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Biomedical subjects

Alan Winston

Publications and source records attributed to Alan Winston.

17 recordsLinked to original sources
PubMed2006

Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers.

INTRODUCTION: Recent studies have described reduced absorption of certain protease inhibitors when administered with agents known to increase gastric pH. No clinically significant interactions between saquinavir absorption and gastric pH have previously been shown. We evaluated the effect of omeprazole, a proton-pump-inhibitor, on the pharmacokinetics of the recently developed saquinavir-500 mg formulation co-administered with ritonavir. METHODS: Eighteen healthy subjects (n = 6 women and 12 men) received 1000/100 mg saquinavir/ritonavir twice daily in an open-label study for 15 days. On days 11-15, subjects were administered omeprazole 40 mg daily with the morning dose. Serial plasma samples were collected for 12-h pharmacokinetic profiles of saquinavir and ritonavir on days 10 and 15 and safety analysis on days 1, 4, 10, 15 and 29. RESULTS: The geometric mean and 95% confidence interval (CI), for the area under time-concentration curve (AUC; ng h/ml), trough plasma concentration (C trough; ng/ml) and maximum observed plasma concentration (Cmax; ng/ml) of saquinavir were 20599 (14396-29360) and 37511 (28733-48970); 737 (482-1127) and 1521 (1039-2227); 3227 (2370-4393) and 5611 (4507-7710) on days 10 and 15, respectively, with geometric mean ratios of 1.82, 2.06 and 1.75. No significant changes were observed in saquinavir elimination half life, ritonavir pharmacokinetic parameters or in safety laboratory tests. No unexpected adverse events attributed to study medication were noted. CONCLUSIONS: In the presence of omeprazole, total saquinavir plasma exposure is significantly increased (82% increase in AUC). The mechanism of this interaction requires elucidation. Despite the significant increase in saquinavir exposure, no short term toxicities were observed.

Adolescent↗
PubMed2006

Nonnucleoside reverse transcriptase inhibitor fold change or plasma concentration as a predictor of virological response over 48 weeks in highly treatment experienced HIV-positive individuals.

The nonnucleoside reverse transcriptase inhibitors (NNRTI) have low genetic barriers to resistance. Resistance can sometimes be overcome by increasing drug exposure. We assessed factors associated with 48-week virological response in treatment-experienced individuals receiving NNRTI therapy including resistance testing results and plasma drug exposure. Of 62 individuals assigned a new NNRTI-based regimen following resistance testing therapy consisted of efavirenz in 35 (56%) and nevirapine in 27 (44%) individuals. NNRTI fold change (FC) was determined from resistance test at baseline and plasma drug concentration at week 4. Mean time weighted change from baseline VL was -0.68 log over 48 weeks. Significant associations with change from baseline VL included baseline VL and FC whereas plasma drug concentration was not associated. In this cohort of highly treatment-experienced individuals treated with NNRTI regimens, we did not observe a significant association between NNRTI plasma concentration and virological response.

Alkynes↗
PubMed2006

The clinical pharmacology of antiretrovirals in development.

Drugs in development for the management of HIV type 1 (HIV-1) infection include agents in existing classes and agents of novel classes. Of existing classes, new protease inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors are in development. Novel therapeutic approaches include the development of chemokine receptor (CCR)5 antagonists, integrase inhibitors and maturation inhibitors. CCR5 antagonists are thought to inhibit HIV-1 entry into host cells by occupying a specific site on the CCR5 receptor, preventing attachment of the HIV-1 envelope protein gp120. Integrase inhibitors are small synthetically prepared molecules that block RNA/DNA interactions and modify protein or enzyme synthesis. Data on the pharmacokinetics and pharmacodynamics of these new antiretroviral agents continue to generate interest. This review reports the known data on the pharmacokinetics of experimental antiretrovirals, and describe the main drug-drug interactions studied so far.

Animals↗
PubMed2006

The clinical implications of antiretroviral pharmacogenomics.

Heterogeneity exists in the effectiveness and toxic effects of antiretroviral agents between individuals and populations. Although patient-related clinical variables such as age, sex and ethnic origin have been associated with drug response, inherited predispositions may have a significant effect on treatment outcome. The role of host and pathogen pharmacogenomics is gaining increasing interest in the field of both antiretrovirals in development, such as the chemokine (C-C motif) receptor 5 (CCR5) inhibitors, and in established therapies where toxicity and efficacy may be predicted. Despite numerous studies available in the literature, the interpretation of the relationship between genetic polymorphisms and clinical outcomes is often posed with many confounding variables, making clinical interpretations of these results difficult. This review summarizes the key findings in the growing knowledge between human genetics and response to antiretroviral drugs and how these findings may be effectively applied in a clinical context.

