Modifying the diffusion layer of soluble salts of poorly soluble basic drugs to improve dissolution performance.

The dissolution mechanism of soluble salts of poorly soluble bases can be complex because both the dissolution of the salt and precipitation of the free base can occur depending on the experimental conditions and properties of the molecule. The dissolution of three soluble salts of poorly soluble bases is described in this paper. Two of these compounds precipitate as free base under normal stomach pH conditions (pH from 2-4) during dissolution. This free base precipitation is a result of formation of free base on the surface of the dissolving salt. Diffusion Layer modulated (DLM) solids are defined and presented that can effectively counteract this precipitation mechanism. These DLM materials employ excipients in order to modify the pH or solubility conditions at the surface of the dissolving salt to minimize precipitation of the free base that can occur. Rotating disk dissolution data is presented which shows how these formulated solids can act to improve the dissolution profile for these materials.

Systematic review: Helicobacter pylori infection and impaired drug absorption.

BACKGROUND: Impaired acid secretion may affect drug absorption and may be consequent to corporal Helicobacter pylori-gastritis, which may affect the absorption of orally administered drugs. AIM: To focus on the evidence of impaired drug absorption associated with H. pylori infection. METHODS: Data sources were the systematic search of MEDLINE/EMBASE/SCOPUS databases (1980-April 2008) for English articles using the keywords: drug malabsorption/absorption, stomach, Helicobacter pylori, gastritis, gastric acid, gastric pH, hypochlorhydria, gastric hypoacidity. Study selection was made from 2099 retrieved articles, five studies were identified. Data were extracted from selected papers, investigated drugs, study type, main features of subjects, study design, intervention type and results were extracted. RESULTS: In all, five studies investigated impaired absorption of l-dopa, thyroxine and delavirdine in H. pylori infection. Eradication treatment led to 21-54% increase in l-dopa in Parkinson's disease. Thyroxine requirement was higher in hypochlorhydric goitre with H. pylori-gastritis and thyrotropin levels decreased by 94% after treatment. In H. pylori- and HIV-positive hypochlorhydric subjects, delavirdine absorption increased by 57% with orange juice administration and by 150% after eradication. CONCLUSIONS: A plausible mechanism of impaired drug absorption is decreased acid secretion in H. pylori-gastritis patients. Helicobacter pylori infection and hypochlorhydria should be considered in prescribing drugs the absorption of which is potentially affected by intragastric pH.

Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine.

This study examined drug interactions between buprenorphine, an opioid partial agonist medication used in the treatment of opioid dependence, and the nonnucleoside reverse-transcriptase inhibitors (NNRTIs) efavirenz (EFV) and delavirdine (DLV). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per NNRTI) participated in 24-h sessions to determine pharmacokinetics of buprenorphine and of buprenorphine with either EFV or DLV after administration of standard doses of either antiretroviral for 15 or 7 days, respectively. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined before and after antiretroviral administration in opioid-dependent participants. The pharmacokinetics of NNRTIs in healthy control participants were used to determine the effect of buprenorphine on NNRTIs. EFV decreased the buprenorphine area under the concentration-time curve (P<.001). DLV increased buprenorphine concentrations (P<.001). Clinically significant consequences of these interactions were not observed. Buprenorphine did not alter antiretroviral pharmacokinetics. Adjustments of doses of either buprenorphine or EFV or DLV are not likely to be necessary when these drugs are administered for the treatment of opiate dependence and HIV disease.

Drug interactions between opioids and antiretroviral medications: interaction between methadone, LAAM, and delavirdine.

