Second International Congress Drug Therapy in HIV Infection 18-22 November 1994 Glasgow, UK

A PILOT STUDY OF THE SAFETY, TOLERANCE, PHARMACOKINETICS AND PHARMACODYNAMICS OF U-8720IE IN HIV INFECTED PERSONS

AMM Been-Tiktak¹, HM Vrehen¹, ICC Borleffs¹, I Richens², D Aldam², I Williams², IVD Weller², AM van Loon³, R van den Akker³, P Ward⁴.
¹ University Hospital Utrecht, P.O. Box 85500, 3508 GA Utrecht, Netherlands; ² University College London Medical School, London, UK; ³ National Institute of Public Health and Environmental Protection, Netherlands; ⁴ Upjohn, UK.

Int Cong Drug Therapy HIV 1994 Nov 18-22;2:Abstract No. 11.4
AIDS 1994, Vol. 8 (Suppl. 4);S10

BACKGROUND: U-8720IE (Atevirdine Mesylate) a bisheteroarylpiperazine (BHAP) is a new HIV reverse transcriptase (RT) inhibitor. In vitro the compound inhibits HIV replication with an IC₅₀ of 1 μM and has shown potential for synergy with nucleoside RT inhibitors.

OBJECTIVE: To investigate the safety, pharmocokinetics/dynamics, and effect of U-8720IE on immunological and viral load markers in asymptomatic HIV infected persons with CD4 cell counts between 200 and 500 x 10⁶/l.

METHODS: Following a 6 week screening period 30 patients were randomised in a double-blind manner to receive either U-8720JE 600 mg tds (n=15) or placebo (n=15) for 12 weeks. Study participants were seen weekly for clinical assessment, ECG monitoring, laboratory safety tests, measurement of CD4+ cell count, P24 antigen, B, microglobulin, neopterin, plasma viraemia (RNA PCR and fresh plasma culture), and drug levels. On day one and 22 blood was drawn for drug assay at half an hour to 2 hourly intervals following a single dose of trial medication. Participants continued to attend for follow-up till week 24.

RESULTS: Preliminary analysis of the effect of U-87201E as compared to placebo shows a decrease in viral load at week 4 as measured by fresh plasma culture and an increase in CD4 cell count above baseline at week 8-12. Further data including RNA PCR will be presented. Seven patients developed an adverse event needing discontinuation of trial medication. Five randomised to receive U-8720IE developed a macular papular rash during the second week of dosing which resolved after discontinuation. Two of these were subsequently rechallenged with an escalating dose-regimen and reestablished. on study mediation. One patient receiving U-8720IE developed a severe acute hepatitis and subsequent renal failure at week 3. One other receiving placebo developed pre-syncopal episodes which resolved on discontinuation, cardiac assessment was normal.

CONCLUSIONS: Preliminary findings indicate that:

1. U-8720IE bas an anti-HIV effect.

2. A macular papular, rash is a common adverse event.

Complete results and analysis will be presented.

Presenting author:

1994-11-18
11.4

Originally published in AIDS Volume 8, Supplement 4 and hosted with permission of the publisher Lippincott Williams & Wilkins, 250 Waterloo Road, London, SE1 8RD, UK. Tel: +44 (0)20 7981 0700 Fax: +44 (0) 7981 0701

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