-
Clinical and Translational Science Nov 2020Maribavir is an orally bioavailable benzimidazole riboside in clinical development for treatment of cytomegalovirus infection in patients who undergo transplantation....
Maribavir is an orally bioavailable benzimidazole riboside in clinical development for treatment of cytomegalovirus infection in patients who undergo transplantation. Maribavir was evaluated in a thorough QT (TQT) study to determine any effects on cardiac repolarization. The effect of maribavir 100 and 1,200 mg oral doses on the baseline-adjusted and placebo-adjusted corrected QT (QTc) interval (delta delta QTc (ddQTc)) and other electrocardiogram (ECG) parameters was assessed in a randomized, phase I, placebo-controlled, four-period crossover study in healthy participants (men and women ages 18-50 years). Additionally, maribavir pharmacokinetics, safety, and tolerability were investigated. Moxifloxacin (400 mg) was used as a positive control to demonstrate the study's ability to detect QT prolongation. Digital 12-lead Holter ECG monitoring was performed over 22 hours following study drug administration. Individual, Fridericia's, and Bazett's QTc intervals were calculated. Of 52 randomized participants (29 ± 8.1 years old; 31 men (60%)), 50 (96%) completed the study. For both 100-mg and 1200-mg doses of maribavir, analysis of ddQTc demonstrated that the upper bound of the two-sided 90% confidence interval was below the 10-ms threshold at all time points. The concentration-effect analysis demonstrated no relationship between ddQTc and plasma concentrations of maribavir (and its metabolite). There were no clinically meaningful changes in heart rate and systolic blood pressure. The most common adverse event was dysgeusia; no serious adverse events were reported. This TQT study demonstrated that maribavir did not have impact on cardiac repolarization.
Topics: Administration, Oral; Adolescent; Adult; Antiviral Agents; Benzimidazoles; Blood Pressure; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Dysgeusia; Electrocardiography; Female; Healthy Volunteers; Heart Rate; Humans; Long QT Syndrome; Male; Middle Aged; Moxifloxacin; Ribonucleosides; Young Adult
PubMed: 32506738
DOI: 10.1111/cts.12814 -
CPT: Pharmacometrics & Systems... May 2023Maribavir was approved by the US Food and Drug Administration for the treatment of patients aged ≥12 years and weighing ≥35 kg with posttransplant...
Population pharmacokinetic modeling and simulation of maribavir to support dose selection and regulatory approval in adolescents with posttransplant refractory cytomegalovirus.
Maribavir was approved by the US Food and Drug Administration for the treatment of patients aged ≥12 years and weighing ≥35 kg with posttransplant cytomegalovirus infection/disease refractory (with/without resistance) to valganciclovir, ganciclovir, cidofovir, or foscarnet, with an oral dose of 400 mg twice daily. With no pediatric clinical data available and difficulty in trial recruitment, population pharmacokinetic modeling and simulations were conducted to predict the pharmacokinetics and inform maribavir dosing in adolescents.
Topics: United States; Humans; Adolescent; Cytomegalovirus; Antiviral Agents; Ganciclovir; Cytomegalovirus Infections; Benzimidazoles; Ribonucleosides
PubMed: 36789522
DOI: 10.1002/psp4.12943 -
Current Opinion in Organ Transplantation Apr 2024Human cytomegalovirus (CMV) continues to be the most important infectious complication following solid organ transplantation (SOT). (Review)
Review
PURPOSE OF REVIEW
Human cytomegalovirus (CMV) continues to be the most important infectious complication following solid organ transplantation (SOT).
RECENT FINDINGS
Universal prophylaxis and preemptive therapy are the most adopted strategies for prevention of CMV disease globally. Prophylaxis with valganciclovir is the most widely used approach to CMV prevention, however leukopenia and late onset CMV disease after discontinuation of prophylaxis requires new strategies to prevent this complication. The use of assays detecting CMV-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. Letermovir has been recently approved for prophylaxis in kidney transplant recipients. CMV-RNAemia used together with CMV-DNAemia in the viral surveillance of CMV infection provides accurate information on viral load kinetics, mostly in patients receiving letermovir prophylaxis/therapy. The development of refractory and resistant CMV infection remains a major challenge and a new treatment with maribavir is currently available. In the present paper we will review the most recent advances in prevention and treatment of CMV diseases in SOT recipients.
SUMMARY
Recent findings, summarized in the present paper, may be useful to optimize prevention and treatment of CMV infection in SOT.