Understanding the drug interactions between antiretrovirals and opioid therapies may decrease toxicities and enhance adherence with improved HIV outcomes in opioid-dependent individuals. The authors report the results of a clinical pharmacology study designed to determine whether significant pharmacokinetic and/or pharmacodynamic interactions occur between the non-nucleoside reverse transcriptase inhibitor, delavirdine (DLV), and either methadone or levo-alpha acetyl methadol (LAAM) (n = 40). DLV significantly decreased methadone clearance (p = .018) and increased the methadone elimination half-life (p < .001) with a resultant increase in AUC of 19% and C(min)of 29%. The combined effect of DLV on the total concentration of LAAM and its active metabolites, norLAAM and dinorLAAM, was to significantly increase AUC by 43% (p < .001), C(max) by 30% (p = .013), and C(min) by 59% (p = .004) while decreasing T(max) (p = .05). Cognitive deficits over the seven-day study period as measured by the Mini-Mental State Examination, opioid withdrawal symptoms as measured by the Objective Opioid Withdrawal Scale, or complaints of adverse symptoms were not observed. Methadone and LAAM did not affect DLV concentrations. The findings from this study show that DLV treatment in methadone- or LAAM-maintained individuals results in altered opioid pharmacokinetics with an increased exposure and potential risk for opioid toxicity with methadone or LAAM treatment and an increased risk of cardiac toxicity with concomitant LAAM and DLV administration.

Population pharmacokinetics of delavirdine and N-delavirdine in HIV-infected individuals.

OBJECTIVE: Delavirdine is a non-nucleoside reverse transcriptase inhibitor used in combination regimens for the treatment of HIV-1 infection. Our objective was to characterise the population pharmacokinetics of delavirdine in HIV-infected patients who participated in the adult AIDS Clinical Trials Group (ACTG) 260 and 261 studies. METHODS: ACTG 261 was a randomised, double-blind study of delavirdine 400mg three times daily, in various combination regimens; ACTG 260 was a concentration-targeted monotherapy study. Two hundred and thirty-four patients, and 1254 and 1251 plasma concentrations for delavirdine and N-delavirdine, respectively, were available for population pharmacokinetic analysis. The pharmacokinetic model (and initial parameters), based on previous studies, included two compartments for delavirdine (peripheral and central) and parallel clearance pathways (nonlinear conversion to N-delavirdine and first order clearance from the body). The model was one compartment for N-delavirdine with first order clearance. Diurnal variation of delavirdine and N-delavirdine oral clearance was modelled as a cosine function, with amplitude variation a fitted parameter. Pharmacokinetic parameter estimates were derived from iterative two-stage analysis; observed delavirdine and N-delavirdine concentrations fit with weighting by the inverse observation variance. Covariates were analysed by multiple general linear modelling. RESULTS: The mean (percent coefficient of variation [%CV]) CD4 count was 315 (109) cells/mm(3), weight 76.9 (14.7) kg, age 37 (8.5) years, and 15% of the population were women. Mean (%CV) population pharmacokinetic parameter estimates for delavirdine were: volume of distribution at steady state 67.6 (100) L, intrinsic oral clearance 19.8 (64) L/h, concentration at half the maximum velocity of metabolism (V(max)) 6.3 (69) micromol/L and first order oral clearance 0.57 (86) L/h. For N-delavirdine, the mean (%CV) apparent volume of distribution was 24.7 (75) L and apparent clearance 29.7 (42) L/h. The mean V(max) was 1376 (68) mg/day. The final model for average intrinsic clearance of delavirdine included race, sex, weight and age as significant covariates (p < 0.05); however, these covariates do not explain a significant proportion of the overall variability in the population. CONCLUSIONS: Delavirdine disposition exhibits nonlinear pharmacokinetics and large interpatient variability, and is significantly altered by time of day (impacting potential therapeutic drug monitoring and future pharmacokinetic study designs). Although race and sex appear to influence delavirdine pharmacokinetics, men and women and patients of different races should receive similar mg/kg dosage regimens. The presence of large interpatient variability supports the further investigation of the utility of therapeutic drug monitoring for delavirdine, if target drug concentrations can be better defined.

Long-term pharmacokinetics of amprenavir in combination with delavirdine in HIV-infected children.

