Phase I dose escalation pharmacokinetics of O -(chloroacetylcarbamoyl) fumagillol (TNP-470) and its metabolites in AIDS patients with Kaposi's sarcoma

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Abstract
The pharmacokinetics of TNP-470 and its major metabolites were investigated in AIDS patients enrolled in a phase I dose escalation trial for the treatment of Kaposi's sarcoma. The patients received TNP-470 by 1-h intravenous infusion in dose cohorts of 10, 20, 30, 40, 50 and 70 mg/m2. The parent drug and metabolites, MII and MIV, were measured by high-performance liquid chromatography/mass spectrometry (HPLC/MS) in plasma samples collected during and out to 168 h after the beginning of the infusion. Both metabolites were detected in all patients' plasma, while the parent drug was undetectable at time-points as early as 5 min after the end of infusion for some patients. A large interpatient variability of pharmacokinetic parameters among the dosing cohorts was observed for TNP-470, with a mean (±SD) plasma elimination half-life (t1/2) of 0.06 ± 0.04 h, plasma clearance (CL) of 1487 ± 1216 l/h and an area under the concentration versus time curve (AUC) of 49.9 ± 35.8 ng/ml · h. Time to maximum plasma concentration (Tmax) typically occurred before the end of the infusion. The predominant plasma metabolite was MII with a t1/2 of 1.21 ± 0.43 h, AUC of 1226 ± 2303 l/h and a Tmax occurring between 5 and 15 min after infusion. The reported active metabolite MIV had a t1/2 of 0.24 ± 0.13 h, AUC of 24.9 ± 32.6 ng/ml · h and a Tmax occurring between the midpoint of the infusion and 15 min after infusion. The parent drug was undetectable by HPLC/MS/MS in urine samples collected and pooled between 0–6 and 6–24 h from the beginning of drug administration. Metabolite MIV was present in the 0–6-h urine pool of two patients enrolled in the highest dosing cohorts, equivalent to 0.4% of the administered dose. Metabolite MII was present in all 0–6-h samples analyzed and represented 1.12 ± 0.9% of the administered dose. Renal clearance (CLR) for MII was 140 ± 70 ml/h.

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