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Caroline Gatey - One of the best experts on this subject based on the ideXlab platform.
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Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy with tenofovir/emtricitabine/Maraviroc/raltegravir in treatment-naive HIV patients
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: Pierre Pradat, Mary Anne Trabaud, Jacques Izopet, Jacques Durant, C. Brochier, Jacqueline Cottalorda-dufayard, François Raffi, Frédéric Lucht, Marie-claude Gagnieu, Caroline GateyAbstract:OBJECTIVE: We assessed the virological efficacy of a 6 month Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with Maraviroc/raltegravir. METHODS: HIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received Maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA \\textless50 copies/mL stopped tenofovir/emtricitabine at week (W) 24 and pursued Maraviroc/raltegravir until W48. The primary endpoint was the virological response defined by HIV-RNA \\textless50 copies/mL at W48. RESULTS: Thirty-three patients were analysed. Patients were mostly male (94%), Caucasians (91%), MSM (82%); their median age was 42 years. At baseline, median CD4 cell count was 453 cells/mm3 and HIV-RNA was 4.3 log copies/mL. All patients had CCR5-tropic viruses by genotropism and phenotropism assays. All but one patient had an HIV-RNA \\textless 50 copies/mL at W24 and entered the simplification phase. Virological success was maintained at W48 in 88% (90% CI 79%-97%) of patients. N155H mutation was detected at failure in one patient. No tropism switch was observed. Raltegravir and Maraviroc plasma exposure were satisfactory in 92% and 79% of 41 samples from 21 patients. Five severe adverse events (SAEs) were observed up to W48; none was related to the study drugs. Four patients presented grade 3 AEs; none was related to the study. No grade 4 AE was observed. No patient died. CONCLUSIONS: Maraviroc/raltegravir maintenance therapy following a 6 month induction phase with Maraviroc/raltegravir/tenofovir/emtricitabine was well tolerated and maintained virological efficacy in these carefully selected patients
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Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy with tenofovir/emtricitabine/Maraviroc/raltegravir in treatment-naive HIV patients
The Journal of antimicrobial chemotherapy, 2016Co-Authors: Pierre Pradat, Mary Anne Trabaud, Jacques Izopet, Jacques Durant, C. Brochier, Jacqueline Cottalorda-dufayard, François Raffi, Frédéric Lucht, Marie-claude Gagnieu, Caroline GateyAbstract:OBJECTIVE We assessed the virological efficacy of a 6 month Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with Maraviroc/raltegravir. METHODS HIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received Maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA
Jacques Izopet - One of the best experts on this subject based on the ideXlab platform.
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Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy with tenofovir/emtricitabine/Maraviroc/raltegravir in treatment-naive HIV patients
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: Pierre Pradat, Mary Anne Trabaud, Jacques Izopet, Jacques Durant, C. Brochier, Jacqueline Cottalorda-dufayard, François Raffi, Frédéric Lucht, Marie-claude Gagnieu, Caroline GateyAbstract:OBJECTIVE: We assessed the virological efficacy of a 6 month Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with Maraviroc/raltegravir. METHODS: HIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received Maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA \\textless50 copies/mL stopped tenofovir/emtricitabine at week (W) 24 and pursued Maraviroc/raltegravir until W48. The primary endpoint was the virological response defined by HIV-RNA \\textless50 copies/mL at W48. RESULTS: Thirty-three patients were analysed. Patients were mostly male (94%), Caucasians (91%), MSM (82%); their median age was 42 years. At baseline, median CD4 cell count was 453 cells/mm3 and HIV-RNA was 4.3 log copies/mL. All patients had CCR5-tropic viruses by genotropism and phenotropism assays. All but one patient had an HIV-RNA \\textless 50 copies/mL at W24 and entered the simplification phase. Virological success was maintained at W48 in 88% (90% CI 79%-97%) of patients. N155H mutation was detected at failure in one patient. No tropism switch was observed. Raltegravir and Maraviroc plasma exposure were satisfactory in 92% and 79% of 41 samples from 21 patients. Five severe adverse events (SAEs) were observed up to W48; none was related to the study drugs. Four patients presented grade 3 AEs; none was related to the study. No grade 4 AE was observed. No patient died. CONCLUSIONS: Maraviroc/raltegravir maintenance therapy following a 6 month induction phase with Maraviroc/raltegravir/tenofovir/emtricitabine was well tolerated and maintained virological efficacy in these carefully selected patients
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Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy with tenofovir/emtricitabine/Maraviroc/raltegravir in treatment-naive HIV patients
