RESCRIPTOR®
brand of delavirdine mesylate tablets
DESCRIPTION
RESCRIPTOR Tablets contain delavirdine mesylate, a synthetic non-nucleoside reverse transcriptase inhibitor of the human immunodeficiency virus type 1 (HIV-1). The chemical name of delavirdine mesylate is piperazine, 1-[3-[(1-methyl-ethyl)amino]-2-pyridinyl]-4-[[5-[(methylsulfonyl)amino]-1H-indol-2-yl]carbonyl]-, monomethanesulfonate. Its molecular formula is C22H28N6O3S • CH4O3S, and its molecular weight is 552.68. The structural formula is:
Delavirdine mesylate is an odorless white-to-tan crystalline powder. The aqueous solubility of delavirdine free base at 23° C is 2942 µg/mL at pH 1.0, 295 µg/mL at pH 2.0, and 0.81 µg/mL at pH 7.4.
Each RESCRIPTOR Tablet, for oral administration, contains 100 or 200 mg of delavirdine mesylate (henceforth referred to as delavirdine). Inactive ingredients consist of lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, and carnauba wax. In addition, the 100-mg tablet contains Opadry White YS-1-7000-E and the 200-mg tablet contains hypromellose, Opadry White YS-1-18202-A and Pharmaceutical Ink Black.
MICROBIOLOGY
Mechanism of Action
Delavirdine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Delavirdine binds directly to reverse transcriptase (RT) and blocks RNA-dependent and DNA-dependent DNA polymerase activities. Delavirdine does not compete with template: primer or deoxynucleoside triphosphates. HIV-2 RT and human cellular DNA polymerases α, γ, or δ are not inhibited by delavirdine. In addition, HIV-1 group O, a group of highly divergent strains that are uncommon in North America, may not be inhibited by delavirdine.
In Vitro HIV-1 Susceptibility
In vitro anti–HIV-1 activity of delavirdine was assessed by infecting cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and clinical isolates of HIV-1. IC50 and IC90 values (50% and 90% inhibitory concentrations) for laboratory isolates (N=5) ranged from 0.005 to 0.030 µM and 0.04 to 0.10 µM, respectively. Mean IC50 of clinical isolates (N=74) was 0.038 µM (range 0.001 to 0.69 µM); 73 of 74 clinical isolates had an IC50≤0.18 µM. The IC90 of 24 of these clinical isolates ranged from 0.05 to 0.10 µM. In drug combination studies of delavirdine with zidovudine, didanosine, zalcitabine, lamivudine, interferon-α, and protease inhibitors, additive to synergistic anti–HIV-1 activity was observed in cell culture. The relationship between the in vitro susceptibility of HIV-1 RT inhibitors and the inhibition of HIV replication in humans has not been established.
Drug Resistance
Phenotypic analyses of isolates from patients treated with RESCRIPTOR as monotherapy showed a 50-fold to 500-fold reduced susceptibility in 14 of 15 patients by week 8 of therapy. Genotypic analysis of HIV-1 isolates from patients receiving RESCRIPTOR plus zidovudine combination therapy (N=79) showed resistance conferring mutations in all isolates by week 24 of therapy. In RESCRIPTOR treated patients the mutations in RT occurred predominantly at amino acid positions 103 and less frequently at positions 181 and 236. In a separate study, an average of 86-fold increase in the zidovudine susceptibility of patient isolates (N=24) was observed after 24-weeks of RESCRIPTOR and zidovudine combination therapy. The clinical relevance of the phenotypic and the genotypic changes associated with RESCRIPTOR therapy has not been established.
Cross-resistance
RESCRIPTOR may confer cross-resistance to other non-nucleoside RT inhibitors when used alone or in combination. Mutations at positions 103 and/or 181 have been found in resistant virus during treatment with RESCRIPTOR and other non-nucleoside RT inhibitors. These mutations have been associated with cross-resistance among non-nucleoside RT inhibitors in vitro.
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