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.

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.

Late breaking news: two additional DHHS guidelines changes. Department of Health and Human Services.

AIDS: A recent revision was made in the Use of Antiretroviral Therapy for Adults and Adolescents Guidelines. Delavirdine is added to nevirapine as an acceptable or equivalent non-nucleoside reverse transcriptase inhibitor, in the Alternative Options category. In addition, invirase plus two nucleoside reverse transcriptase inhibitors, are demoted from the Alternative Options category.^ieng

Delavirdine combination and viral load.

AIDS: Evidence indicates that delavirdine (Rescriptor), when combined with AZT and 3TC, lowers HIV viral load more effectively than either AZT plus 3TC, or AZT plus delavirdine. Greater increases in CD4 counts were not statistically significant. Subjects either were antiretroviral naive or had received fewer than six months of AZT monotherapy.^ieng

Strategy update: protease-sparing regimens.

AIDS: Protease-sparing regimens are sometimes considered the best initial therapy because they can effectively reduce viral load, while allowing the individual to reserve potent protease inhibitor therapy for later treatment. Others contend that the more potent therapy should be used first, to give a patient the best shot at long-term viral suppression. The debate continues with the promotion of efavirenz (Sustiva), a non-nucleoside reverse transcriptase inhibitor (NNRTI), sometimes prescribed as the initial course of therapy. Several reasons are explored for re-evaluating this decision, which is largely based on limited information from one trial with significant results. A table compares efavirenz with Nevirapine and Delavirdine, two other NNRTIs. There are still not enough data to support a recommendation about the use of protease-sparing treatment or the comparative value of the three NNRTIs listed.^ieng

Solid lipid nanoparticles comprising internal Compritol 888 ATO, tripalmitin and cacao butter for encapsulating and releasing stavudine, delavirdine and saquinavir.

Solid lipid nanoparticles (SLNs) with complex internal phase were fabricated for formulating stavudine (D4T), delavirdine (DLV), and saquinavir (SQV). The lipids including Compritol 888 ATO, tripalmitin, and cacao butter were stabilized by L-α-phospatidylcholine, cholesteryl hemisuccinate, and taurocholate to form SLNs. The results revealed that the morphology of SLNs was spheroidal with shallow surface pits. An increase in the weight percentage of Compritol 888 ATO increased the average diameter of D4T-entrapping SLNs and decreased that of DLV- and SQV-entrapping SLNs. Preservation at 4°C over 6 weeks slightly enhanced the size of SLNs. For a specific drug, an increase in the entrapment efficiency enlarged the nanocarriers. The order of drug in the average particle diameter and in the entrapment efficiency was SQV>DLV>D4T, in general. In addition, the dissolution of the three drugs from SLNs showed the characteristics of sustained release. The order of drug in the cumulative release percentage was D4T>DLV>SQV. SLNs containing Compritol 888 ATO, tripalmitin, and cacao butter are efficient in carrying antiretroviral agents for medicinal application.

The home as an appropriate setting for women undertaking cervical ripening before the induction of labour.

OBJECTIVES: to explore women's experiences of cervical ripening using isosorbide mononitrate (IMN) in the home as part of the main randomised controlled trial. DESIGN: qualitative study with semi-structured interviews carried out at three weeks post partum. Interview transcripts were analysed to identify recurrent themes, focusing on why women became involved in the study, their views about both the self-medication and the home setting, and whether they would repeat the experience. SETTING: the home. PARTICIPANTS: twenty women enrolled in the main randomised controlled trial. INTERVENTION: the study is part of a double-blind randomised controlled trial with 350 patients investigating whether a nitric oxide donor (IMN) used in cervical ripening improves the process of induction of labour. FINDINGS: women liked the opportunity to remain at home during the cervical ripening process. Timing and setting were central issues; women hoped that it would hasten labour, while the home was seen as a setting offering freedom, security and reassurance, as opposed to the hospital, seen as constraining. Two women reported problems with IMN but the remainder reported that they would repeat the experience. IMPLICATIONS FOR PRACTICE: women were very positive about the opportunity to undertake cervical ripening at home. It is important to explore this setting further for appropriate interventions.

US and UK versions of the EQ-5D preference weights: does choice of preference weights make a difference?

