Zhou XJ, Squires K, Bernhard S, Deloach L, Duchin KL, Sommadossi JP; Conference on Retroviruses and Opportunistic Infections.
Program Abstr 3rd Conf Retrovir Oppor Infect Conf Retrovir Oppor Infect 3rd 1996 Wash D C. 1996 Jan 28-Feb 1; 3rd: 78.
Depts of Pharmacol. & Med., Univ. of Alabama at Birmingham, Birmingham, AL.
AZT-P-ddI (IVX-E-59, 3'-azido-3' -deoxythymidiyl-(5',5') -2',3'-dideoxy-5'-inosinic acid) is a heterodimer composed of one molecule of AZT and one molecule of ddI linked through their 5 positions by a phosphate bond. IVX-E-59 has shown enhanced antiviral activity and selectivity in vitro as compared to AZT and ddI alone. The pharmacokinetics of the dimer were studied in 12 adult patients with CD4 counts greater than 200 cells/mm3. [(14)C]-AZT- P-[(3)H]-ddI was administered intravenously (50 and 100 mg), and 1 month later orally (100 and 200 mg) to 8 patients. One group of patients (n=4) received only a 450 mg oral dose of IVX-E-59. After iv infusion, plasma levels of IVX-E-59 declined rapidly and were undetectable 0.5 hr post infusion. Following po administration, IVX-E-59 was not detectable, suggestive of gastrointestinal and/or hepatic first-pass effect. AZT-P-ddI was enzymatically cleaved in vivo to AZT and ddI which were further subject to their respective pharmacokinetic processes. While GAZT was the main metabolize of AZT, no detectable levels of AMT were observed. A major and previously unrecognized metabolize of ddI, referred as ddI-M, was detected and identified by FAB/MS and NMR techniques as R-(-)-dihydro-5 -(hydroxymethyl)-2 (3H)-furanone. Formation of all metabolites was increased after administration of oral dose vs. iv infusion of IVX-E-59 with AUC ratio of metabolize / AZT or ddI being 7.7 and 5.7 (po), and 3.8 and 1.1 (iv), respectively. ddI-M exhibited sustained plasma levels for extended time periods with apparent t(1/2) approximating 10 hr after oral administration of IVX-E-59. The pharmacodynamic effects of ddI-M are being investigated. Recovery of radioactivity associated with 3H and (14)C in urine was complete within 48 hr after po and iv administration of IVX-E-59. High oral bioavailability of AZT and ddI with values of 74 % and 43%, respectively, and large tissue distribution as evidenced by Vss of 207.7 and 125.31 for AZT and ddI further demonstrate favorable pharmacologic properties of IVX-E-59 and warrant subsequent clinical trials.
Publication Types:
Keywords:
- 3'-azido-3'-deoxy-5'-O-beta-glucopyranuronosylthymidine
- AIDS Vaccines
- Acquired Immunodeficiency Syndrome
- Administration, Oral
- Adult
- Antigens, CD4
- Antiviral Agents
- Biological Availability
- Didanosine
- HIV Infections
- HIV Seropositivity
- Humans
- In Vitro
- Infusions, Intravenous
- Zidovudine
- immunology
- pharmacokinetics
- scriptene
- urine
Other ID:
UI: 102216190
From Meeting Abstracts