-
The Medical Letter on Drugs and... Nov 2022
Topics: Humans; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole
PubMed: 36397194
DOI: No ID Found -
Journal of Clinical Pharmacology May 2024Maribavir, an orally available antiviral agent, has been approved in multiple countries for the treatment of patients with refractory post-transplant cytomegalovirus...
Maribavir, an orally available antiviral agent, has been approved in multiple countries for the treatment of patients with refractory post-transplant cytomegalovirus (CMV) infection and/or disease. Maribavir is primarily metabolized by CYP3A4; coadministration with CYP3A4 inducers and inhibitors may significantly alter maribavir exposure, thereby affecting its efficacy and safety. The effect of CYP3A4 inducers and inhibitors on maribavir exposure was evaluated based on a drug-drug interaction (DDI) study and physiologically-based pharmacokinetic (PBPK) modeling. The effect of rifampin (a strong inducer of CYP3A4 and moderate inducer of CYP1A2), administered at a 600 mg dose once daily, on maribavir pharmacokinetics was assessed in a clinical phase 1 DDI study in healthy participants. A full PBPK model for maribavir was developed and verified using in vitro and clinical pharmacokinetic data from phase 1 studies. The verified PBPK model was then used to simulate maribavir DDI interactions with various CYP3A4 inducers and inhibitors. The DDI study results showed that coadministration with rifampin decreased the maribavir maximum plasma concentration (C), area under the plasma concentration-time curve (AUC), and trough concentration (C) by 39%, 60%, and 82%, respectively. Based on the results from the clinical DDI study, the coadministration of maribavir with rifampin is not recommended. The PBPK model did not predict a clinically significant effect of CYP3A4 inhibitors on maribavir exposure; however, it predicted that strong or moderate CYP3A4 inducers, including carbamazepine, efavirenz, phenobarbital, and phenytoin, may reduce maribavir exposure to a clinically significant extent, and may prompt the consideration of a maribavir dosing increase, in accordance with local approved labels and/or regulations.
Topics: Humans; Drug Interactions; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Rifampin; Models, Biological; Male; Adult; Benzimidazoles; Cytochrome P-450 CYP3A; Antiviral Agents; Female; Young Adult; Middle Aged; Area Under Curve; Dichlororibofuranosylbenzimidazole
PubMed: 38009271
DOI: 10.1002/jcph.2385 -
Current Infectious Disease Reports Nov 2019Transplant recipients are at risk for cytomegalovirus (CMV) infection and associated morbidity and mortality. We summarize recently introduced or currently investigated... (Review)
Review
PURPOSE OF REVIEW
Transplant recipients are at risk for cytomegalovirus (CMV) infection and associated morbidity and mortality. We summarize recently introduced or currently investigated modalities for prevention and treatment of CMV infection in hematopoietic cell (HCT) and solid organ transplant (SOT) recipients.
RECENT FINDINGS
Letermovir was recently approved for CMV prevention in HCT recipients. Data from real world studies support its role to improve outcomes in this population. Letermovir is currently under investigation for broader patient populations and indications. Maribavir is in late stages of development for CMV treatment and may provide a safer alternative to currently available anti-CMV drugs. Promising CMV vaccine candidates and adoptive cell therapy approaches are under evaluation. CMV immune monitoring assays are predicted to play a more central role in our clinical decision making. In recent years, major advances have been made in CMV prevention and treatment in transplant recipients. Rigorous research is ongoing and is anticipated to further impact our ability to improve outcomes in this population.
PubMed: 31732823
DOI: 10.1007/s11908-019-0699-0 -
Current Opinion in Organ Transplantation Aug 2019Cytomegalovirus (CMV) is the most common infection after organ transplant. In addition to causing a viral syndrome and infection, it also increases the risk for... (Review)
Review
PURPOSE OF REVIEW
Cytomegalovirus (CMV) is the most common infection after organ transplant. In addition to causing a viral syndrome and infection, it also increases the risk for complications in the organ transplant, along with higher overall morbidity and mortality. Prevention and ideal treatment of CMV is paramount for optimal outcomes, both for individuals as well as for transplant programs. New guidelines and novel therapies are changing the way we manage disease.
