Standard pentostatin dose reductions in renal insufficiency are not adequate: selected patients with steroid-refractory acute graft-versus-host disease.

BACKGROUND AND OBJECTIVE: Pentostatin is an irreversible inhibitor of adenosine deaminase and has been used to prevent graft-versus-host disease (GVHD) and to treat both acute and chronic GVHD. Dose reduction equations for patients with renal insufficiency are based on few patients with limited pharmacokinetic and clinical results. This phase II study (NCT00201786) was conducted to assess pentostatin efficacy and infectious complications seen from our previous phase I study in steroid-refractory acute GVHD (aGVHD). PATIENTS AND METHODS: Hospitalized patients with steroid-refractory aGVHD were given pentostatin 1.5 mg/m(2)/day intravenously on days 1-3 of each 14-day cycle. Prior to each dose, dose modifications were based on Cockcroft-Gault estimated creatinine clearance (eCrCL) with 30-50 mL/min/1.73 m(2) leading to a 50 % dose reduction and eCrCL less than 30 mL/min/1.73 m(2) leading to study removal. Plasma pentostatin area under the concentration-time curve (AUC) and incidence of infectious complications were evaluated. RESULTS: Two of the eight patients treated demonstrated excessive pentostatin exposure as determined by measurement of AUC. One of these patients had renal impairment, whereas the other patient demonstrated borderline renal function. Despite dose reduction to 0.75 mg/m(2), AUCs were significantly increased compared to the other patients in this study. Seven of eight patients treated with pentostatin had cytomegalovirus (CMV) viremia after pentostatin treatment; however none developed proven CMV disease. CONCLUSION: A 50 % dose reduction in patients with eCrCL 30-50 mL/min/1.73 m(2) seems reasonable. However, the eCrCL should be interpreted with extreme caution in patients who are critically ill and/or with poor performance status. Renal function assessment based on the Cockcroft-Gault method could be significantly overestimated thus risking pentostatin overdosing. These results imply a need to closely monitor pentostatin exposure in patients with renal insufficiency.

Pentostatin pharmacokinetics and dosing recommendations in patients with mild renal impairment.

PURPOSE: The purpose of this study was to determine the pharmacokinetic parameters of pentostatin in renally impaired patients in order to establish dosing guidelines for this population. METHODS: Pentostatin doses were administered as 15-min intravenous infusions to patients based on their measured creatinine clearance (CLcr) as follows. Patients with normal renal function (NRF), defined as CLcr >60 ml/min, received 4 mg/m(2) repeated every14 days. Patients with impaired renal function (IRF) included those with CLcr 41-60 ml/min who received 3 mg/m(2) and those with CLcr 21-40 ml/min who received 2 mg/m(2), also repeated every 14 days. Heparinized plasma samples were collected during drug infusion and out through 96 h after dosing, except in two patients in whom sampling was extended to 144 h after dosing. Urine sampling extended to 96 h after dosing, and all samples were analyzed by a validated enzyme immunoassay for pentostatin concentrations. RESULTS: Enrolled in the study were 13 patients (7 IRF and 6 NRF), of whom 12 contributed samples for pharmacokinetic analysis. Median baseline CLcr values were 71.5 ml/min for NRF patients and 44 ml/min for IRF patients. Following the end of intravenous infusion, pentostatin plasma concentrations declined biexponentially with time. In some patients there was a transient increase in pentostatin equivalents 2 to 4 h after dosing. There was a good correlation between measured CLcr and pentostatin total plasma clearance. The AUC(0- infinity ) values seen in IRF patients, at lower doses, were within the range of the AUC(0- infinity ) values seen in patients with normal CLcr. Toxicities observed in the two groups of patients were similar. CONCLUSIONS: The pentostatin doses used in the study appear to be appropriate for administration to cancer patients with varying degrees of renal impairment.