Anti-HIV Agents↗
PubMed2005

The normalized inhibitory quotient of boosted protease inhibitors is predictive of viral load response in treatment-experienced HIV-1-infected individuals.

OBJECTIVE: The normalized inhibitory quotient (NIQ) has been proposed as a measure for refining the precision of HIV resistance testing when selecting antiretroviral therapy (ART). We undertook an assessment of NIQ and 48-week virological outcome in patients commencing ritonavir-boosted protease inhibitor (PI) regimens. DESIGN: A cohort of 87 HIV-infected individuals who all had extensive prior exposure to ART were assigned a new boosted PI regimen following resistance testing. PI therapy consisted of lopinavir, indinavir, saquinavir and amprenavir at 50, 32, 11 and 6%, respectively. Fold change (FC) for each PI was determined from the resistance test at baseline. Trough drug concentration (Cmin) was determined at week 4. METHODS: NIQ was derived individually by taking the logarithm of the ratio of Cmin/FC divided by the fixed ratio of population mean trough drug concentration/clinical cut off. Associations between viral load (VL) response over 48 weeks with baseline VL, FC, Cmin, NIQ and selected PI were assessed. RESULTS: Mean change from baseline VL reduced by 0.83 log at week 48. In multivariate analyses, baseline VL and NIQ were the parameters most associated with change from baseline VL at week 48 (P = 0.012 and 0.003, respectively). FC, Cmin and selected PI were not significantly associated with VL changes. CONCLUSION: In this cohort of highly treatment-experienced individuals treated with boosted PI regimens, baseline VL and NIQ were significantly predictive of virological response over 48 weeks whereas FC and Cmin were not. These results support the use of a NIQ at week 4, as a tool for predicting response to therapy in this setting.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Atazanavir trough plasma concentration monitoring in a cohort of HIV-1-positive individuals receiving highly active antiretroviral therapy.

OBJECTIVES: Atazanavir is a recently approved HIV protease inhibitor (PI). As with other PIs, careful attention to potential pharmacokinetic drug interactions in clinical practice is necessary. The aim of this study was to assess the clinical associations with plasma atazanavir concentrations in HIV-positive individuals. METHODS: Individuals established on an atazanavir-containing regimen, completed an interviewer-administered questionnaire recording atazanavir dosing characteristics, concomitant medication use and adherence. After completion, plasma atazanavir concentrations were measured. RESULTS: Of 100 individuals, mean trough plasma atazanavir concentrations (mug/L) were 282 (95% CI 95-468, n = 19) and 774 (95% CI 646-902, n = 81) in those on non- and ritonavir-boosted atazanavir regimens, respectively. Eighty-five individuals had HIV RNA <50 copies/mL. Seven individuals had atazanavir plasma concentrations below the assay limit of detection (<50 microg/L), all of whom had undetectable plasma HIV RNA. In a multivariate analysis, nevirapine use was associated with significantly lower trough atazanavir concentrations (P = 0.011) and lopinavir/ritonavir use with higher trough atazanavir concentrations (P = 0.032). Dosing characteristics (including food taken), concomitant medications (including drugs used for dyspepsia) and HIV RNA were not significantly associated with trough atazanavir concentrations. CONCLUSIONS: In this cohort, despite the wide inter-individual variability of atazanavir trough concentrations, no significant association with dosing characteristics, concomitant medication (with the exception of nevirapine and lopinavir/ritonavir) or virological response was observed. Further work is needed to assess the optimal dosing regimen when using atazanavir with nevirapine.

Anti-HIV Agents↗
PubMed2005

The management of HIV-1 protease inhibitor pharmacokinetic interactions.

The HIV-1 protease inhibitors (PIs) are widely used in combination antiretroviral therapy for the management of HIV-1 infection. Certain characteristics of the PIs, in particular their metabolism being mainly via the cytochrome P450 isoenzyme group and their gastric absorption being pH dependent, make them prone to clinically significant drug interactions with other antiretrovirals, concomitant medication and complementary treatments. Owing to the nature of the disease, individuals with HIV are frequently prescribed complex treatment regimens (both for the management of intolerance, toxicity and viral resistance to antiretroviral therapy, and in the management of co-morbid states) that may interact with PI therapy. For many of these potential interactions, few data are available. This review will focus on the current use of PIs, highlighting some important management issues encountered with common pharmacokinetic interactions seen in clinical practice.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Host determinants of antiretroviral drug activity.