Five heavily pretreated HIV-infected children were put on amprenavir and delavirdine plus two nucleoside inhibitors to reverse transcriptase to boost amprenavir levels and to use the antiretroviral activity of a non-nucleoside reverse transcriptase inhibitor. No data are available about this combination in children. It w;as well tolerated, and the median reduction in viral load was 1.5 log after 18 months. Delavirdine boosted amprenavir trough levels more than 10-fold, and delavirdine trough levels remained i several fold above susceptible HIV strains.

Dose-dependent pharmacokinetics of delavirdine in combination with amprenavir in healthy volunteers.

OBJECTIVES: To investigate different dose combinations of amprenavir and delavirdine in order to assess an optimal dose suitable for clinical use. METHODS: This was a prospective, open-label, controlled, three-period, multiple-dose study with nine healthy volunteers. The volunteers received three different dose combinations of amprenavir and delavirdine twice a day for 10 days with a subsequent 12 h pharmacokinetic evaluation. Combination 1: amprenavir 600 mg and delavirdine 600 mg; combination 2: amprenavir 600 mg and delavirdine 800 mg; combination 3: amprenavir 450 mg and delavirdine 1000 mg. The combinations were taken at least 2 weeks apart. RESULTS: Differences in median delavirdine Cmax, C12 and AUC0-12 were seen when comparing the three combinations (3 > 2>1) (P<0.04). A considerable and clinically important higher median C12 was seen with combination 3 when compared to combination 1 (835 to 3944 ng/mL) (P=0.0039). Only small differences in the amprenavir pharmacokinetic parameters were seen between the three dose combinations, with a median C12 of 412, 434 and 536 ng/mL, respectively. CONCLUSIONS: In this study, an increase of 472% in median delavirdine C12 was seen with a delavirdine dose increase of only 67% (600 to 1000 mg). Saturation of the CYP3A4 enzymes and/or possibly also P-glycoprotein could be involved. Combination 3 was considered most suitable for clinical use, but because of the large inter-individual variation in steady-state concentrations, the use of the combination should be supported by therapeutic drug monitoring and restricted to certain patients.

Pharmacokinetics of ritonavir and delavirdine in human immunodeficiency virus-infected patients.

To evaluate the pharmacokinetic effect of adding delavirdine mesylate to the antiretroviral regimens of human immunodeficiency virus (HIV)-infected patients stabilized on a full dosage of ritonavir (600 mg every 12 h), 12 HIV-1-infected subjects had delavirdine mesylate (400 mg every 8 h) added to their current antiretroviral regimens for 21 days. Ritonavir pharmacokinetics were evaluated before (day 7) and after (day 28) the addition of delavirdine, and delavirdine pharmacokinetics were evaluated on day 28. The mean values (+/- standard deviations) for the maximum concentration in serum (C(max)) of ritonavir, the area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and the minimum concentration in serum (C(min)) of ritonavir before the addition of delavirdine were 14.8 +/- 6.7 micro M, 94 +/- 36 micro M. h, and 3.6 +/- 2.1 micro M, respectively. These same parameters were increased to 24.6 +/- 13.9 micro M, 154 +/- 83 micro M. h, and 6.52 +/- 4.85 micro M, respectively, after the addition of delavirdine (P is <0.05 for all comparisons). Delavirdine pharmacokinetic parameters in the presence of ritonavir included a C(max) of 23 +/- 16 micro M, an AUC(0-8) of 114 +/- 75 micro M. h, and a C(min) of 9.1 +/- 7.5 micro M. Therefore, delavirdine increases systemic exposure to ritonavir by 50 to 80% when the drugs are coadministered.

Delavirdine malabsorption in HIV-infected subjects with spontaneous gastric hypoacidity.