The Journal of antimicrobial chemotherapy, 2016Co-Authors: Pierre Pradat, Mary Anne Trabaud, Jacques Izopet, Jacques Durant, C. Brochier, Jacqueline Cottalorda-dufayard, François Raffi, Frédéric Lucht, Marie-claude Gagnieu, Caroline GateyAbstract:OBJECTIVE We assessed the virological efficacy of a 6 month Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with Maraviroc/raltegravir. METHODS HIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received Maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA
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Primary resistance of CCR5-tropic HIV-1 to Maraviroc cannot be predicted by the V3 sequence
The Journal of antimicrobial chemotherapy, 2013Co-Authors: Pierre Delobel, Stéphanie Raymond, Michelle Cazabat, Adrien Saliou, Claire Loiseau, Lucile Coassin, Mary Requena, Bruno Marchou, Patrice Massip, Jacques IzopetAbstract:Objectives: Resistance of HIV-1 to CCR5 antagonists can occur without coreceptor switching by mutations in envelope glycoproteins that enable virus entry using the inhibitor-bound form of CCR5. We investigated whether mutations in the V3 region of HIV-1 from subjects naive to Maraviroc could be associated with primary resistance to this drug. Methods: The frequency of CCR5-tropic HIV-1 subtype B isolates harbouring putative V3 Maraviroc resistance mutations was assessed among the HIV tropism database of Toulouse University Hospital, France. Phenotypic assessment of Maraviroc susceptibility was performed for 14 isolates representative of the main mutation patterns and 14 controls. V3 mutations were reversed or introduced by site-directed mutagenesis. Results: Ninety-three of 951 (9.8%) isolates harboured V3 mutations assumed to be associated with Maraviroc resistance. Maraviroc completely blocked virus entry for all but 1 of the 14 isolates harbouring V3 mutations [IC50 8.6 nM; 95% CI (6.6-47.4)], as in the 14 control isolates [IC50 13.4 nM; 95% CI (7.7-50.3)] (P = 0.24). Primary resistance to Maraviroc, with a plateau in entry inhibition, was found in one isolate (harbouring a 20F/21I genotype). Site-directed mutagenesis showed that V3 mutations are necessary but not sufficient to induce Maraviroc resistance. Conclusions: The impact of V3 mutations depended on the env context in which they occurred. Simple assessment of the V3 genotype thus cannot accurately predict Maraviroc resistance. Rather, phenotypic assessment of virus particles expressing the envelope glycoprotein as a whole is required. This approach revealed that primary resistance of CCR5-tropic HIV-1 subtype B isolates to Maraviroc seems uncommon.
Marilyn Lewis - One of the best experts on this subject based on the ideXlab platform.
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clonal analysis of hiv 1 genotype and function associated with virologic failure in treatment experienced persons receiving Maraviroc results from the motivate phase 3 randomized placebo controlled trials
PLOS ONE, 2018Co-Authors: Marilyn Lewis, Julie Mori, Elna Van Der Ryst, Jonathan Toma, Mike Mosley, Wei Huang, Paul Simpson, Roy Mansfield, Charles Craig, David RobertsonAbstract:Detailed clonal phenotypic/genotypic analyses explored viral-escape mechanisms during Maraviroc-based therapy in highly treatment-experienced participants from the MOTIVATE trials. To allow real-time assessment of samples while maintaining a blind trial, the first 267 enrolled participants were selected for evaluation. At failure, plasma samples from 20/50 participants (16/20 Maraviroc-treated) with CXCR4-using virus and all 38 (13 Maraviroc-treated) with CCR5-tropic virus were evaluated. Of those Maraviroc-treated participants with CXCR4-using virus at failure, genotypic and phenotypic clonal tropism determinations showed >90% correspondence in 14/16 at Day 1 and 14/16 at failure. Phylogenetic analysis of clonal sequences detected pre-treatment progenitor CXCR4-using virus, or on-treatment virus highly divergent from the Day 1 R5 virus, excluding possible co-receptor switch through Maraviroc-mediated evolution. Re-analysis of pre-treatment samples using the enhanced-sensitivity Trofile® assay detected CXCR4-using virus pre-treatment in 16/20 participants failing with CXCR4-using virus. Post-Maraviroc reversion of CXCR4-use to CCR5-tropic occurred in 7/8 participants with follow-up, suggesting selective Maraviroc inhibition of CCR5-tropic variants in a mixed-tropic viral population, not emergence of de novo mutations in CCR5-tropic virus, as the main virologic escape mechanism. Maraviroc-resistant CCR5-tropic virus was observed in plasma from 5 treated participants with virus displaying reduced maximal percent inhibition (MPI) but no evidence of IC50 change. Env clones with reduced MPI showed 1-5 amino acid changes specific to each V3-loop region of env relative to Day 1. However, transferring on-treatment resistance-associated changes using site-directed mutagenesis did not always establish resistance in Day 1 virus, and key 'signature' mutation patterns associated with reduced susceptibility to Maraviroc were not identified. Evolutionary divergence of the CXCR4-using viruses is confirmed, emphasizing natural selection not influenced directly by Maraviroc; Maraviroc simply unmasks pre-existing lineages by inhibiting the R5 virus. For R5-viral failure, resistance development through drug selection pressure was uncommon and manifested through reduced MPI and with virus strain-specific mutational patterns.
