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: Varsha Gandhi, John M Kilpatrick, William Plunkett, Mary Ayres, Leigh Harman, Min Du, Shanta Bantia, Jan Davisson, William G Wierda, Stefan Faderl, Hagop Kantarjian, Deborah Thomas
• Journal: Blood (Blood) Vol. 106 Issue 13 Pg. 4253-60 (Dec 15 2005) ISSN: 0006-4971 [Print] United States
• PMID: 16131572 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Deoxyguanine Nucleotides
• Enzyme Inhibitors
• Purine Nucleosides
• Pyrimidinones
• Pyrroles
• forodesine
• deoxyguanosine triphosphate
• Purine-Nucleoside Phosphorylase

Topics

• Adult
• Aged
• Deoxyguanine Nucleotides (metabolism)
• Enzyme Inhibitors (chemistry, pharmacokinetics, pharmacology)
• Female
• Humans
• Leukemia, Lymphoid (drug therapy, pathology, urine)
• Male
• Middle Aged
• Molecular Structure
• Purine Nucleosides
• Purine-Nucleoside Phosphorylase (antagonists & inhibitors, metabolism)
• Pyrimidinones (adverse effects, chemistry, pharmacokinetics, pharmacology)
• Pyrroles (adverse effects, chemistry, pharmacokinetics, pharmacology)
• Treatment Outcome