Delavirdine, a bisheteroarylpiperazine derivative, is a potent nonnucleoside RT inhibitor of activity specific for HIV-1. The U.S. FDA has approved this drug for use in combination with other anti-HIV agents. In Phase I/II study trials, it demonstrated sustained improvements in CD4 cell counts, p24 antigen levels, and RNA viral load. Promising results were obtained when the drug was used in two- or three-drug combinations with nucleoside drugs. Combination of delavirdine with ddI, ddC, or ZDV demonstrated additive or synergistic effects. Delavirdine with ZDV, however, was more beneficial in early HIV infection. Combinations of nevirapine and delavirdine had an antagonistic effect on HIV-1 RT inhibition.
A bisheteroarylpiperazine (BHAP) reverse transcriptase inhibitor.
Delavirdine (Rescriptor) is approved for the treatment
of HIV-1 infection in adults and adolescents over age 16
as part of a combination therapy. Rash accompanied by
pruritus is the most frequent adverse effect of this
agent; however, it usually resolves within several weeks
of treatment. Severe skin reactions are rare. Headache,
nausea, vomiting, diarrhea, fatigue, and elevated hepatic
enzymes also may be associated with delavirdine administration.
ChEBI: The amide resulting from the formal condensation of 5-[(methylsulfonyl)amino]-1H-indole-2-carboxylic acid and 4-amino group of 1-[3-(isopropylamino)pyridin-2-yl]piperazine, delavirdine is a non-nucleoside reverse transcriptase inhibitor
ith activity specific for HIV-1. Viral resistance emerges rapidly when delavirdine is used alone, so it is therefore used (as the methanesulfonic acid salt) with other antiretrovirals for combination therapy of HIV infection.
The predominant amino acid substitution associated with
resistance is at position 236 of the HIV reverse transcriptase.
Delavirdine (Rescriptor) must be used with at least twoadditional antiretroviral agents to treat HIV-1 infections.The oral absorption of delavirdine is rapid, and peakplasma concentrations develop in 1 hour. Extensive metabolismoccurs in the liver by CYP isozyme 3A (CYP3A) orpossibly CYP2D6. Bioavailability is 85%. Unlike nevirapine,which is 48% protein bound, delavirdine is more than98% protein bound. The half-life is 2 to 11 hours, andelimination is 44% in feces, 51% in urine, and less than 5%unchanged in urine. Delavirdine induces its own metabolism.Oral dosage forms are supplied as a 200-mg capsuleand a 100-mg tablet.
Pharmaceutical Applications
A complex piperazine derivative, formulated for oral administration.
Delavirdine directly inhibits RT and DNA-directed DNA polymerase activities of HIV-1 after the formation of the enzyme–substrate complexes, thereby causing chain-termination effects.
Oral absorption: Not known/available
Cmax 400 mg oral thrice daily: c. 19.3 mg/L
Cmin 400 mg oral thrice daily: c. 8.3 mg/L
Plasma half-life: c. 6 h
Volume of distribution: c. 0.7 L/kg
Plasma protein binding: c. 98%
Absorption and distribution
It is rapidly absorbed following oral administration. Food has no significant effect on absorption. It is distributed predominantly into blood plasma and CNS penetration is poor. The semen:plasma ratio is about 0.02. It is not known if it is distributed into breast milk.
Metabolism and excretion
Several metabolites are formed by the CYP3A4 isoform of cytochrome P450 and it is a potent inhibitor of this enzyme system. Around 44% of the drug is recovered in feces and 51% in urine, about 5% as unchanged drug. Given the predominant hepatic metabolism, caution should be exercised in patients with impaired hepatic function.
Treatment of HIV disease in adults and children over 12 years of age (in
combination with other antiretroviral agents)
Delavirdine has fallen out of favor with the increasing preference
for antiretrovirals than can be dosed twice or once daily.
Around 18% of patients experience a diffuse, maculopapular,
erythematous and often pruritic rash. Dose titration does not
appear to reduce the incidence of this side effect. The rash
usually first appears within 1 month of commencing therapy
and resolves within 2 weeks without dose modification. In
about 4% of cases it is severe enough to warrant discontinuation
of treatment.
