title: Phase I dose escalation pharmacokinetics of O-(chloroacetylcarbamoyl) fumagillol (TNP-470) and its metabolites in AIDS patients with Kaposi's sarcoma.
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 x 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 x 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.
authors.affiliation: University of Alabama at Birmingham, 35294, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Moore
authors.forename: B J
authors.initials: BJ
authors.lastname: Dezube
authors.forename: P
authors.initials: P
authors.lastname: Gill
authors.forename: X J
authors.initials: XJ
authors.lastname: Zhou
authors.forename: E P
authors.initials: EP
authors.lastname: Acosta
authors.forename: J P
authors.initials: JP
authors.lastname: Sommadossi
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D003510:Cyclohexanes; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007262:Infusions, Intravenous; D013058:Mass Spectrometry; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012514:Sarcoma, Kaposi / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D012680:Sensitivity and Specificity; D012717:Sesquiterpenes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol