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Drugs of Today (Barcelona, Spain : 1998) Nov 2007Maraviroc, first in a new pharmacological class of antiretroviral agents known as CCR5 antagonists, has been approved by the U.S. Food and Drug Administration for the... (Review)
Review
Maraviroc, first in a new pharmacological class of antiretroviral agents known as CCR5 antagonists, has been approved by the U.S. Food and Drug Administration for the treatment of HIV-infected adult patients who are infected with only CCR5-tropic HIV-1 virus and who have HIV-1 strains resistant to multiple antiretroviral agents. Maraviroc has demonstrated in vitro activity against a wide range of CCR5 tropic clinical isolates, including those resistant to the four currently existing drug classes of antiretroviral agents. In the two pivotal phase III studies, MOTIVATE-1 and -2, maraviroc, in combination with optimized background therapy (OBT), demonstrated superior virologic and immunologic treatment outcomes than OBT alone in treatment-experienced patients infected with CCR5-tropic HIV-1. In these studies, maraviroc also demonstrated acceptable safety and tolerability profiles with adverse events and discontinuation rates in general comparable to those noted in the placebo arms.
Topics: Animals; Controlled Clinical Trials as Topic; Cyclohexanes; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; Female; Food-Drug Interactions; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Maraviroc; Triazoles
PubMed: 18174962
DOI: 10.1358/dot.2007.43.11.1131763 -
Polski Merkuriusz Lekarski : Organ... Oct 2021According to International Association for the Study of Pain (IASP) neuropathic pain is defined as a pain caused by a lesion or disease of the somatosensory nervous... (Review)
Review
According to International Association for the Study of Pain (IASP) neuropathic pain is defined as a pain caused by a lesion or disease of the somatosensory nervous system. In general population 7-8% adults suffer from chronic pain with neuropathic characteristic. The most common causes include: lumbar radiculopathy, postherpetic neuropathy, HIV infection, autoimmune diseases (multiple sclerosis), metabolic diseases (diabetic neuropathy), stroke or spinal cord injury. Current pharmacotherapy of neuropathic pain has insufficient effectiveness, so comprehension of neuropathic pain mechanism is necessary for research of new therapeutic methods. In the study we verify the analgesic effect of maraviroc (antagonist of the chemokine receptor - CCR5) and its potential role in the treatment of neuropathic pain. In the study we focused on dependency between opioid and chemokine receptors, because of similar structure between this receptors occurs cross-desensitization phenomenon. Chemokine antagonist maraviroc belongs to a group of entry inhibitors, antiretroviral drug. It enhances analgesic properties of opioids by inhibition of crossdesensitization of opioid's receptor. Application of maraviroc with morphine can reduce effective dosage of morphine 2,3 fold. Moreover, research show that prophylactic administration of maraviroc without opioid analgesics suppresses development of neuropathic pain symptoms. It has influence on glial phenotype, decreases secretion of proinflammatory cytokines and increases anti-inflammatory cytokine secretion. Furthermore it decreases expression of chemikine receptor mRNA and chemikine ligand's secreted by microglia and astrocytes as a result of nerve injury. We conclude that maraviroc has immunomodulatory properties, potentiates opioid analgesics effect, and can be used in neuropathic pain therapy as a potential co-analgesic.
Topics: Analgesics, Opioid; HIV Infections; Humans; Maraviroc; Morphine; Neuralgia
PubMed: 34800029
DOI: No ID Found -
The Lancet. Haematology Mar 2019Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate... (Comparative Study)
Comparative Study Randomized Controlled Trial
Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with...
BACKGROUND
Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial.
METHODS
In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m intravenous bolus on day 1 and 10 mg/m intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037.
FINDINGS
Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively).
INTERPRETATION
Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial.
FUNDING
US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.
Topics: Aged; Bortezomib; Cyclophosphamide; Drug Interactions; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Maraviroc; Methotrexate; Middle Aged; Mycophenolic Acid; Tacrolimus; Transplantation Conditioning
PubMed: 30824040
DOI: 10.1016/S2352-3026(18)30221-7 -
The Pediatric Infectious Disease Journal Nov 2022Treatment and prophylaxis options for neonatal HIV are limited. This study aimed to develop a population pharmacokinetic model to characterize the disposition of...
BACKGROUND
Treatment and prophylaxis options for neonatal HIV are limited. This study aimed to develop a population pharmacokinetic model to characterize the disposition of maraviroc in neonates to inform dosing regimens and expand available options.
METHODS
Using maraviroc concentrations from neonates who received either a single dose or multiple doses of 8 mg/kg of maraviroc in the first 6 weeks of life, a population pharmacokinetic model was developed to determine the effects of age, sex, maternal efavirenz exposure and concomitant ARV therapy on maraviroc disposition. The final model was used in Monte Carlo simulations to generate expected exposures with recommended dosing regimens.
RESULTS
A total of 396 maraviroc concentrations, collected in the first 4 days of life, at 1 week, at 4 weeks and at 6 weeks, from 44 neonates were included in the analysis. After allometrically scaling for weight, age less than 4 days was associated with a 44% decreased apparent clearance compared with participants 7 days to 6 weeks of life. There were no differences identified in apparent clearance or volume of distribution from ages 7 days to 6 weeks, sex, maternal efavirenz exposure or concomitant nevirapine therapy. Monte Carlo simulations with FDA-approved weight band dosing resulted in the majority of simulated patients (84.3%) achieving an average concentration of ≥75 ng/mL.
CONCLUSIONS
While maraviroc apparent clearance is decreased in the first few days of life, the current FDA-approved maraviroc weight band dosing provides maraviroc exposures for neonates in the first 6 weeks of life, which were consistent with adult maraviroc exposure range. Maraviroc provides another antiretroviral treatment option for very young infants.
Topics: Adult; Alkynes; Benzoxazines; Cyclopropanes; HIV Infections; Humans; Infant; Infant, Newborn; Maraviroc; Nevirapine
PubMed: 35980827
DOI: 10.1097/INF.0000000000003665 -
American Journal of Health-system... Apr 2009The mechanism of action, pharmacology, pharmacokinetics, clinical efficacy, drug interactions, adverse effects, dosage and administration, cost, and role in therapy of... (Review)
Review
PURPOSE
The mechanism of action, pharmacology, pharmacokinetics, clinical efficacy, drug interactions, adverse effects, dosage and administration, cost, and role in therapy of maraviroc are reviewed.
SUMMARY
Maraviroc is the first CCR5 coreceptor antagonist to receive marketing approval from the Food and Drug Administration (FDA) for the treatment of CCR5-tropic human immunodeficiency virus (HIV) infection as part of an optimized antiretroviral regimen in treatment-experienced patients. As 50% or more of treatment-experienced patients may be infected with CXCR4-tropic virus, a tropism assay should be performed before initiating maraviroc therapy. The majority of evidence supporting maraviroc's use comes from two studies of HIV-infected, treatment-experienced patients. Pooled analysis from these two studies revealed that twice-daily maraviroc decreased HIV-1 RNA by 1.84 log copies/mL, compared with 0.78 log copy/mL with placebo. Forty-six percent of subjects attained an HIV-1 RNA concentration of <50 copies/mL, compared with only 17% with placebo. In a trial of treatment-naive HIV-infected individuals, maraviroc failed to show noninferiority to efavirenz. Maraviroc is metabolized by cytochrome P-450 isoenzyme 3A4 and is subject to interactions with inhibitors and inducers of that isoenzyme, such as the protease inhibitors (except tipranavir), efavirenz, and rifampin. Resistance has been reported with maraviroc, but specific mechanisms are still poorly understood. The most common adverse effects reported with maraviroc were diarrhea, nausea, fatigue, and headache.
CONCLUSION
Available data support the use of maraviroc, the first CCR5 antagonist to receive FDA marketing approval, as part of an optimized antiretroviral regimen in treatment-experienced patients infected with CCR5-tropic HIV.
Topics: Animals; CCR5 Receptor Antagonists; Cyclohexanes; Disease Management; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Receptors, CCR5; Triazoles
PubMed: 19336831
DOI: 10.2146/ajhp080206 -
Expert Opinion on Drug Safety Sep 2008Maraviroc represents the first licensed CCR5 co-receptor antagonist from the new antiretroviral (ARV) drug-class of entry inhibitors. (Review)
Review
BACKGROUND
Maraviroc represents the first licensed CCR5 co-receptor antagonist from the new antiretroviral (ARV) drug-class of entry inhibitors.
RESULTS
Results of Phase III clinical trials in three-drug-class experienced patients have presented maraviroc as a promising new agent for treatment of HIV-1-infection. Maraviroc (b.i.d./q.d.) + optimised background therapy (OBT) provided significantly superior virological control and CD4+ increases compared with placebo + OBT at 48 weeks, with no clinically relevant differences in the safety profile between the maraviroc and the placebo groups.