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deep v3 sequencing for hiv type 1 tropism in treatment naive patients a reanalysis of the merit trial of Maraviroc
Clinical Infectious Diseases, 2011Co-Authors: Luke C Swenson, Simon Portsmouth, Winnie Dong, Xiaoyin Zhong, Conan K Woods, Alexander Thielen, Mark A Jensen, David J H F Knapp, Douglass Chapman, Marilyn LewisAbstract:Background. Deep sequencing is a highly sensitive technique that can detect and quantify the proportion of non-R5 human immunodeficiency virus (HIV) variants, including small minorities, that may emerge and cause virologic failure in patients who receive Maraviroc-containing regimens. We retrospectively tested the ability of deep sequencing to predict response to a Maraviroc-containing regimen in the Maraviroc versus Efavirenz in TreatmentNaive Patients (MERIT) trial. Results were compared with those obtained using the Enhanced Sensitivity Trofile Assay (ESTA), which is widely used in clinical practice. Methods. Screening plasma samples from treatment-naive patients who received Maraviroc and efavirenz in the MERIT trial were assessed. Samples were extracted, and the V3 region of HIV type 1 glycoprotein 120 was amplified in triplicate and combined in equal quantities before sequencing on a Roche/454 Genome Sequencer-FLX (n 5 859). Tropism was inferred from third variable (V3) sequences, with samples classified as non-R5 if$2% of the viral population scored #3.5 using geno2pheno. Results. Deep sequencing distinguished between responders and nonresponders to Maraviroc. Among patients identified as having R5-HIV by deep sequencing, 67% of Maraviroc recipients and 69% of efavirenz recipients had a plasma viral load ,50 copies/mL at week 48, similar to the ESTA results: 68% and 68%, respectively. Conclusions. Reanalysis of the MERIT trial using deep V3 loop sequencing indicates that, had patients originally been screened using this method, the Maraviroc arm would have likely been found to be noninferior to the efavirenz arm.
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reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the ccr5 antagonist Maraviroc utilize inhibitor bound receptor for entry
Journal of Virology, 2007Co-Authors: Mike Westby, Patrick Dorr, Julie Mori, Caroline Smithburchnell, Marilyn Lewis, Michael Mosley, Mark Stockdale, Giuseppe Ciaramella, Manos PerrosAbstract:Maraviroc is a CCR5 antagonist in clinical development as one of a new class of antiretrovirals targeting human immunodeficiency virus type 1 (HIV-1) coreceptor binding. We investigated the mechanism of HIV resistance to Maraviroc by using in vitro sequential passage and site-directed mutagenesis. Serial passage through increasing Maraviroc concentrations failed to select Maraviroc-resistant variants from some laboratory-adapted and clinical isolates of HIV-1. However, high-level resistance to Maraviroc was selected from three of six primary isolates passaged in peripheral blood lymphocytes (PBL). The SF162 strain acquired resistance to Maraviroc in both treated and control cultures; all resistant variants were able to use CXCR4 as a coreceptor. In contrast, Maraviroc-resistant virus derived from isolates CC1/85 and RU570 remained CCR5 tropic, as evidenced by susceptibility to the CCR5 antagonist SCH-C, resistance to the CXCR4 antagonist AMD3100, and an inability to replicate in CCR5 Δ32/Δ32 PBL. Strain-specific mutations were identified in the V3 loop of Maraviroc-resistant CC1/85 and RU570. The envelope-encoding region of Maraviroc-resistant CC1/85 was inserted into an NL4-3 background. This recombinant virus was completely resistant to Maraviroc but retained susceptibility to aplaviroc. Reverse mutation of gp120 residues 316 and 323 in the V3 loop (numbering from HXB2) to their original sequence restored wild-type susceptibility to Maraviroc, while reversion of either mutation resulted in a partially sensitive virus with reduced maximal inhibition (plateau). The plateaus are consistent with the virus having acquired the ability to utilize Maraviroc-bound receptor for entry. This hypothesis was further corroborated by the observation that a high concentration of Maraviroc blocks the activity of aplaviroc against Maraviroc-resistant virus.
