Dosing of thioTEPA for myeloablative therapy

Abstract

High-dose thioTEPA is used frequently in myeloablative regimens for marrow transplantation, but the need for dose adjustments in obese patients has not been explored. We determined the pharmacokinetics of thioTEPA and its metabolite TEPA during first-dose infusion of thioTEPA 150-250 mg/m2 given daily for 3 days in combination with busulfan and cyclophosphamide, and evaluated the results for correlations with toxicity and dosing strategies. The study included 15 adults undergoing marrow transplantation for hematologic malignancies. Plasma samples were obtained at various times over a 24-h period, and concentrations of thioTEPA and TEPA were measured by gas chromatography. At 22-24 h after initiation of a 4-h infusion, the mean +/- SE plasma concentration of thioTEPA was 124 +/- 63 ng/ml, while that of TEPA was 235 +/- 69 ng/ml. For CFU-GM and BFU-E growth in vitro, the IC50(s) of thioTEPA were 83 ng/ml and 16 ng/ml, respectively, and the IC50(s) of TEPA were 141 ng/ml and 47 ng/ml, respectively. Using a two-compartment model, the mean thioTEPA Vc was 47.4 +/- 4.7 1/m2, t1/2 alpha 19 +/- 5 min, t1/2 beta 3.7 +/- 0.5 h, and plasma clearance 302 +/- 21 ml/min per m2. The mean AUCs were 6.9-16.2 mg h/1 for thioTEPA and 8.9-21.2 mg h/1 for TEPA, while the mean peak concentrations were 0.95-2.08 micrograms/ml for thioTEPA and 0.88-1.90 micrograms/ml for TEPA. There was a significant association of grades 2-4 maximum regimen-related toxicity (RRT) with TEPA peak > 1.75 micrograms/ml and with combined thioTEPA and TEPA AUC > 30 mg h/1 (5/6 vs 0/9, P = 0.01 for both comparisons), suggesting that drug exposure was an important determinant of toxicity and, potentially, efficacy. ThioTEPA Vc correlated best with adjusted body weight (r = 0.74, P = 0.0015). In an evaluation of 74 adults receiving thioTEPA 750 mg/m2 in combination with busulfan and cyclophosphamide, the maximum RRT for patients at ideal weight was significantly greater than that for obese patients dosed on ideal weight (mean RRT grade 1.7 vs 1.0, P = 0.004) but did not differ from the maximum RRT for obese adults dosed on actual or adjusted weights. We recommend that for obese patients thioTEPA be dosed on adjusted body weight. Measurements at time-points after 24 h are needed to determine when thioTEPA and TEPA concentrations are below myelosuppressive levels and safe for marrow infusion.