Pharmacokinetic optimization of immunosuppressive therapy in thoracic transplantation: part I

Although immunosuppressive treatments and therapeutic drug monitoring (TDM) have significantly contributed to the increased success of thoracic transplantation, there is currently no consensus on the best immunosuppressive strategies. Maintenance therapy typically consists of a triple-drug regimen including corticosteroids, a calcineurin inhibitor (ciclosporin or tacrolimus) and either a purine synthesis antagonist (mycophenolate mofetil or azathioprine) or a mammalian target of rapamycin inhibitor (sirolimus or everolimus). The incidence of acute and chronic rejection and of mortality after thoracic transplantation is still high compared with other types of solid organ transplantation. The high allogenicity and immunogenicity of the lungs justify the use of higher doses of immunosuppressants, putting lung transplant recipients at a higher risk of drug-induced toxicities. All immunosuppressants are characterized by large intra- and interindividual variability of their pharmacokinetics and by a narrow therapeutic index. It is essential to know their pharmacokinetic properties and to use them for treatment individualization through TDM in order to improve the treatment outcome. Unlike the kidneys and the liver, the heart and the lungs are not directly involved in drug metabolism and elimination, which may be the cause of pharmacokinetic differences between patients from all of these transplant groups. TDM is mandatory for most immunosuppressants and has become an integral part of immunosuppressive drug therapy. It is usually based on trough concentration (C(0)) monitoring, but other TDM tools include the area under the concentration-time curve (AUC) over the (12-hour) dosage interval or the AUC over the first 4 hours post-dose, as well as other single concentration-time points such as the concentration at 2 hours. Given the peculiarities of thoracic transplantation, a review of the pharmacokinetics and TDM of the main immunosuppressants used in thoracic transplantation is presented in this article. Even more so than in other solid organ transplant populations, their pharmacokinetics are characterized by wide intra- and interindividual variability in thoracic transplant recipients. The pharmacokinetics of ciclosporin in heart and lung transplant recipients have been explored in a number of studies, but less is known about the pharmacokinetics of mycophenolate mofetil and tacrolimus in these populations, and there are hardly any studies on the pharmacokinetics of sirolimus and everolimus. Given the increased use of these molecules in thoracic transplant recipients, their pharmacokinetics deserve to be explored in depth. There are very few data, some of which are conflicting, on the practices and outcomes of TDM of immunosuppressants after thoracic transplantation. The development of sophisticated TDM tools dedicated to thoracic transplantation are awaited in order to accurately evaluate the patients' exposure to drugs in general and, in particular, to immunosuppressants. Finally, large cohort TDM studies need to be conducted in thoracic transplant patients in order to identify the most predictive exposure indices and their target values, and to validate the clinical usefulness of improved TDM in these conditions. In part I of the article, we review the pharmacokinetics and TDM of calcineurin inhibitors. In part II, we will review the pharmacokinetics and TDM of mycophenolate and mammalian target of rapamycin inhibitors, and provide an overall discussion along with perspectives.