Topics: Humans; Antiviral Agents; Cytomegalovirus Infections; Valganciclovir; Transplant Recipients; Organ Transplantation; Acetates; Quinazolines
PubMed: 38288947
DOI: 10.1097/MOT.0000000000001139 -
Antiviral Research Apr 2020Cytomegalovirus (CMV) drug resistance mutation maps are updated with recent information for polymerase inhibitors, the terminase inhibitor letermovir and the UL97 kinase... (Review)
Review
Cytomegalovirus (CMV) drug resistance mutation maps are updated with recent information for polymerase inhibitors, the terminase inhibitor letermovir and the UL97 kinase inhibitor maribavir. Newly mapped mutations and their phenotypes provide more detail on cross-resistance properties and suggest the need to expand the CMV gene regions covered in diagnostic testing. Next-generation deep sequencing technology offers a more sensitive, higher resolution view of emerging antiviral resistance and is recommended for use in clinical trials. Issues of standardization and diagnostic utility in comparison with traditional Sanger sequencing remain unresolved. Quality control is important for the accurate and reproducible detection of mutant viral populations in clinical specimens.
Topics: Antiviral Agents; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Multiple, Viral; Genotype; Genotyping Techniques; High-Throughput Nucleotide Sequencing; Humans; Mutation; Viral Proteins
PubMed: 31940472
DOI: 10.1016/j.antiviral.2020.104711 -
Antimicrobial Agents and Chemotherapy Apr 2006Maribavir (1263W94, VP-41263) is an oral anticytomegalovirus agent under clinical development. The pharmacokinetics and safety of maribavir and the effects of maribavir... (Randomized Controlled Trial)
Randomized Controlled Trial
Maribavir pharmacokinetics and the effects of multiple-dose maribavir on cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-acetyltransferase-2, and xanthine oxidase activities in healthy adults.
Maribavir (1263W94, VP-41263) is an oral anticytomegalovirus agent under clinical development. The pharmacokinetics and safety of maribavir and the effects of maribavir on the activities of cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) were evaluated in a randomized, double-blind, placebo-controlled study. Twenty healthy subjects received a five-drug phenotyping cocktail of caffeine (CYP 1A2, NAT-2, XO), warfarin plus vitamin K (CYP 2C9), omeprazole (CYP 2C19), dextromethorphan (CYP 2D6), and midazolam (CYP 3A) 4 days before and after 7 days of treatment with maribavir at 400 mg twice daily (16 subjects) or placebo (4 subjects) for 10 days. Maribavir did not affect the CYP 1A2, CYP 2C9, CYP 3A, NAT-2, or XO activities. Bioequivalence was not demonstrated for CYP 2C19 and CYP 2D6, suggesting a decrease or inhibition of CYP 2C19 and CYP 2D6 activities. The pharmacokinetics of maribavir following a single dose and after 10 days of treatment were similar, with minimal accumulation at steady state. Maribavir was safe and well tolerated. Taste disturbance was the most frequently reported adverse event. These results will further guide evaluation of the drug interaction potential and clinical development of maribavir.
Topics: Adult; Antiviral Agents; Aryl Hydrocarbon Hydroxylases; Arylamine N-Acetyltransferase; Benzimidazoles; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Double-Blind Method; Drug Interactions; Humans; Mixed Function Oxygenases; Ribonucleosides; Therapeutic Equivalency; Xanthine Oxidase
PubMed: 16569820
DOI: 10.1128/AAC.50.4.1130-1135.2006 -
Current Hematologic Malignancy Reports Apr 2020CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often... (Review)
Review
PURPOSE OF REVIEW
CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often limited by toxicities and resistance. Agents with novel mechanisms and favorable toxicity profiles are critically needed. We review recent developments in CMV antivirals and immune-based approaches to mitigating CMV infection.
RECENT FINDINGS
Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, is currently in two phase 3 treatment studies. Adoptive immunotherapy using third-party T cells has proven safe and effective in preliminary studies. Vaccine development continues, with several promising candidates currently under study. No longer limited to DNA polymerase inhibitors, the prevention and treatment of CMV infections in the HCT recipient is a rapidly evolving field which should translate into improvements in CMV-related outcomes.