To determine the impact of gastric hypoacidity and acidic beverages on delavirdine mesylate pharmacokinetics in HIV-infected subjects, matched subjects with (n = 11) and without (n = 10) gastric hypoacidity received delavirdine 400 mg tid with either water or an acidic beverage (usually orange juice). The pharmacokinetics of delavirdine and its N-desalkyl metabolite were determined over 8 hours after 14 days of each treatment. Gastric pH was measured at baseline and during each pharmacokinetic evaluation. Delavirdine exposure (Cmax, AUC0-->8 h, and Cmin) was approximately 50% lower and the extent of delavirdine metabolism was higher in subjects with gastric hypoacidity. Orange juice produced a lower mean gastric pH compared to water and increased delavirdine absorption by 50% to 70% in subjects with gastric hypoacidity. However, orange juice had a marginal impact on delavirdine exposure in subjects without gastric hypoacidity. HIV-infected subjects with gastric hypoacidity significantly malabsorb delavirdine. Delavirdine administration with acidic beverages improves, but dose not normalize, absorption in these subjects.

Pharmacokinetic interaction between amprenavir and delavirdine after multiple-dose administration in healthy volunteers.

AIMS: To evaluate the safety and the pharmacokinetic interaction between amprenavir and delavirdine after multiple dose administration in healthy volunteers. METHODS: This was a prospective, open-label, randomized, controlled, two-sequence, two-period multiple dose study with 18 healthy subjects. Volunteers were randomly assigned to amprenavir, 600 mg twice a day, or delavirdine, 600 mg twice a day, for 10 days, followed by both drugs for another 10 days with pharmacokinetic evaluation on day 10 and day 20. Adverse events were recorded throughout the study. RESULTS: Amprenavir decreased all the delavirdine pharmacokinetic parameters apart from tmax. Delavirdine C12h dropped from 7,916 to 933 ng ml-1 (median decrease 5,930 ng ml-1, 95% CI 3,013, 8,955 ng ml-1). A decrease in amprenavir t(1/2) was also seen leading to almost identical median amprenavir C24h values. No serious clinical adverse events were observed during the study. The most frequently reported effects were gastrointestinal symptoms, headache, fatigue and rash. CONCLUSIONS: Amprenavir is an effective inducer of delavirdine metabolism, probably through its effect on hepatic CYP3A4. This could have consequences in other drug-drug interaction situations. Delavirdine is an inhibitor of amprenavir metabolism. The regimen of amprenavir 600 mg and delavirdine 600 mg twice a day is not recommended when an antiretroviral effect from delavirdine is required.

Pharmacokinetic interaction between amprenavir and delavirdine: evidence of induced clearance by amprenavir.

OBJECTIVE: Our objective was to determine the pharmacokinetic interaction between amprenavir and delavirdine. METHODS: Healthy volunteers participated in 2 open-label, 3-period, longitudinal studies. In the first study, 12 volunteers received a single dose of amprenavir, 1200 mg, alone and then again after 7 days of delavirdine, 600 mg twice daily. In the second study, another 12 subjects received amprenavir, 1200 mg twice daily, alone for 7 days. After a 7-day washout period, subjects received delavirdine, 600 mg twice daily, alone for 7 days followed by a combination with amprenavir, 600 mg twice daily, for another 7 days. Amprenavir and delavirdine pharmacokinetics when given alone and in combination were compared. RESULTS: All 12 subjects completed the first study, and 11 subjects completed the second study. Delavirdine significantly increased the area under the curve (AUC) of single-dose amprenavir by 4-fold (P =.0001). Amprenavir, 600 mg twice daily, with delavirdine produced higher levels of amprenavir AUC, minimum concentration (C(min)), and maximum concentration (C(max)), by 30%, 90%, and 18%, respectively, than those of amprenavir, 1200 mg twice daily, alone (P <.05). In contrast, amprenavir decreased delavirdine AUC, C(min), and C(max) by 50%, 70%, and 30%, respectively (P <.005). CONCLUSIONS: Because of the inhibitory effect of delavirdine on the cytochrome P450 3A4-mediated metabolism of amprenavir, the combination of a reduced dose of amprenavir, 600 mg twice daily, with delavirdine resulted in a higher amprenavir exposure than the standard dose of amprenavir, 1200 mg twice daily. However, amprenavir induced the clearance of delavirdine, resulting in a reduction in delavirdine exposure. Further clinical studies are needed to determine the appropriate dosing regimens for delavirdine and amprenavir during coadministration.

