Pharmacokinetics, pharmacodynamics and pharmacogenetics of immunosuppressants in liver transplant recipients

Abstract

Liver transplantation is an established treatment in patients with end-stage liver disease. After solid organ transplantation immunosuppressive drugs are needed as rejection prophylaxis. The immunosuppressive regimen in liver transplant recipients consists of mycophenolic acid (MPA), tacrolimus and corticosteroids (prednisolone and methylprednisolone). Individualization of this therapy may improve clinical outcome. The aims of this thesis were to study the pharmacokinetics, pharmacodynamics and pharmacogenetics of immunosuppressants in the first weeks after liver transplantation. To study the pharmacokinetics of corticosteroids a quantitative LC-MS/MS (liquid chromatography tandem mass spectrometry) assay was developed and validated. Large intra- and inter-individual variability was observed in the pharmacokinetics of prednisolone and prednisone in adult liver transplant recipients. Dose per body weight adjusted exposure of prednisolone increased significantly during the follow-up period. In parallel to the findings for prednisolone, the variability in tacrolimus pharmacokinetics was large in the same study population. The tacrolimus exposure was relative low the first week after transplantation, with significant increases in dose per bodyweight adjusted AUC0-12h during the study period, with a subsequent doubled median tacrolimus dose to attain target C0-concentrations. A trend towards a lower degree of IMPDH (inosine monophosphate dehydrogenase) inhibition was observed in patients with episodes of acute rejection, compared to the patients without rejection episodes. More than 50% of the patients fell below the suggested target range for MPA exposure (30-60 mg*h/L), suggesting that the initial dose might be too low the first days post-transplant in some of the patients. Pharmacodynamic monitoring of MPA, by measuring the IMPDH acitivity, may assist in identifying patients with a suboptimal effect of MPA. The overall conclusion of this thesis is that in the adult liver transplant population studied, the intra- and inter-individual varibility in the pharmacokinetics of immunosuppressive drugs is large short-term after transplantation. As a consequence, a significant proportion of patients may be at sub-therapeutic immunosuppression in a period when the risk of acute rejection episodes is highest. The factors responsible for this variability must be further addressed and taken into account in order to further individualize the dosing of these immunosuppressive drugs.