Mary Anne Trabaud - One of the best experts on this subject based on the ideXlab platform.
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Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy with tenofovir/emtricitabine/Maraviroc/raltegravir in treatment-naive HIV patients
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: Pierre Pradat, Mary Anne Trabaud, Jacques Izopet, Jacques Durant, C. Brochier, Jacqueline Cottalorda-dufayard, François Raffi, Frédéric Lucht, Marie-claude Gagnieu, Caroline GateyAbstract:OBJECTIVE: We assessed the virological efficacy of a 6 month Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with Maraviroc/raltegravir. METHODS: HIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received Maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA \\textless50 copies/mL stopped tenofovir/emtricitabine at week (W) 24 and pursued Maraviroc/raltegravir until W48. The primary endpoint was the virological response defined by HIV-RNA \\textless50 copies/mL at W48. RESULTS: Thirty-three patients were analysed. Patients were mostly male (94%), Caucasians (91%), MSM (82%); their median age was 42 years. At baseline, median CD4 cell count was 453 cells/mm3 and HIV-RNA was 4.3 log copies/mL. All patients had CCR5-tropic viruses by genotropism and phenotropism assays. All but one patient had an HIV-RNA \\textless 50 copies/mL at W24 and entered the simplification phase. Virological success was maintained at W48 in 88% (90% CI 79%-97%) of patients. N155H mutation was detected at failure in one patient. No tropism switch was observed. Raltegravir and Maraviroc plasma exposure were satisfactory in 92% and 79% of 41 samples from 21 patients. Five severe adverse events (SAEs) were observed up to W48; none was related to the study drugs. Four patients presented grade 3 AEs; none was related to the study. No grade 4 AE was observed. No patient died. CONCLUSIONS: Maraviroc/raltegravir maintenance therapy following a 6 month induction phase with Maraviroc/raltegravir/tenofovir/emtricitabine was well tolerated and maintained virological efficacy in these carefully selected patients
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Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy with tenofovir/emtricitabine/Maraviroc/raltegravir in treatment-naive HIV patients
The Journal of antimicrobial chemotherapy, 2016Co-Authors: Pierre Pradat, Mary Anne Trabaud, Jacques Izopet, Jacques Durant, C. Brochier, Jacqueline Cottalorda-dufayard, François Raffi, Frédéric Lucht, Marie-claude Gagnieu, Caroline GateyAbstract:OBJECTIVE We assessed the virological efficacy of a 6 month Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with Maraviroc/raltegravir. METHODS HIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received Maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA
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Virological failure of patients on Maraviroc-based antiretroviral therapy
Journal of Antimicrobial Chemotherapy, 2015Co-Authors: Stéphanie Raymond, Anne Maillard, Corinne Amiel, Gilles Peytavin, Mary Anne Trabaud, Delphine Desbois, Pantxika Bellecave, Constance Delaugerre, Cathia Soulie, Anne Geneviève MarcelinAbstract:OBJECTIVES: Virological failure (VF) in patients on Maraviroc-based treatment has been associated with altered HIV tropism and resistance to Maraviroc. This multicentre study aimed to characterize VF in patients treated with Maraviroc. METHODS: We analysed 27 patients whose treatment failed between 2008 and 2011. They had been screened for HIV tropism before Maraviroc initiation using population-based V3 genotyping. HIV-1 tropism and resistance of R5 viruses to Maraviroc at VF and at baseline were determined retrospectively using an ultrasensitive recombinant virus assay (RVA). RESULTS: Viruses from 27 patients given Maraviroc on the basis of the R5 genotype were characterized at the time of treatment failure. The RVA indicated that 12 patients harboured CXCR4-using viruses and 15 (56%) had pure R5 viruses at failure. One-third of those harbouring CXCR4-using viruses (4/12) were infected with R5X4/X4 viruses according to the RVA before Maraviroc initiation. We analysed the phenotypic resistance to Maraviroc of four patients harbouring R5 viruses at failure; two harboured viruses whose maximum percentage inhibition was reduced by 65%-90%, while the other two were infected with susceptible viruses. All patients had effective concentrations of drugs. CONCLUSIONS: Half of the Maraviroc-treated patients who experienced VF harboured CXCR4-using viruses at failure, one-third of them were detected by a phenotypic method before Maraviroc initiation. Phenotypic assessment of R5 virus resistance to CCR5 antagonists at failure could help optimize antiretroviral therapy
Gary J. Muirhead - One of the best experts on this subject based on the ideXlab platform.