RECENT FINDINGS
Several new antiviral agents have emerged in recent times, including letermovir, maribavir, and brincidofovir, enhancing our ability to prevent and treat CMV. Recent data on novel agents will be reviewed, with an emphasis on recent guidelines and best practices.
SUMMARY
Optimal treatment, influenced by recent advances in the field, including management of resistant virus, results in better outcomes with this significant and virulent virus.
Topics: Antiviral Agents; Cytomegalovirus Infections; Humans
PubMed: 31157669
DOI: 10.1097/MOT.0000000000000666 -
Antiviral Research Jul 2023Cytomegalovirus (CMV) is a significant human pathogen, especially for immunocompromised patients, often treated with one or more antiviral drugs. Although the prevalence...
Cytomegalovirus (CMV) is a significant human pathogen, especially for immunocompromised patients, often treated with one or more antiviral drugs. Although the prevalence of resistance is low, the impact of drug resistant CMV infections on patient outcomes is high and genotypic testing is recommended when resistance is suspected. To assess the prevalence of CMV drug resistance mutations among samples submitted for genotypic testing, 2750 patient sample results were analyzed. Testing was performed by sequencing for ganciclovir (GCV), cidofovir (CDV), foscarnet (FOS), maribavir (MBV) and/or letermovir (LMV) resistance conferring mutations. Of the 2750 patient samples, 826 (30.04%) had resistance to one or more anti-CMV drug. Resistance mutations were most common in UL97, with 27.64% and 9.96% of samples having GCV and MBV mutations, respectively. Resistance mutations in UL54 were less common, with 6.11%, 5.98% and 1.76% of samples having GCV, CDV and FOS mutations, respectively. For LMV, resistance mutations in UL56 were present in 7.17% of samples, with mutations at codon 325 representing 80.95% of the observed LMV resistance mutations. Resistance to two drugs was identified in 215 samples and to 3 or more drugs in 35 samples. While a high prevalence of CMV resistance mutations was identified, this must be taken in the context of healthcare providers submitting samples from patients with suspected resistant CMV strains. For these patients, rapid monitoring for resistance allows treatment modifications based on objective results rather than empiric drug selection, which is particularly relevant given the presence of mutations conferring resistance to more than one drug.
Topics: Humans; Cytomegalovirus; Prevalence; Transplant Recipients; DNA-Directed DNA Polymerase; Viral Proteins; Antiviral Agents; Ganciclovir; Foscarnet; Cidofovir; Drug Resistance, Viral; Mutation; Benzimidazoles
PubMed: 37150409
DOI: 10.1016/j.antiviral.2023.105623 -
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 -
The Journal of Infectious Diseases Sep 2022In separate phase 2 trials, 120 patients received maribavir for cytomegalovirus (CMV) infection failing conventional therapy (trial 202) and 119 received maribavir for...
BACKGROUND
In separate phase 2 trials, 120 patients received maribavir for cytomegalovirus (CMV) infection failing conventional therapy (trial 202) and 119 received maribavir for asymptomatic infection (trial 203). Overall, 172 cleared their CMV infection (CMV DNA <200 copies/mL) within 6 weeks.
METHODS
Baseline and posttreatment plasma samples were tested for mutations in viral genes UL97, UL54, and/or UL27. Selected viral mutants were phenotyped for drug susceptibility.
RESULTS
Baseline samples revealed UL54 mutations newly phenotyped as conferring resistance to standard DNA polymerase inhibitor(s), including K493N, P497S, K513T, L565V, V823A, A987V, and E989D. Of 29 patients (including 25 from trial 202) who cleared but later experienced recurrent CMV infection while on maribavir, 23 had available UL97 genotyping data; 17 had known resistance mutations (T409M or H411Y) and 5 additional had UL97 C480F alone. The newly phenotyped mutation C480F conferred high-grade maribavir resistance and low-grade ganciclovir resistance. Among 25 who did not respond to >14 days of therapy, 9 showed T409M or H411Y and 4 others showed C480F alone.
