min), C(max), concentration at 2 hours after dosing and AUC to modify dosages of tacrolimus and ciclosporin. Less certain are any conclusions about whether, in order to obtain better immunosuppressive control, higher doses must be administered when these drugs are given in the evening to compensate for the higher levels of interleukin-2.