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assessment of the pharmacokinetics safety and tolerability of Maraviroc a novel ccr5 antagonist in healthy volunteers
British Journal of Clinical Pharmacology, 2008Co-Authors: Samantha Abel, Caroline E Ridgway, Elna Van Der Ryst, Maria C Rosario, Christine G Medhurst, Richard J Taylorworth, Gary J. MuirheadAbstract:AIMS To evaluate the pharmacokinetics, safety and tolerability of single and multiple oral doses of Maraviroc in healthy volunteers. METHODS Three double-blind, placebo-controlled, dose-escalation studies with either single or multiple doses of Maraviroc were conducted in healthy volunteers. Plasma and urine samples were collected to investigate the pharmacokinetics of Maraviroc and evaluate any changes with respect to dose and duration/frequency of dosing. Safety and toleration of Maraviroc were also assessed. RESULTS Maraviroc is rapidly absorbed following oral administration, and plasma Tmax is achieved within 0.5–4.0 h postdose. Steady-state plasma concentrations are achieved after 7 consecutive days of dosing. Although the pharmacokinetics of Maraviroc is nonproportional over the dose range studied (3–1200 mg), the degree of nonproportionality is small at clinically relevant doses. Renal clearance is approximately 10–12 l h−1 and appears unaffected by increasing Maraviroc doses. Maraviroc does not significantly modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. There were no serious adverse events in any of these studies, and doses up to 900 mg were generally well tolerated, with postural hypotension being the dose-limiting event. There was no pattern or dose relationship observed with Maraviroc with regard to laboratory abnormalities, including hepatic transaminases. No clinically significant increases in QTc were noted at clinically relevant doses. CONCLUSIONS Maraviroc is absorbed into the systemic circulation and reaches steady state by day 7 of multiple dosing. It does not significantly influence the activity of major drug-metabolizing enzymes and is well tolerated at clinically relevant doses, with most adverse events being mild or moderate.
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a novel probe drug interaction study to investigate the effect of selected antiretroviral combinations on the pharmacokinetics of a single oral dose of Maraviroc in hiv positive subjects
British Journal of Clinical Pharmacology, 2008Co-Authors: Anton L Pozniak, Caroline E Ridgway, Deborah Russell, Marta Boffito, Gary J. MuirheadAbstract:AIMS Maraviroc (UK-427 857), an antagonist of the CCR5 receptor with potent anti-HIV activity, was recently approved for use in treatment-experienced patients infected with CCR5-tropic HIV-1. The aim of this study was to evaluate the effect of selected commonly used antiretroviral therapy (ART) combinations on the pharmacokinetics of a single oral dose of Maraviroc 300 mg in HIV-positive subjects compared with historical controls. METHODS In this study, four cohorts of HIV-positive patients (n = 8 each) receiving one of the following combination therapies were recruited: cohort 1 – efavirenz + Combivir® (lamivudine/zidovudine); cohort 2 – efavirenz + didanosine + tenofovir; cohort 3 – nevirapine + lamivudine + tenofovir; cohort 4 – Kaletra® (lopinavir/ritonavir) + stavudine + lamivudine. Subjects continued on their prescribed ART and also received a single oral dose of Maraviroc 300 mg. Serial blood samples and urine for determination of Maraviroc pharmacokinetics were collected over 12 h postdose. Plasma pharmacokinetic parameters from this study were compared with historical data generated in HIV-positive subjects receiving Maraviroc monotherapy in a Phase IIa study. RESULTS A total of 29 subjects were recruited (eight each in cohorts 1–3, and five in cohort 4). The geometric mean ratios for AUC12 and Cmax for each treatment group compared with Maraviroc monotherapy were: 47% and 67% (cohort 1); 48% and 76% (cohort 2); 101% and 154% (cohort 3); and 265% and 180% (cohort 4), respectively. Tmax was similar in all treatment groups. Mean values for renal clearance ranged from 8.2 l h−1 (cohort 1) to 13.2 l h−1 (cohort 4). There were no renal clearance data collected in the comparator study. CONCLUSIONS The results of this study support those previously seen in healthy volunteer studies that showed that efavirenz reduces Maraviroc exposure, whereas lopinavir/ritonavir increases Maraviroc exposure. These data also suggest that nevirapine does not lead to a clinically significant effect on Maraviroc pharmacokinetics.
