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Delavirdine

A Review of its Use in HIV Infection

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Summary

Abstract

Delavirdine, a bisheteroarylpiperazine derivative, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that allosterically binds to HIV-1 reverse transcriptase, inhibiting both the RNA-and DNA-directed DNApolymerase functions of the enzyme.

Delavirdine in combination with nucleoside reverse transcriptase inhibitors (NRTIs) produced sustained reductions in plasma viral loads and improvements in immunological responses in large randomised, double-blind, placebo-controlled studies of 48 to 54 weeks’ duration. In patients with advanced HIV infection, triple therapy with delavirdine, zidovudine and lamivudine, didanosine or zalcitabine for 1 year significantly prolonged the time to virological failure compared with dual therapy (delavirdine plus zidovudine or 2 NRTIs; p < 0.0001). After 50 weeks’ treatment, plasma HIV RNA levels were below the limit of detection (LOD; <50 copies/ml) for 40% of patients receiving triple therapy but for only 6% of those receiving dual NRTI therapy.

Preliminary results suggest that delavirdine also has beneficial effects on surrogate markers as a component of protease inhibitor-containing triple or quadruple regimens. At 16 to 48 weeks, the minimum mean reduction in plasma viral load from baseline was 2.5 log 10 copies/ml and mean CD4+ counts increased by 100 to 313 cells/µ1. The proportion of patients with plasma HIV RNA levels below the LOD (usually 200 to 500 copies/ml) ranged from 48 to 100% after ≥16 weeks. Delavirdine was also effective as a component of saquinavir soft gel capsule-containing salvage regimens.

Since delavirdine shares a common metabolic pathway (cytochrome P450 3A pathway) with other NNRTIs, HIV protease inhibitors and several drugs used to treat opportunistic infections in patients infected with HIV, the drug is associated with a number of pharmacokinetic interactions. Some of these drug interactions are clinically significant, necessitating dosage adjustments or avoidance of co-administration. Delavirdine is not recommended for use with lovastatin, sim-vastatin, rifabutin, rifampicin, sildenafil, ergot derivatives, quinidine, midazolam, carbamazepine, phenobarbital or phenytoin. Importantly, the drug favourably increases the plasma concentration of several protease inhibitors.

Delavirdine is generally well tolerated. Skin rash is the most frequently reported adverse effect, occurring in 18 to 50% of patients receiving delavirdine-containing combination therapy in clinical trials. Although a high proportion of patients developed a rash, it was typically mild to moderate in intensity, did not result in discontinuation or adjustment of treatment in most patients and resolved quickly. The occurrence of Stevens-Johnson syndrome was rare (1 case in 1000 patients). A retrospective analysis of pooled clinical trial data indicated that there was no significant difference in the incidence of liver toxicity, liver failure or noninfectious hepatitis between delavirdine-containing and non-delavirdine-containing antiretroviral treatment groups. In addition, the incidence of lipodystrophy, metabolic lipid disorders, hyperglycaemia and hypertriglyceridaemia was not significantly different between these 2 treatment groups.

Conclusions: In combination with NRTIs, delavirdine produces sustained improvements in surrogate markers of HIV disease and prolongs the time to virological failure in adult patients with HIV infection. Preliminary data of delavirdine as a component of protease inhibitor-containing triple or quadruple highly active antiretroviral therapy regimens indicate that patients achieve marked improvements in virological and immunological markers. The drug is generally well tolerated, with a transient skin rash, typically of mild to moderate intensity, being the most common adverse effect. Delavirdine is an effective component of recommended antiretroviral treatment strategies for adult patients with HIV infection and, in combination with 2 NRTIs as a first-line therapy, the drug has the advantage of sparing protease inhibitors for subsequent use. Since delavirdine favourably increases plasma concentrations of several protease inhibitors, the drug may also be beneficial as a component of salvage therapy in combination with protease inhibitors.

Pharmacodynamic Profile

Delavirdine, a bisheteroarylpiperazine derivative, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that prevents HIV-1 replication by noncompetitively inhibiting reverse transcriptase. Allosteric binding of the drug results in a stable conformational change in the polymerase site that inhibits both the RNA-and DNA-directed DNA polymerase functions of the enzyme.

