A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rescriptor Online, Description, Chemistry, Ingredients - Delavirdine mesylate
Rescriptor Online, Description, Chemistry, Ingredients - Delavirdine mesylate
RESCRIPTORÒ
brand of delavirdine mesylate tablets
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WARNING
RESCRIPTOR Tablets are indicated for the treatment of
HIV-1 infection in combination with appropriate antiretroviral agents
when therapy is warranted. This indication is based on surrogate marker
changes in clinical studies. Clinical benefit was not demonstrated for
RESCRIPTOR based on survival or incidence of AIDS-defining clinical events
in a completed trial comparing RESCRIPTOR plus didanosine with didanosine
monotherapy (see DESCRIPTION OF CLINICAL
STUDIES).
Resistant virus emerges rapidly when RESCRIPTOR is administered
as monotherapy. Therefore, RESCRIPTOR should always be administered in
combination with appropriate antiretroviral therapy.
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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
molecularweight is 552.68.
Delavirdine mesylate is an odorless white-to-tan crystalline
powder. The aqueous solubility of delavirdine free base at 23 °C is 2942 mg/mL
at pH 1.0, 295 mg/mL at pH 2.0, and 0.81 mg/mL
at pH 7.4.
Each RESCRIPTOR Tablets, 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 hydroxypropyl methylcellulose, 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 a,
g, or d
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 m M
and 0.04 to 0.10 mM, respectively. Mean IC50
of clinical isolates (N=74) was 0.038 m M
(range 0.001 to 0.69 mM); 73 of 74 clinical
isolates had an IC50 £ 0.18 mM.
The IC90 of 24 of these clinical isolates ranged from 0.05 to 0.10
mM. In drug combination studies of delavirdine
with zidovudine, didanosine, zalcitabine, lamivudine, interferon-a,
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 delavirdine as monotherapy showed a 50-fold to 500-fold
reduction in sensitivity in 14 of 15 patients by week 8 of therapy. Genotypic
analyses of HIV-1 isolates from patients receiving delavirdine plus zidovudine
combination therapy (N=19) showed mutations in 16 of 19 isolates by week 24
of therapy. Mutations occurred predominantly at position 103 and less frequently
at positions 181 and 236. In a separate study, an average 86-fold increase in
the zidovudine sensitivity of patient isolates (N=24) was observed after 24
weeks on delavirdine and zidovudine combination therapy. The clinical relevance
of the phenotypic and the genotypic changes associated with delavirdine therapy
has not been determined.
Cross-resistance: Rapid emergence of HIV strains that
are cross-resistant to certain NNRTIs has been observed in vitro. Mutations
at positions 103 and 181 have been associated with resistance to other NNRTIs.
RESCRIPTOR may confer cross-resistance to other non-nucleoside reverse transcriptase
inhibitors when used alone or in combination.
The potential for cross-resistance between delavirdine and
protease inhibitors is low because of the different enzyme targets involved.
The potential for cross-resistance between NNRTIs and nucleoside analogue RT
inhibitors is low because of different sites of binding on the viral RT and
distinct mechanisms of action.
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