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The effects of cotrimoxazole or tenofovir co‐administration on the pharmacokinetics of Maraviroc in healthy volunteers
British Journal of Clinical Pharmacology, 2008Co-Authors: Samantha Abel, Caroline E Ridgway, Deborah Russell, Lyndsey A. Whitlock, Gary J. MuirheadAbstract:AIMS To assess the potential of cotrimoxazole and tenofovir, drugs which are inhibitors and/or substrates of renal transporters, to alter the pharmacokinetic profile of Maraviroc. METHODS Two randomized, placebo-controlled, two-way crossover studies were conducted in healthy male and female subjects. In study 1, 16 subjects, aged 18–45 years, received Maraviroc (300 mg b.i.d.) with and without cotrimoxazole (960 mg b.i.d.; 160 mg trimethoprim and 800 mg sulfamethoxazole). In study 2, 12 subjects, aged 21–45 years, received Maraviroc (300 mg b.i.d.) with and without tenofovir (300 mg q.d.). For study 1, blood was collected predose and on days 1–7. In study 2, blood was collected predose, on day 1 and days 3–7. In both studies, blood was collected at intervals up to 12 h postdose on day 7. Urine was collected on day 7, 0–12 h post morning dose. Blood and urine were analysed for Maraviroc using liquid chromatography/tandem mass spectrometry. RESULTS The geometric mean ratios for Cmax and AUC12 were 119% and 111%, respectively, for Maraviroc plus cotrimoxazole and 104% and 103%, respectively, for Maraviroc plus tenofovir, compared with Maraviroc plus placebo. Renal clearance of Maraviroc plus placebo was 8.3 l h−1 and 8.5 l h−1 and was 7.8 l h−1 for Maraviroc plus cotrimoxazole and Maraviroc plus tenofovir. There were no serious or severe adverse events or any clinically significant changes in laboratory tests, blood pressure, or electrocardiograms. CONCLUSIONS Neither cotrimoxazole nor tenofovir caused a clinically significant effect on the pharmacokinetics of Maraviroc. Maraviroc 300 mg b.i.d. was well tolerated when co-administered with either cotrimoxazole or tenofovir.
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The effects of cotrimoxazole or tenofovir co-administration on the pharmacokinetics of Maraviroc in healthy volunteers.
British journal of clinical pharmacology, 2008Co-Authors: Samantha Abel, Caroline E Ridgway, Deborah Russell, Lyndsey A. Whitlock, Gary J. MuirheadAbstract:To assess the potential of cotrimoxazole and tenofovir, drugs which are inhibitors and/or substrates of renal transporters, to alter the pharmacokinetic profile of Maraviroc. Two randomized, placebo-controlled, two-way crossover studies were conducted in healthy male and female subjects. In study 1, 16 subjects, aged 18-45 years, received Maraviroc (300 mg b.i.d.) with and without cotrimoxazole (960 mg b.i.d.; 160 mg trimethoprim and 800 mg sulfamethoxazole). In study 2, 12 subjects, aged 21-45 years, received Maraviroc (300 mg b.i.d.) with and without tenofovir (300 mg q.d.). For study 1, blood was collected predose and on days 1-7. In study 2, blood was collected predose, on day 1 and days 3-7. In both studies, blood was collected at intervals up to 12 h postdose on day 7. Urine was collected on day 7, 0-12 h post morning dose. Blood and urine were analysed for Maraviroc using liquid chromatography/tandem mass spectrometry. The geometric mean ratios for C(max) and AUC(12) were 119% and 111%, respectively, for Maraviroc plus cotrimoxazole and 104% and 103%, respectively, for Maraviroc plus tenofovir, compared with Maraviroc plus placebo. Renal clearance of Maraviroc plus placebo was 8.3 l h(-1) and 8.5 l h(-1) and was 7.8 l h(-1) for Maraviroc plus cotrimoxazole and Maraviroc plus tenofovir. There were no serious or severe adverse events or any clinically significant changes in laboratory tests, blood pressure, or electrocardiograms. Neither cotrimoxazole nor tenofovir caused a clinically significant effect on the pharmacokinetics of Maraviroc. Maraviroc 300 mg b.i.d. was well tolerated when co-administered with either cotrimoxazole or tenofovir.