Topics: Animals; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Drug Resistance, Viral; Foscarnet; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Immunotherapy; Immunotherapy, Adoptive; Molecular Targeted Therapy; Opportunistic Infections; Risk Factors; T-Lymphocytes; Treatment Outcome
PubMed: 31981100
DOI: 10.1007/s11899-020-00557-6 -
Antimicrobial Agents and Chemotherapy May 2008Maribavir, an oral antiviral drug with activity against cytomegalovirus, is currently undergoing studies to assess its efficacy and safety as cytomegalovirus prophylaxis... (Randomized Controlled Trial)
Randomized Controlled Trial
Maribavir, an oral antiviral drug with activity against cytomegalovirus, is currently undergoing studies to assess its efficacy and safety as cytomegalovirus prophylaxis following stem cell or solid organ transplantation. The main objective of this study was to assess the effects of oral ketoconazole, a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) isoenzyme, on the pharmacokinetics of maribavir. This was an open-label crossover study with 20 healthy adults. Subjects were administered a single dose of maribavir at 400 mg. After a washout period, subjects received a single dose of ketoconazole at 400 mg followed by a single dose of maribavir. Blood samples were collected for each drug sequence, and pharmacokinetic parameters for maribavir and its principal metabolite, VP 44469, were determined. Safety was evaluated by physical examination, clinical laboratory testing, 12-lead electrocardiogram, and monitoring for adverse events. Ketoconazole moderately reduced the clearance of both maribavir and VP 44469; oral clearance values were 35% and 13% lower, respectively, for maribavir-plus-ketoconazole treatment than for maribavir alone. Based on the assumption of complete inhibition of CYP3A4 activity, CYP3A4 is responsible for 35% of the overall clearance of maribavir. Treatment was generally well tolerated. The most-common adverse event was dysgeusia (taste disturbance), reported by nine (47%) and seven (35%) subjects in the maribavir alone and maribavir-plus-ketoconazole groups, respectively. The pharmacokinetic findings, in combination with the acceptable tolerability within the maribavir and maribavir-plus-ketoconazole treatment groups, suggest that no dose adjustment of maribavir is necessary when coadministered with CYP3A4 inhibitors or substrates.
Topics: Adolescent; Adult; Antiviral Agents; Area Under Curve; Benzimidazoles; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Ketoconazole; Middle Aged; Ribonucleosides
PubMed: 18316526
DOI: 10.1128/AAC.00951-07 -
Expert Review of Hematology Jun 2016Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared... (Review)
Review
Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared complication, still associated with significant morbidity and mortality. Today, first line treatment of CMV infection/reactivation is still based on dated antiviral compounds Ganciclovir (GCV), Foscarnet (FOS) and Cidofovir (CDF) with their burdensome weight of side effects. Maribavir (MBV), Letermovir (LMV) and Brincidofovir (BDF) are three new promising anti-CMV drugs without myelosuppressive properties or renal toxic effects that are under investigation in randomized phase II and III trials. Adoptive T-cell therapy (ATCT) in CMV infection possesses a strong rationale, demonstrated by several proof of concept studies; its feasibility is currently under investigation by clinical trials. ATCT from third-party and naïve donors could meet the needs of HSCT recipients of seronegative donors and cord blood grafts. In selected patients such as recipients of T-cell depleted grafts, ATCT, based on CMV-specific host T-cells reconstitution kinetics, would be of value in the prophylactic and/or preemptive CMV treatment. Vaccine-immunotherapy has the difficult task to reduce the incidence of CMV reactivation/infection in highly immunocompromised HSCT patients. Newer notions on CMV biology may represent the base to flush out the Troll of transplantation.
Topics: Animals; Antiviral Agents; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Drug Resistance, Viral; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; T-Lymphocytes; Transplantation, Homologous; Treatment Outcome
PubMed: 27043241
DOI: 10.1080/17474086.2016.1174571 -
Viruses Jul 2023Solid organ transplant recipients (SOTRs) are at high risk of human herpesvirus (HHV)-related morbidity and mortality due to the use of immunosuppressive therapy. We aim... (Review)
Review
Solid organ transplant recipients (SOTRs) are at high risk of human herpesvirus (HHV)-related morbidity and mortality due to the use of immunosuppressive therapy. We aim to increase awareness and understanding of HHV disease burden in SOTRs by providing an overview of current prevention and management strategies as described in the literature and guidelines. We discuss challenges in both prevention and treatment as well as future perspectives.
Topics: Humans; Organ Transplantation; Herpesviridae Infections; Herpesvirus 6, Human; Herpes Simplex; Transplant Recipients
PubMed: 37515280
DOI: 10.3390/v15071595 -
Cancers Jun 2018Epstein⁻Barr virus (EBV) infects up to 95% of the adult human population, with primary infection typically occurring during childhood and usually asymptomatic....
Epstein⁻Barr virus (EBV) infects up to 95% of the adult human population, with primary infection typically occurring during childhood and usually asymptomatic. However, EBV can cause infectious mononucleosis in approximately 35⁻50% cases when infection occurs during adolescence and early adulthood. Epstein⁻Barr virus is also associated with several B-cell malignancies including Burkitt lymphoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disease. A number of antiviral drugs have proven to be effective inhibitors of EBV replication, yet have resulted in limited success clinically, and none of them has been approved for treatment of EBV infections.
PubMed: 29899236
DOI: 10.3390/cancers10060197