PURPOSE OF REVIEW: As physicians are confronted with a diversity of adverse events and variability in response to medication among patients, this review will focus on the available evidence regarding the impact of genetic variation on drug response. Specifically, variation in drug metabolizing enzymes such as the cytochrome P450s, drug transporters and human leucocyte antigen (for idiosyncratic drug reactions). The potential role of pharmacogenetics in the management of HIV-1 infected individuals and drug discovery will be discussed. RECENT FINDINGS: Wide inter-individual variability of antiretroviral therapy efficacy and toxicity in HIV-infected patients has been extensively reported in the literature. Since treatment involves multiple drugs and drug classes with the potential for significant variability in drug-host as well as drug-drug interactions, antiretroviral drug therapy represents a significant challenge. Despite this inherent complexity, considerable recent advances have led to a greater understanding of interactions between genetic and host factors that influence the efficacy and toxicity of these agents. SUMMARY: The goal of pharmacogenetics in antiretroviral therapy is to outline differences within a given population that influence drug efficacy and toxicity. Although to date, despite the numerous studies available in the literature, conclusions on how the analysis of the relationship between single nucleotide polymorphisms and drug efficacy may not always be clinically useful. Further studies are warranted to clarify the role of pharmacogenetics and antiretroviral drug management.

Anti-HIV Agents↗
PubMed2005

The rationale and development of new drugs to treat HIV infection.

Fewer than one million HIV infected individuals are currently receiving antiretroviral therapy. Present antiretroviral therapy costs between 10,000 dollars and 20,000 dollars per year, which provides excellent value for money in developed countries with a cost of about 10,000 dollars per life year saved; this compares very favourably with other therapies in chronic use. Recent studies have demonstrated a dramatic decline in HIV and AIDS related morbidity and mortality across developed countries and these reductions have been sustained since the introduction of highly active antiretroviral therapy (HAART) since 1996. The use of HAART has been associated with specific toxicities related to the drug class, problems with adherence with the subsequent emergence of viral isolates and resistance associated mutations. The replacement of older therapies with newer drugs that avoid cross resistance even within the same class of antiretroviral, represents a new hope in retroviral targeting.

Anti-HIV Agents↗
PubMed2005

New drugs for old.

The use of highly active antiretroviral therapy (HAART) has led to the emergence of viral isolates with resistance-associated mutations. Currently, new cases of highly resistant HIV infections associated with rapid progression to AIDS are being reported. The features of a new drug for HIV treatment must include selective potent activity against wild-type virus as well as against mutant virus that has been selected by the use of current antiretroviral treatment regimens. As patients in industrialised countries may live with HIV infection for decades, new drugs must also encourage adherence with simplified dosing regimens associated with favourable toxicity profiles. The replacement of older therapies with newer drugs that avoid cross resistance, even within the same class of antiretroviral, represents a new hope in retroviral targeting.

Anti-HIV Agents↗
PubMed2004

Dose escalation or immediate full dose when switching from efavirenz to nevirapine-based highly active antiretroviral therapy in HIV-1-infected individuals?

Efavirenz induces the metabolism of co-administered drugs through the induction of CYP A4. It is often necessary to switch fron efavirenz to nevirapine because of intolerance or toxicity. In a pharmacokinetic study we determined whether to dose-escalate nevirapine or start the full dose when switching from efavirenz. It was found that when changing from efavirenz to nevirapine individuals should commence on 200 mg twice a day, as this dose is associated with therapeutic plasma drug levels.

Adult↗
PubMed2002

The prevalence and determinants of the K65R mutation in HIV-1 reverse transcriptase in tenofovir-naive patients.

The K65R mutation in HIV-1 reverse transcriptase is associated with reduced susceptibility to abacavir and tenofovir. We established its prevalence within a large clinical database, and investigated correlations with other resistance-associated mutations and antiretroviral history. The presence of K65R is associated with previous abacavir use. Although rare, it is preferentially selected within non-thymidine analogue-containing regimens, compared with concurrent zidovudine or stavudine use, which is associated with thymidine analogue mutations. Both genetic routes may compromise abacavir and tenofovir activity.

Adenine↗
PubMed2002

Recurrent hypersensitivity to Combivir.

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are commonly used in combination antiretroviral therapy and are associated with hypersensitivity reactions on induction therapy. We report a case of recurrent hypersensitivity associated with Combivir, when there was a delay in determining the cause as the NNRTIs were considered to be the more likely cause.

Adult↗