The drug is highly selective for HIV-1 reverse transcriptase, with minimal effects against HIV-2 reverse transcriptase or human DNA polymerase α or δ. The 50% inhibitory concentrations (IC50) of delavirdine ranged from 0.008 to 0.9 µmol/L against laboratory strains of HIV-1 in various cell culture studies. Delavirdine also exhibited good inhibitory activity against patient-derived HIV strains in cultured peripheral blood mononuclear cells, including isolates that were highly resistant to zidovudine or didanosine.

When combined with other antiretroviral agents, delavirdine has additive or synergistic activity against HIV-1 strains. There were no reports of cytotoxic or antagonistic effects of delavirdine in combination with other antiretroviral agents at 75 to 95% inhibition levels.

Resistance with delavirdine monotherapy develops rapidly. However, administration with other antiretroviral agents markedly slows the rate of acquisition of mutations. The most frequent resistance mutations associated with delavirdine occur at codons 103 [lysine to asparagine (K103N)] and 181 [tyrosine to cysteine (Y181C)], which confer resistance to nearly all NNRTIs. A single amino acid change in HIV-1 reverse transcriptase is sufficient to confer high level resistance to delavirdine, as is the case for other NNRTIs. Importantly, the potential for cross-resistance between delavirdine-resistant mutants and protease inhibitors or nucleoside reverse transcriptase inhibitors (NRTIs) is probably low.

Pharmacokinetic Profile

Delavirdine is rapidly absorbed following oral administration. Maximum plasmaconcentrations after single or multiple delavirdine 400mg doses were 7.22 and 26.6 µmol/L, respectively, and were reached in 1.17 and 2.23 hours. The reported oral bioavailability of the drug is 85%.

Administration of multiple 400mg doses of delavirdine with food does not significantly affect the rate or extent of absorption. However, concomitant administration with antacids or in patients with gastrohypoacidity reduced the rate and extent of absorption of delavirdine at steady state in HIV-infected patients.

The apparent volume of distribution of oral delavirdine was 65L. The drug is highly bound to plasma proteins (≈98%) in humans, primarily to albumin. The high level of plasma protein binding limits the amount of delavirdine available for CNS penetration, with cerebrospinal fluid concentrations averaging 0.39% of the corresponding plasma concentrations.

With regard to elimination, delavirdine demonstrates nonlinear pharmacoki-netics. The plasma elimination half-life values with single and multiple 400mg doses of delavirdine were 2.39 and 4.12 hours, with corresponding oral clearance values of 60.3 and 7.79 L/h. In healthy volunteers, similar amounts of radio-labelled drug were excreted in both faeces (≈44%) and urine (=51%).

Delavirdine undergoes extensive hepatic metabolism, with <5% of the drug appearing unchanged in the urine in healthy volunteers. The cytochrome P450 (CYP) 3A pathway is the major metabolic route, although ≈20% is metabolised by CYP2D6. The drug is extensively metabolised, mainly to desalkyl-delavirdine and unidentified pyridine hydroxy metabolites, all of which are biologically in-active. Delavirdine reversibly inhibits the activity of CYP3A and also inhibits CYP2C9.

Since delavirdine shares a common metabolic pathway (CYP3A pathway) with other NNRTIs, HIV protease inhibitors and several drugs used to treat opportunistic infections in patients infected with HIV (e.g. fluconazole, rifampicin and rifabutin), the drug is associated with a number of pharmacokinetic interactions. Some of these drug interactions are clinically significant, necessitating dosage adjustments or avoidance of coadministration. Importantly, delavirdine favourably increases the plasma concentration of several protease inhibitors.

Clinical Efficacy

In combination with nucleoside reverse transcriptase inhibitors (NRTIs): Triple therapy with delavirdine and 2 NRTIs effectively suppressed HIV viral loads (mean change from baseline 0.73 to 2.1 log10 HIV RNA copies/ml) and improved immunological responses (mean increase from baseline 65 to 111 CD4+ cells/µl) in antiretroviral-naive and -experienced patients in large randomised, double-blind, multicentre studies of 48 to 54 weeks’ duration. In patients with advanced HIV infection, delavirdine in combination with zidovudine plus lamivudine, didanosine or zalcitabine for 1 year significantly prolonged the time to virological failure compared with dual therapy (delavirdine plus zidovudine or 2 NRTIs; p < 0.001). After 50 weeks’ treatment, plasma HIV RNA levels were below the limit of detection (LOD; 50 copies/ml) for 40% of patients receiving triple therapy but for only 6% of those receiving dual NRTI therapy.

