RESUMEN
Patient variability in clinical response to the calcineurin inhibitors (CNIs) cyclosporine A and tacrolimus partly results from differences in CNI exposure. For tacrolimus drug interactions and genetic variability relate to tacrolimus exposure. Patients carrying the CYP3A5*1 allele have an increased tacrolimus metabolism, hence lower drug exposure. Adjusting the tacrolimus dose to this genotype is a tool to optimize therapy from a pharmacokinetic perspective. In contrast, no genetic variants have been found to clearly relate to cyclosporine A exposure. Despite therapeutic drug monitoring aimed at individualizing CNI therapy, patients still suffer from acute or chronic rejection and CNI toxicity. To further optimize CNI therapy future research may incorporate genetic polymorphisms in proteins involved in CNI pharmacodynamics (i.e. drug target). Proteins potentially relevant for drug response are calcineurin and the CNI binding proteins immunophilins. Moreover, since the expression of the nuclear factor of activated T-cells (NFAT) is reduced after calcineurin inhibition, genetic polymorphisms in the genes encoding NFAT may also be interesting candidates for studying inter-patient differences in CNI efficacy and toxicity. In addition, the existence of isoforms and differences in tissue distribution of the calcineurin protein could potentially explain variable drug response. At present, the focus has been on the metabolism of CNIs and not on variability in the drug target. Therefore, future improvements in CNI therapy are likely to occur from a systems pharmacology approach taking into account genetic markers for both CNI pharmacokinetics and pharmacodynamics.
Asunto(s)
Inhibidores de la Calcineurina , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Tacrolimus/uso terapéutico , Ciclosporina/farmacocinética , Ciclosporina/farmacología , Humanos , Inmunosupresores/farmacocinética , Inmunosupresores/farmacología , Tacrolimus/farmacocinética , Tacrolimus/farmacologíaRESUMEN
CsA is commonly used after haematological SCT (HSCT) as GVHD prophylaxis. In solid organ transplantation, area under the blood concentration vs time curve (AUC) correlates with clinical outcome. However, in HSCT, it has not been determined whether the AUC is superior to trough level monitoring to optimize clinical efficacy of CsA therapy. Therefore, the aim of this study was to investigate the relationships between CsA trough levels and/or AUC early after HSCT with clinical outcome. A total of 91 children (1.1-17.3 years) were treated consecutively with HSCT for a haematological malignancy. CsA trough levels were obtained and were used to estimate the AUC, retrospectively, with a NONMEM (Non-Linear Mixed Effects Modelling) method. Subsequently, these exposure parameters were correlated to the occurrence of acute GVHD, relapse risk (RR) and OS. Low CsA trough levels were found to correlate with the occurrence of acute GVHD. In addition, a CsA AUC over 3000 mcg h/l in AML patients was associated with a higher RR and a reduced OS. This was not the case for ALL patients. Thus, monitoring CsA exposure early after HSCT and adjusting the CsA dose to a predefined target trough level and AUC may provide a tool to influence GVHD/GVL balance.