Links between cyclosporin exposure in tissues and graft-versus-host disease in pediatric bone marrow transplantation: analysis by a PBPK model.

PURPOSE

In hematopoietic stem cell transplantation (HSCT), cyclosporin is used to prevent graft-versus-host disease (GVHD). However, cyclosporin distribution in tissues is not linear, resulting in uncertainty regarding optimal dosing and monitoring. The objective of this study was to link the probability and severity of acute GVHD to cyclosporin exposure in blood, GVHD target organs, and lymphoid organs.

METHODS

A physiologically based pharmacokinetic model of cyclosporin disposition and logistic regression models were used. Sixty-one pediatric patients undergoing HSCT were studied. Cyclosporin was administered by intermittent (n = 31) or continuous infusion (n = 30).

RESULTS

At steady state (1 day before acute GVHD), exposures in all organs were related with the probability and severity of acute GVHD. Average cyclosporin concentration or, equivalently, its area under the curve (AUC) was the pharmacokinetic index best correlated with the anti-GVHD effect. Cyclosporin AUC in interstitial fluid of lymphoid organs was a superior index than that in blood, but marginally.

CONCLUSION

Hence, AUC in blood maybe used as an index of cyclosporin efficacy. Using our model, target AUCs in blood could be defined for malignant and non-malignant diseases, as well as the equivalent target values for C(2) and C(0) concentrations.