Antiretroviral therapy-naive patients with advanced HIV infection receiving triple therapy with delavirdine plus zidovudine and a second NRTI achieved more marked improvements in CD4+ cell counts than recipients of dual therapy (mean increase at 54 weeks was 122 vs 63 cells/µl; p = 0.006). 23.4% of recipients of delavirdine-containing therapy had plasma viral loads below the LOD (50 copies/ml) compared with 5.5% of recipients of dual NRTI therapy at 54 weeks (p < 0.05). In patients with prior antiretroviral experience, 13.8% achieved plasma viral loads below the LOD (50 copies/ml) with delavirdine-containing triple therapy compared with 1.6% of recipients of dual NRTI therapy.

In combination with protease inhibitors and NRTIs: Delavirdine also demonstrated beneficial effects on surrogate markers as a component of protease inhibitor-containing triple or quadruple regimens, with marked and sustained reductions in plasma viral loads (minimum mean change from baseline in HIV RNA of 2.5 logio copies/ml) and improvements in immunological responses (mean increase from baseline in CD4+ count of 100 to 313 cells/µl) at 16 to 48 weeks. Respective changes from baseline in non-delavirdine-containing therapy groups were a minimum mean decrease in HIV RNA of 1.9 logio copies/ml and an increase of 45 to 313 CD4+ cells/µl. The proportion of patients with plasma HIV RNA levels below the LOD (usually 200 to 500 copies/ml) ranged from 48 to 100% after ≥16 weeks.

There were no significant differences in beneficial effects on surrogate markers with delavirdine-containing quadruple therapy compared with triple therapy. At 24 weeks, all patients receiving delavirdine, indinavir, zidovudine and lamivudine had plasma viral loads below the LOD (400 copies/ml) compared with 67 and 95% of those receiving triple therapy with delavirdine, indinavir and zidovudine or lamivudine and 73% of those receiving indinavir, lamivudine and zidovudine. All of these groups had increases in CD4+ cell counts (≥168 cells/µl) at 48 weeks, with marked reductions in plasma viral loads (2.8 log10 copies/ml). Moreover, delavirdine plus zidovudine and indinavir significantly (p < 0.05) prolonged the time to virological failure compared with non-delavirdine-containing triple therapy.

In patients with limited antiretroviral therapy experience, delavirdine 600mg twice daily in combination with nelfinavir, stavudine and/or didanosine showed a sustained reduction in mean plasma viral load of ≥1.9 logio copies/ml (LOD 400 copies/ml) from weeks 24 to 48, with a mean change from baseline in CD4+ cell counts during this period of ≥150 cells/µl. 85% of patients achieved reductions in plasma viral load below the LOD (400 copies/ml), with 50% of patients having viral loads below 50 copies/ml.

Preliminary 16-week results indicate that recipients of delavirdine twice daily (1200 mg/day) in combination with saquinavir soft gel capsules (SGC), lamivudine and/or zidovudine achieved similar virological and immunological responses to those receiving delavirdine 3 times daily (1200 mg/day) in combination with these drugs. Delavirdine was also effective as a component of saquinavir SGC salvage regimens in patients with a median of 14 months’ indinavir experience and extensive NRTI experience. Of the 30% of patients achieving a virological response by 16 weeks (plasma viral load <500 copies/ml), 59% had sustained reductions in viral load at 48 weeks.

Tolerability

Adverse effect data from clinical trials of oral delavirdine (at a dosage of 1200 mg/day) in adult patients with HIV infection indicate the drug is generally well tolerated when given in combination with NRTIs and/or protease inhibitors. In phase I/II clinical studies, the most frequent adverse effects occurring with delavirdine, zidovudine and/or didanosine treatment were skin rash (38.3% of patients vs 4.8% with zidovudine and didanosine), headache (24.2 vs 14.6%), nausea (14.8 vs 4.9%), fatigue (14.1 vs 9.8%) and pruritus (10.2 vs 7.3%). In phase II and III clinical trials, skin rash occurred in 18 to 50% of patients receiving delavirdine-containing antiretroviral therapy and resulted in discontinuation of the drug in 4.3% of patients.