Determination of delavirdine in very small volumes of plasma by high-performance liquid chromatography with fluorescence detection.

Delavirdine is a newly developed anti-HIV-1 drug for AIDS therapy. This study describes a sensitive high-performance liquid chromatographic method for the determination of delavirdine in 50 microl of plasma. Samples were deproteinized with 150 microl of a solution of internal standard (cisapride 10 microg/ml) in acetonitrile. An aliquot of the supernatant was injected onto the column. HPLC separation was achieved on a C18 column with the mobile phase of acetonitrile-50 mM sodium dihydrogen phosphate (60:40, v/v) at a flow-rate of 1 ml/min. The eluants were measured by fluorescence detection with excitation at 295 nm and emission filtration at 425 nm. The retention time was about 5.3 min for delavirdine and 6.5 min for cisapride. The specificity was demonstrated, as there were no interferences from plasma samples of different batches in the regions of peak interest. Calibration curves were linear from 25 to 25000 ng/ml. The limit of quantitation was 25 ng/ml. The within- and between-day precision (C.V.) was 9.3%, or less, and the accuracy was within 9.2% of the nominal concentration. The small sample volume needed is especially advantageous for the application both in pharmacokinetic studies in HIV-infected adults and pediatric patients, and in small animals, where limited samples are available.

Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a diverse group of compounds that induce allosteric changes in the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, thus rendering the enzyme incapable of converting viral RNA to DNA. Unlike nucleoside analogue inhibitors of reverse transcriptase, NNRTIs do not require sequential phosphorylation to elicit antiretroviral activity. There are currently 3 approved NNRTIs: nevirapine, delavirdine and efavirenz. Although possessing a common mechanism of action, these agents can be differentiated by both molecular and pharmacokinetic characteristics. Each of the NNRTIs is metabolised to some degree by the cytochrome P450 (CYP) system of enzymes, making them prone to clinically significant drug interactions. In addition, they elicit variable effects on other medications, acting as either inducers or inhibitors of drugs metabolised by CYP. These drug interactions are an important consideration in the clinical use of these agents as a part of combination antiretroviral therapy. Additional factors such as the influence of food and pH on oral absorption, and protein binding, must also be considered.

Delavirdine: clinical pharmacokinetics and drug interactions.

Delavirdine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a potent and specific inhibitor of HIV-1 reverse transcriptase. The approved therapeutic regimen for delavirdine is 400mg 3 times daily in combination with appropriate antiretroviral agents; however, a dose of 600mg twice daily appears to provide similar systemic exposure. The steady-state pharmacokinetics of delavirdine are not appreciably affected by food. Delavirdine undergoes extensive metabolism by cytochrome P450 (CYP) with little urinary excretion of unchanged drug. Metabolic drug interactions between delavirdine and nucleoside reverse transcriptase inhibitors are unlikely as their metabolic pathways differ; delavirdine has no effect on the pharmacokinetics of zidovudine. Concomitant use of CYP inducers, such as rifampicin (rifampin), rifabutin, phenytoin, phenobarbital or carbamazepine, should be avoided since delavirdine plasma concentrations are significantly lowered. Reduction in gastric acidity (pH > 3) decreases the extent of delavirdine absorption, so administration of antacids and the buffered formulations of didanosine should be separated from that of delavirdine by at least 1 hour. Delavirdine, unlike other currently available NNRTI agents, is an inhibitor rather than an inducer of CYP isozymes. Consequently, the drug interaction profile and rationale for combining delavirdine with other antiretroviral agents is unique among the current NNRTI agents. Delavirdine inhibits the CYP3A4-mediated metabolism of HIV protease inhibitors and thereby increases systemic exposure to protease inhibitors. The ability of delavirdine to enhance the pharmacokinetic profiles of protease inhibitors may permit the use of simplified administration regimens. Combining delavirdine and indinavir removes the food restrictions during indinavir administration. Furthermore, the superior virological response observed in antiretroviral regimens containing delavirdine and protease inhibitors has been attributed to the favourable pharmacokinetic interactions and the introduction of a new drug class in NNRTI-naïve therapy-experienced patients. Pharmacokinetic drug interactions are an important consideration in selecting an HIV treatment regimen, due to the multiplicity of drugs that are coadministered and the varying direction and magnitude of interaction that can occur. Considerations for utilising delavirdine in a treatment regimen are different than for other NNRTI agents due to the unique drug interaction profile of delavirdine.

