Posttransplant day significantly influences pharmacokinetics of cyclosporine after hematopoietic stem cell transplantation

Abstract

Cyclosporine-based immunosuppression is common after allogeneic hematopoietic stem cell transplantation (HSCT). Elevated cyclosporine concentrations are associated with significant toxicity and often result in the temporary cessation or discontinuation of cyclosporine. Low blood concentrations also result in significant immunologic risks, primarily graft-versus-host disease and loss of stem cell graft. The pharmacokinetics of cyclosporine are highly complex, and maintaining therapeutic and safe cyclosporine concentrations are challenging. Several clinical factors are known to independently influence in vivo cyclosporine pharmacokinetic behavior. However, in the critically ill patient, several of these clinical factors are generally present simultaneously. Unfortunately, there are no studies that have evaluated the combined effects of these clinical factors on cyclosporine disposition in HSCT. The objective of our study is to determine the population pharmacokinetic parameters of intravenous and oral cyclosporine, evaluate the effects of clinical covariates on cyclosporine pharmacokinetics, and develop a model that estimates clearance (Cl) and dose requirements for an individual HSCT patient with these clinical covariates. The authors analyzed 740 cyclosporine steady-state whole blood concentrations in 129 adult patients obtained between day 0 and discharge or 60 days posttransplant, whichever came first. Patients received intravenous cyclosporine at 2.5 mg/kg every 12 hours if body weight was greater than 50 kg, 2.5 mg/kg every 8 hours if less than 50 kg, or 5 to 7.5 mg/kg/d given as a continuous infusion, beginning on day-3. Patients were converted to oral therapy as tolerated. The influence of clinical covariates on the Cl of cyclosporine was tested with a nonlinear mixed effects model (NONMEM). The tested clinical covariates were age, height, body weight on admission, body surface area, sex, type of hematologic malignancy, transplant type, preparative regimen, baseline serum creatinine, T-cell depletion of graft, number of methotrexate doses, day of onset, and maximum grade of acute graft-versus-host disease. The route and frequency of cyclosporine administration, day posttransplant, total bilirubin level, serum creatinine level, actual body weight, presence of concurrent CYP450 enzyme inhibitors and inducers, or nephrotoxins on the day of the cyclosporine blood measurement were also evaluated. Cyclosporine Cl significantly decreased each week posttransplant. The authors found no significant effect of any of the other tested covariates including total bilirubin on Cl. The final regression model for the estimation of Cl is: Cl (L/hr) = ([body weight in kg − 70] ∗ 0.183 + 22.3) ∗ (day posttransplant factor). The corresponding day posttransplant factor estimates are 1.46, 1.32, 1.20, and 1.0 during days 0 to 7, 8 to 14, 15 to 21 and greater than 21 posttransplant, respectively. The interindividual variability in Cl was 27.7%. The dose of intravenous or oral cyclosporine can be calculated using the estimated Cl. Understanding cyclosporine pharmacokinetics and the clinical events that lead to alterations in Cl and exposure is critical in optimizing immunosuppressive therapy. The authors found that cyclosporine Cl significantly decreased posttransplant until day 21. A pharmacokinetics model was developed that incorporates the day posttransplant to predict cyclosporine Cl. Cyclosporine dose requirements in an individual HSCT patient to achieve the desired therapeutic blood target can be estimated using this model.