Skin rash was generally an erythematous, macropapular rash of mild to moderate intensity, was mildly pruritic, often confluent and usually developed 7 to 15 days after commencing delavirdine treatment. The rash typically peaked over 2 to 3 days and then resolved. Continuation of therapy in the presence of the rash (>85% of patients continued) did not affect the rate of resolution of the rash. Severe or life-threatening rash (e.g. erythema multiform, Stevens-Johnson syndrome) has only been reported rarely (1 case in 1000 patients) and usually resolved on discontinuation of delavirdine therapy. Rash occurred more frequently in patients with low CD4+ cell counts (<300 cells/µl), particularly those with CD4+ cell counts below 100 cells/µl, although there was no change in the severity of the rash.

A retrospective analysis of pooled clinical trial data indicated that there was no significant difference in the incidence of liver toxicity, liver failure or non-infectious hepatitis between the delavirdine and control groups receiving NRTIs and/or protease inhibitors. The incidence of grade 3 to 4 elevations of bilirubin or of the liver enzymes AST and ALT was not significantly different between the delavirdine combination (n = 5330) and non-delavirdine combination (n = 1690) therapy groups. The respective incidence of liver failure in these 2 groups was 0.11 and 0.12%, with no incidence of liver failure attributable to delavirdine therapy. Noninfectious hepatitis occurred in 0.24 and 0.29% of recipients, respectively, in the overall study population.

In addition, retrospective analysis of these pooled data indicated that the incidence of lipodystrophy, metabolic lipid disorders, hyperglycaemia and hyper-triglyceridaemia was not significantly different between delavirdine-containing and non-delavirdine-containing therapy groups.

Dosage and Administration

The recommended dosage for delavirdine in adults aged ≥16 years is 400mg (2 × 200mg tablets) 3 times daily. The drug should be used as part of a combination regimen with at least 2 other antiretroviral agents. Delavirdine may be taken without regard to food. Patients with achlorhydria should take delavirdine with an acidic beverage and the drug should be taken at least 1 hour apart from antacids. When given in combination with didanosine, delavirdine should be taken 1 hour before didanosine.

As <5% of the drug is excreted unchanged in the urine, renal impairment is not anticipated to affect plasma delavirdine concentrations; however, it is not known yet whether dosage adjustment is required in patients with HIV infection and renal impairment. Delavirdine should be used with caution in patients with hepatic impairment.

There are a number of clinically relevant drug interactions with delavirdine, necessitating dosage modifications of the drug and/or interacting agents. Coadministration of delavirdine with lovastatin, simvastatin, rifabutin, rifampicin, sildenafil, ergot derivatives, quinidine, midazolam, carbamazepine, phenobarbital or phenytoin is not recommended. Although no specific dosage adjustments have been recommended for most protease inhibitors, dosage adjustment of indinavir has been suggested. In combination with nelfinavir, the requirement for dosage adjustment of either agent is still to be determined; however, when these drugs are used in combination, absolute neutrophil counts should be monitored.

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    Lesley J. Scott & Caroline M. Perry

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Correspondence to Lesley J. Scott.

Additional information

Various sections of the manuscript reviewed by: M. Barry, National Centre for Pharmacoeconomics, St. James’s Hospital, Dublin, Ireland; B.G. Gazzard , Chelsea and Westminster Hospital, London, England; P. Hay, St. George’s Healthcare NHS Trust, St.George’s Hospital, London, England; L. Naessens, Rega Institute for Medical Research, Katholieke University Leuven, Leuven, Belgium; M. Para, Division of Infectious Diseases, Ohio State University Hospitals, Columbus, Ohio, USA; A-M. Taburet, Bicêtre Hospital, Paris, France

Data Selection

Sources: Medical literature published in any language since 1980 on Delavirdine, identified using Medline and EMBASE supplemented by AdisBase (a proprietary database of Adis International, Auckland, New Zealand). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘Delavirdine’ or ‘Delavirdine mesylate’ or ‘U-90152’ or ‘U-90152S’. EMBASE search terms were ‘Delavirdine’ or ‘Delavirdine mesylate’ or ‘U-90152’ or ‘U-90152S’. AdisBase search terms were ‘Delavirdine’ or ‘Delavirdine-mesylate’ or ‘U-90152’ or ‘U-90152S’. Searches were last updated 31 Oct 2000.

Selection: Studies in patients with HIV infection who received delavirdine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: HIV infection, non-nucleotide reverse transcriptase inhibitor, pharmacodynamics, pharmacokinetics, therapeutic use.

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Scott, L.J., Perry, C.M. Delavirdine. Drugs 60, 1411–1444 (2000). https://doi.org/10.2165/00003495-200060060-00013

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