BACKGROUND: Most US studies that estimate EQ-5D index score generally apply the UK preference weights. We compared the validity of a newly-developed US weights to the UK weights for use of EQ-5D as a measure of health-related quality of life. METHODS: Data were collected from a randomized clinical trial for patients with HIV (n = 1,126) in the US. Convergent validity was examined by comparing Pearson correlations of EQ-5D index scores with the MOS-HIV Health Survey scale scores and Physical and Mental Health Summary (PHS, MHS) scores using the US and UK weights. Known-groups validity of EQ-5D US versus UK index scores was compared using clinical variables (CD4+ cell count and HIV viral load), and the MOS-HIV PHS and MHS. Score changes in the EQ-5D index from baseline to week 50 were examined using effect size (ES) estimates. RESULTS: The mean EQ-5D index scores was slightly higher using US weights than UK weights (0.87 vs. 0.84, respectively). The correlation coefficient for EQ-5D utilities using the US and UK weights was 0.98. The correlations of EQ-5D index scores with the MOS-HIV scores were moderate and similar using the US and UK weights. The EQ-5D index scores discriminated equally well for both versions between levels of CD4+ count, HIV viral load, and PHS and MHS scores (P < 0.05), suggesting equivalent known-groups validity. The changes in EQ-5D index scores from baseline to week 50 were similar for both versions (ES: 0.21 vs. 0.22 for US and UK, respectively), suggesting equivalent responsiveness to score changes. CONCLUSIONS: EQ-5D index scores generated using UK and US preference weights showed equivalent psychometric properties. For assessing treatment benefit in a single population, the use of either the UK or US weights as a measure of HRQOL will not change inferences. However, for comparisons across US and UK populations, the choice between these two weights should be based on their relevance to the study population.

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.

In situ determination of delavirdine mesylate particle size in solid oral dosage forms.

PURPOSE: The in-situ particle size of delavirdine mesylate in dry mix and tablets was determined. METHODS: Optical microscopy and fluorescence microscopy combined with image analysis were used for qualitative and quantitative measurements. RESULTS: Using optical microscopy, it was demonstrated qualitatively that fragmentation of the large drug particles was occurring during tablet compression. Quantitative comparisons between dry mix and tablet samples showed that in the dry mix, drug particles remain intact, with particle lengths exceeding 200 microm. In the tablets, no particles longer than 100 microm had been observed. Analysis of multiple tablet lots revealed consistent in-situ drug particle size distributions, regardless of the original bulk drug particle size. CONCLUSIONS: Bulk drug particle size of delavirdine mesylate is not predictive of the particle size in the tablet due to fragmentation of particles during compression. Optical and fluorescence microscopy are valuable tools for probing in-situ particle size in complex matrices.

Tablet dissolution affected by a moisture mediated solid-state interaction between drug and disintegrant.

PURPOSE: To investigate the cause for decrease in delavirdine mesylate 200 mg tablet dissolution upon exposure to high humidity. METHODS: Dissolution testing was performed using the USP 2 (paddle) apparatus. Water in tablets was measured by Karl Fischer titration. 13C CP/MAS NMR was used to identify and quantify delavirdine form changes in tablets. FT-IR spectroscopy was used to monitor delavirdine form change in tablets and component mixes, and to investigate a solid state reaction with the disintegrant. RESULTS: Dissolution extent of delavirdine mesylate 200 mg tablets was substantially decreased after exposure to high humidity. This effect is related to the amount of water present in the tablet matrix. 13C CP/ MAS NMR detected about 30% conversion from the mesylate salt of delavirdine to its free base form in the tablet matrix. FT-IR spectroscopy demonstrated that a solid state reaction occurs between the freed methanesulfonic acid and the carboxyl sites on the croscarmellose sodium disintegrant. CONCLUSIONS: Water is thought to act as both a reaction medium and a plasticizer for croscarmellose sodium, facilitating protonation of the carboxyl sites on the disintegrant. This reaction has the potential to occur for any acid salt of a free base. The limiting solubility of delavirdine free base formed in the tablets accounts for much of the decrease in the extent of dissolution. A change in inter-particle bonding can explain the reduction in tablet deaggregation during dissolution.

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.

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.

Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team.

To evaluate the antiretroviral activity of delavirdine mesylate, a non-nucleoside reverse transcriptase inhibitor of HIV-1, we performed a phase II, randomized, double-blind, multicenter trial comparing the three-drug combination of delavirdine with zidovudine and didanosine to two-drug combinations of these drugs. Patients with CD4 cell counts between 100 and 500 cells/mm3 without prior or <6 months of monotherapy with zidovudine or didanosine were randomized to one of four arms and observed on a follow-up basis for 48 weeks. In total, 544 patients were evaluated. In those assigned to the three-drug regimen, mean short-term (weeks 4-12) and long-term (weeks 40-48) change in CD4 cells from baseline were 49.3+/-8.1 and 65.4+/-13.4 cells/mm3, respectively; mean short-term and long-term HIV-1 RNA changes from baseline were -1.13 log10+/-0.12 and -0.73+/-0.12 copies/ml, respectively. These responses in CD4 cell counts and HIV-1 RNA levels were better in comparisons with each of the two-drug arms at all study points; however, differences were not consistently significant. Gastrointestinal side effects were experienced by 33% of patients (178 of 544), and 30% (121 of 407) receiving delavirdine experienced rash, only one case of which was severe. In this study, therapy with delavirdine + zidovudine + didanosine was safe and showed modest, but not always significant, antiviral activity and CD4 cell count benefit compared with two-drug regimens with these agents. Key