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Effects of CYP3A4 inhibitors on the pharmacokinetics of Maraviroc in healthy volunteers.
British journal of clinical pharmacology, 2008Co-Authors: Samantha Abel, Caroline E Ridgway, Deborah Russell, Richard J Taylor-worth, Gary J. MuirheadAbstract:To evaluate the influence of cytochrome P450 (CYP) 3A4 inhibitors on the clinical pharmacokinetics of Maraviroc, a novel CCR5 antagonist. Four open-label, randomized, placebo-controlled studies were conducted in healthy subjects to assess the effect of separate and distinct combinations of CYP3A4 inhibitors on the steady-state pharmacokinetics of Maraviroc. Study 1 was a two-way crossover study investigating the influence of saquinavir (SQV; 1200 mg t.i.d.) and ketoconazole (400 mg q.d.) on the pharmacokinetics of Maraviroc (100 mg b.i.d.). All subjects received Maraviroc for 7 days in both study periods. Cohort 1 subjects also received SQV or placebo and cohort 2 subjects also received ketoconazole or placebo. Study 2 was a parallel-group study including four treatment groups investigating the effects of ritonavir-boosted lopinavir (LPV/r; 400 mg/100 mg b.i.d.), ritonavir-boosted saquinavir (SQV/r; 1000 mg/100 mg b.i.d.), and low-dose ritonavir (RTV; 100 mg b.i.d.) on the steady-state pharmacokinetics of Maraviroc (100 mg b.i.d.), and exploring whether Maraviroc dose adjustment can compensate for interaction effects. Treatment lasted 28 days and comprised three distinct phases: (i) Maraviroc alone on days 1-7; (ii) Maraviroc + interactant on days 8-21; and (iii) Maraviroc (adjusted dose) + interactant on days 22-28. Study 3 was a two-way crossover study investigating the effects of atazanavir (ATZ; 400 mg q.d.) and ritonavir-boosted atazanavir (ATZ/r; 300 mg/100 mg b.i.d.) on the pharmacokinetics of Maraviroc (300 mg b.i.d.). All subjects received Maraviroc on days 1-14 of both study periods. Subjects also received ATZ on days 1-7 and ATZ/r on days 8-14 of one treatment period, and placebo on days 1-14 of the other treatment period. Study 4 was a two-way crossover study investigating the effects of ritonavir-boosted tipranavir (TPV/r; 500 mg/200 mg b.i.d.) on the pharmacokinetics of Maraviroc (150 mg b.i.d.). Subjects received Maraviroc plus TPV/r or placebo on days 1-8. All of the drugs/drug combinations tested (except for TPV/r) increased Maraviroc exposure, albeit to different degrees of magnitude. SQV/r caused the largest increase in Maraviroc exposure (8.3-fold increase in AUC(tau)), whereas RTV caused the smallest increase in Maraviroc exposure (2.6-fold increase in AUC(tau)). Downward adjustment of the Maraviroc dose in study 2 during co-administration of HIV protease inhibitors was able to compensate for the interactions. TPV/r had no clinically relevant effect on Maraviroc exposure at steady state. There were no treatment-related serious adverse events or discontinuations due to adverse events in any of the studies, and most adverse events were mild or moderate in severity and resolved without intervention. Potent CYP3A4 inhibitors, including ketoconazole and protease inhibitors (except TPV/r), increase Maraviroc exposure. Downward adjustment of the Maraviroc dose during co-administration with protease inhibitors can compensate for the interaction. TPV/r does not affect the steady-state pharmacokinetics of Maraviroc, and hence no dose adjustment would be warranted.