Therapeutic Drug Monitoring and Pharmacokinetic Analysis of cyclosporine in a Pediatric Patient with Hemophagocytic Lymphohistiocytosis Complicated by Diabetes Insipidus: A Grand Round.

Abstract

BACKGROUND\nHemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease. Initial therapy is based on etoposide, dexamethasone, and cyclosporine (CSA). The pharmacokinetics (PKs) of CSA and other drugs are sometimes altered in patients with HLH complicated by diabetes insipidus (DI) but the precise mechanisms remain unknown.\n\n\nMETHODS\nIn this study, the authors present a case of a 4-year-old boy with HLH complicated by DI. CSA concentrations were determined by enzyme multiplied immunosaasy technique (EMIT), non-compartmental PK analysis of the plasma concentration-time data was performed using PKSolver, linear regression analysis was performed to determine linearity of relationship between urine output and C0 levels of CSA.\n\n\nRESULTS\nAlthough C0 values of CSA were lower than the target levels, the patient was successfully treated and a good clinical outcome was achieved. Linear regression analysis showed a strong negative correlation between urine output and the serum trough concentration (C0) of CSA, pharmacokinetic analysis showed the main PK parameters of CSA as follows: C0, 50.2 μg/L; peak concentration (Cmax), 723.4 μg/L; area under the curve (AUC)0-24, 7478.2 μg·h/L; clearance, 0.77 L/h/kg, elimination half-life, 5.3 h, and volume of distribution, 6.0 L/kg.\n\n\nCONCLUSIONS\nTo the best of the authors knowledge, this is the first report of the CSA PK profile in a patient with HLH complicated by DI. The authors suppose that a large fluid output and input leads to extensive CSA distribution. These results suggest that the monitoring of the Cmax and AUC of CSA might be more clinically and pharmacokinetically significant than that of C0 in patients with HLH complicated by DI. This case highlights the importance of Therapeutic drug monitoring (TDM) and demonstrates PK parameters of CSA in a pediatric patient with HLH complicated by DI.