title: A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine).
abstract: The discovery of purine nucleoside phosphorylase (PNP) deficiency and T lymphocytopenia suggested that inhibition of this enzyme could serve as a therapeutic target. Inhibitors of PNP failed until structure-based synthesis of immucillin-H (BCX-1777, forodesine), a transition-state analog of PNP. The picomolar potency for PNP, T cell-selective cytotoxicity, and animal studies provided the rationale for use of forodesine in T-cell malignancies. Five patients were treated with an intravenous infusion of forodesine (40 mg/m2) on day 1; treatment continued on day 2; forodesine was administered every 12 hours for an additional 8 doses. Plasma and cellular pharmacokinetics and pharmaco-dynamics were investigated. Median peak level of forodesine (5.4 microM) was achieved at the end of infusion. This level was sufficient to increase plasma 2'-deoxyguanosine (dGuo) concentrations in all patients. Intracellular deoxyguanosine triphosphate (dGTP) increased by 2- to 40-fold in 4 of 5 patients (8 of 9 courses) and correlated with antileukemia activity in 4 patients. However, objective responses were not observed. This was the first clinical study in humans to demonstrate the plasma pharmacokinetics and the pharmacodynamic effectiveness of the PNP inhibitor, forodesine; however, regrowth of leukemia cells in the blood and marrow after course 1 suggested that a different therapeutic schedule should be considered for future studies.
authors.affiliation: Department of Experimental Therapeutics, Unit 71, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. vgandhi@mdanderson.org
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: John M
authors.initials: JM
authors.lastname: Kilpatrick
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Mary
authors.initials: M
authors.lastname: Ayres
authors.forename: Leigh
authors.initials: L
authors.lastname: Harman
authors.forename: Min
authors.initials: M
authors.lastname: Du
authors.forename: Shanta
authors.initials: S
authors.lastname: Bantia
authors.forename: Jan
authors.initials: J
authors.lastname: Davisson
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Deborah
authors.initials: D
authors.lastname: Thomas
mesh_terms: D000328:Adult; D000368:Aged; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000473:pathology / Q000652:urine; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D011684:Purine Nucleosides; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011744:Pyrimidinones / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011758:Pyrroles / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D003848:Deoxyguanine Nucleotides; D004791:Enzyme Inhibitors; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011758:Pyrroles; C113101:forodesine; C029603:deoxyguanosine triphosphate; D011683:Purine-Nucleoside Phosphorylase