CONCLUSION
Its proven efficacy in cases of virological failure and three-class ARV-drug resistance is a major benefit of maraviroc compared to the so far commercially available drugs from existing (non-) nucleoside reverse transcriptase inhibitors ([N]NRTI) and protease inhibitors drug-classes, particularly in times of increasing ARV drug resistance. Moreover, the tolerability profile of the drug makes maraviroc particularly appealing as a combination partner in ARV therapy. As maraviroc however is only effective against CCR5-tropic HIV-1, tropism testing is required before initiation of treatment. Tropism-testing possibilities are still limited, and presently only possible at high costs. The main constraints to be considered in the clinical use of maraviroc are the declining number of CCR5-tropic patients with advanced HIV-1 disease owing to tropism-shifting and the occurrence of drug-drug interactions, requiring regular dose adaptations. The true clinical value of this new substance and its future role in the treatment of HIV-1-infection remains to be defined by further data from clinical studies and by future experiences of practitioners.
Topics: CCR5 Receptor Antagonists; Clinical Trials, Phase III as Topic; Cyclohexanes; Drug Resistance, Multiple, Viral; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Triazoles
PubMed: 18759708
DOI: 10.1517/14740338.7.5.559 -
Clinical Therapeutics Jul 2008The emergence of viral resistance is one of the greatest challenges in the treatment of HIV infection. Maraviroc is the first member of a new class of antiretroviral... (Review)
Review
BACKGROUND
The emergence of viral resistance is one of the greatest challenges in the treatment of HIV infection. Maraviroc is the first member of a new class of antiretroviral medications, the CCR5-receptor antagonists. It is approved by the US Food and Drug Administration (FDA) for use in combination with other antiretroviral agents in treatment-experienced patients infected with multidrug-resistant, CCR5-tropic HIV-1.
OBJECTIVE
This article provides an overview of the pharmacology, efficacy, and tolerability of maraviroc in the treatment of HIV-1 infection.
METHODS
Relevant information was identified through a search of MEDLINE (January 2000-May 2008) using the terms maraviroc, UK-427,857, and CCR5-receptor antagonist. Also consulted were abstracts from the International AIDS Society Conference, the Conference on Retroviruses and Opportunistic Infections, and other relevant scientific meetings. Additional publications were found by searching the reference lists of the identified articles and the FDA Web site.
RESULTS
Maraviroc is a selective, reversible, small-molecule CCR5-receptor antagonist. In vitro, it has potent anti-HIV-1 activity, with a mean 90% inhibitory concentration of 2.0 nmol/L. It is widely distributed, with a V(d) of approximately 194 L. Maraviroc is moderately metabolized in the liver (65.3%), primarily via the cytochrome P450 3A4 isozyme. It has an elimination t(1/2) of 15.9 to 22.9 hours. Until more data are available, maraviroc should be avoided in patients with severe hepatic insufficiency; dose adjustment does not appear to be necessary on the basis of age, sex, or renal function. In 2 Phase IIb/III studies, maraviroc 300 mg PO QD or BID was found to be more efficacious than placebo in reducing the viral load at 48 weeks in treatment-experienced, CCR5-tropic HIV-1-infected patients receiving an optimized background regimen (difference vs placebo-QD arm: -0.89 log(10) copies/mL [97.5% CI, -1.17 to -0.62]; BID arm: -1.05 log(10) copies/mL [97.5% CI, -1.33 to -0.78]). The proportion of patients with a viral load < 50 copies/mL was 43.2% in the QD arm and 45.5% in the BID arm, compared with 16.7% in the placebo arm (P < 0.001, both treatment arms vs placebo). In treatment-naive patients infected with CCR5-tropic virus only, maraviroc 300 mg PO BID was not noninferior to oral efavirenz 600 mg QD (difference = -4.2%; lower bound of the 1-sided 97.5% CI, -10.9 [predefined statistical cutoff for noninferiority, -10]). Maraviroc was generally well tolerated in clinical trials. The most frequently reported (> or = 5%) adverse events were upper respiratory tract infection (20.0%), cough (12.7%), pyrexia (12.0%), rash (9.6%), musculoskeletal complaints (8.7%), gastrointestinal and abdominal pain (8.2%), dizziness (8.2%), appetite disorders (7.3%), insomnia (7.0%), herpes infection (6.8%), sinusitis (6.3%), joint complaints (6.1%), bronchitis (5.9%), and constipation (5.4%). The recommended dose of maraviroc differs based on concomitant medications, ranging from 150 to 600 mg BID.
CONCLUSION
When used in combination with other antiretroviral agents, maraviroc appears to be a promising agent for treatment-experienced patients infected with multidrug-resistant, CCR5-tropic HIV-1.
Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Cyclohexanes; Drug Interactions; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Maraviroc; Triazoles
PubMed: 18691983
DOI: 10.1016/s0149-2918(08)80048-3 -
AIDS (London, England) Mar 2021
Topics: CCR5 Receptor Antagonists; Cyclohexanes; HIV Fusion Inhibitors; HIV Infections; Humans; Maraviroc; Thyrotoxicosis
PubMed: 33620876
DOI: 10.1097/QAD.0000000000002754 -
AIDS (London, England) Mar 2021The aim of this study was to evaluate safety and pharmacokinetics of maraviroc administered with standard antiretroviral prophylaxis to HIV-1 exposed infants and to...
OBJECTIVE
The aim of this study was to evaluate safety and pharmacokinetics of maraviroc administered with standard antiretroviral prophylaxis to HIV-1 exposed infants and to determine the appropriate dose of maraviroc during the first 6 weeks of life.
DESIGN
A phase I, multicentre, open-label study enrolling two sequential cohorts.
METHODS
IMPAACT 2007 participants enrolled by day 3 of life and were stratified by exposure to maternal efavirenz. Cohort 1 participants received two single 8 mg/kg maraviroc doses 1 week apart with pharmacokinetic sampling after each dose. Cohort 2 participants received 8 mg/kg maraviroc twice daily through 6 weeks of life with pharmacokinetic sampling at weeks 1 and 4. Maraviroc exposure target was Cavg at least 75 ng/ml. Laboratory and clinical evaluations assessed safety.
RESULTS
Fifteen Cohort 1 and 32 Cohort 2 HIV-exposed neonates were enrolled (median gestational age 39 weeks, 51% male). All 13 evaluable Cohort 1 infants met the pharmacokinetic target. Median exposure for the 25 evaluable Cohort 2 infants met the pharmacokinetic target but variability was high, with 17-33% of infants below target at Weeks 1 and 4. Pharmacokinetic target achievement was similar between efavirenz exposure strata. No Grade 3+ toxicities, early study or treatment discontinuations due to maraviroc occurred.
CONCLUSION
Median maraviroc exposure met the Cavg target in neonates receiving 8 mg/kg twice daily, although exposures were variable. Maternal efavirenz use did not impact maraviroc exposure and no discontinuations were due to maraviroc toxicity/intolerance. No infants acquired HIV-1 infection during follow-up. Maraviroc 8 mg/kg twice daily appears well tolerated during the first 6 weeks of life.
Topics: Adult; Anti-Retroviral Agents; Cohort Studies; Cyclohexanes; Female; HIV Infections; HIV-1; Humans; Infant, Newborn; Male; Maraviroc
PubMed: 33252481
DOI: 10.1097/QAD.0000000000002762 -
International Immunopharmacology Mar 2020It has been shown that the blockade of chemokine receptor type 5 can dampen inflammatory reaction within the central nervous system (CNS). In the present study, we...
It has been shown that the blockade of chemokine receptor type 5 can dampen inflammatory reaction within the central nervous system (CNS). In the present study, we utilized maraviroc, a potent antagonist o CCR5, to examine whether this drug can mitigate neuroinflammation in the spinal cord of mice induced by experimental autoimmune encephalitis (EAE), considered a murine model of multiple sclerosis (MS). For this aim, mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55), followed by pertussis toxin to induce paralysis in EAE mice. The animals intraperitoneally received various doses of maraviroc (5, 25, and 50 mg/kg body weight) when the early clinical signs of EAE appeared. The results demonstrated that the administration of maraviroc led to a marked decrease in the clinical score and improvement in behavioral motor functions. Moreover, our finding indicated that the administration of maraviroc significantly attenuates the infiltration of inflammatory cells to the spinal cord, microgliosis, astrogliosis, pro-inflammatory cytokines, and cell death in EAE mice. The flow cytometry data indicated that a decreased number of CD4+ and CD8+ T cells in the peripheral blood of mice with EAE without affecting the number of T regulatory cells (CD4 + CD25+ forkhead box protein 3+). Finally, it seems that maraviroc is well-tolerated, and targeting CCR5 could open up a new horizon in the treatment of MS.
Topics: Animals; CCR5 Receptor Antagonists; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Caspase 3; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Lymphocyte Count; Maraviroc; Mice; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Pertussis Toxin; Proto-Oncogene Proteins c-bcl-2; Receptors, CCR5; Signal Transduction; Spinal Cord; T-Lymphocytes, Regulatory; bcl-2-Associated X Protein
PubMed: 32007705
DOI: 10.1016/j.intimp.2019.106138