Competing drug-drug interactions among multidrug antiretroviral regimens used in the treatment of HIV- infected subjects: ACTG 884.

OBJECTIVE: To evaluate the steady state concentrations of saquinavir, ritonavir, nelfinavir, delavirdine, and adefovir in six different three- and four-drug combination regimens. DESIGN: Randomized, partially double-blinded, multicenter study in a population of indinavir-experienced subjects with virologic failure. The first seven subjects enrolled in each of the six treatment arms from 10 participating sites were entered into this pharmacokinetic evaluation. SETTING: Multicenter study of the AIDS Clinical Trials Group (ACTG). PATIENTS: HIV-infected subjects. INTERVENTIONS: A 12-hour pharmacokinetic study was conducted after 2 weeks of drug administration. MAIN OUTCOME MEASURES: Area under the concentration-time curve with statistical comparisons to evaluate the effect of the second protease inhibitor and the effect of the non-protease inhibitors. RESULTS: There was no difference in saquinavir concentrations according to whether the second protease inhibitor was ritonavir or nelfinavir. Saquinavir concentrations in the groups receiving the combination of delavirdine plus adefovir dipivoxil were reduced by approximately 50% compared with those receiving delavirdine. Delavirdine concentrations were reduced by approximately 50%, in the delavirdine plus adefovir dipivoxil arms compared with the delavirdine arms. CONCLUSIONS: Saquinavir concentrations were significantly lower in the arms containing the combination of delavirdine and adefovir dipivoxil compared with the arms containing delavirdine. Delavirdine concentrations were significantly lower when coadministered with adefovir dipivoxil. These drug-drug interactions were not expected, the mechanism(s) is (are) not clear, and additional studies are warranted. This study illustrates the need to understand more fully the pharmacokinetic characteristics of complex combination antiretroviral regimens prior to use in patient management.

Delavirdine: a review of its use in HIV infection.

UNLABELLED: 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 DNA polymerase 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 log10 copies/ml and mean CD4+ counts increased by 100 to 313 cells/microl. The proportion of patients with plasma HIV RNAlevels below the LOD (usually 200 to 500 copies/ml) ranged from 48 to 100% after > or = 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, simvastatin, 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 1,000 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.

Efficacy and safety of combination therapy with delavirdine and zidovudine: a European/Australian phase II trial.

The objective of the study was to investigate the safety and antiviral effect of three delavirdine dose regimens or placebo in combination with zidovudine in patients who were already taking zidovudine. Eighty-nine symptomatic HIV-1 seropositive individuals with CD4 cell counts between 50 and 350 cells/microl were included in this trial The influence of combination therapy on viral susceptibility to both zidovudine and delavirdine was investigated. Death or the occurrence, or re-occurrence of an AIDS-defining illness was considered as a clinical endpoint. The addition of delavirdine to the antiretroviral treatment regimen resulted in a significant, but transient, reduction in virus load, as determined by quantitative RNA measurements. CD4+ cell count did not change significantly. Susceptibility to zidovudine remained unchanged after 12 weeks of combination therapy, while 70% of the patients demonstrated a substantial decrease (> 10-fold) in sensitivity to delavirdine. Two patients suffered from an AIDS-defining disease during the study. No deaths occurred. Generally, the drug appeared to be safe. Skin rash was the most frequently observed adverse event (52%). In most patients the rash either resolved spontaneously or was treated successfully with a short course of antihistamines. The definite place of the compound in the management of HIV disease, in particular when given in combination with other antiretroviral agents, remains to be further explored.