CONCLUSIONS
After maribavir therapy (400-1200 mg twice daily), UL97 mutations T409M, H411Y, or C480F emerge to confer maribavir resistance in patients with recurrent CMV infection while on therapy or no response to therapy.
CLINICAL TRIALS REGISTRATION
NCT01611974 and EudraCT 2010-024247-32.
Topics: Humans; Cytomegalovirus; Drug Resistance, Viral; Antiviral Agents; Phosphotransferases (Alcohol Group Acceptor); Cytomegalovirus Infections; Ganciclovir; Mutation; Phenotype
PubMed: 32726419
DOI: 10.1093/infdis/jiaa462 -
Antiviral Research Feb 2024Therapeutic use of maribavir for human cytomegalovirus infection has renewed attention to the extent of cross-resistance with ganciclovir as the existing standard...
Therapeutic use of maribavir for human cytomegalovirus infection has renewed attention to the extent of cross-resistance with ganciclovir as the existing standard therapy. Each drug selects in vivo for a characteristic set of resistance mutations in the viral UL97 kinase gene. To improve the calibration of relative susceptibilities to each drug, genetic variants at relevant UL97 codons were extensively phenotyped using the same baseline viral clone, cell culture conditions and growth readout. Ganciclovir-selected mutations at codons 460, 520, 592, 594, 595 and 603 conferred 2.8-fold (C603Y) to 12-fold (M460I) increases in ganciclovir 50% inhibitory concentrations (EC50) over wild type baseline, while conferring maribavir EC50 fold changes ranging from 0.21-fold (M460I) to 1.9-fold (A594V). Maribavir-selected mutations at codons 409, 411 and 480 conferred maribavir EC50 fold changes ranging from 17 (H411Y) to 210 (C480F), while conferring ganciclovir EC50 fold changes ranging from 0.7 (H411Y) to 2.3 (C480F). The P-loop substitution F342Y, selected by either drug, is confirmed to confer 4.7-fold and 6-fold increases in maribavir and ganciclovir EC50s respectively, and suggests this part of the ATP-binding domain of UL97 to be involved in moderate resistance to both drugs. The maribavir hypersensitivity of M460I and M460V may be advantageous.
Topics: Humans; Ganciclovir; Cytomegalovirus; Antiviral Agents; Mutation; Codon; Drug Resistance, Viral; Phosphotransferases (Alcohol Group Acceptor); Dichlororibofuranosylbenzimidazole
PubMed: 38163624
DOI: 10.1016/j.antiviral.2023.105792 -
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 -
Blood Advances Aug 2018Patients treated with allogeneic hematopoietic cell transplantation (HCT) are at risk of cytomegalovirus (CMV) reactivation and disease, which results in increased... (Review)
Review
Patients treated with allogeneic hematopoietic cell transplantation (HCT) are at risk of cytomegalovirus (CMV) reactivation and disease, which results in increased morbidity and mortality. Although universal antiviral prophylaxis against CMV improves outcomes in solid organ transplant recipients, data have been conflicting regarding such prophylaxis in patients undergoing allogeneic HCT. We conducted a systematic review of randomized trials of prophylactic antivirals against CMV after allogeneic HCT to summarize the evolution of the field over the last 35 years and evaluate the prophylactic potential of antiviral agents against CMV after allogeneic HCT. Electronic databases were queried from database inception through 31 December 2017. For included studies, incidence of CMV infection and all-cause mortality were collected as primary outcomes; CMV disease incidence, use of preemptive therapy, and drug toxicities were collected as secondary outcomes. Nineteen clinical trials conducted between 1981 and 2017 involving a total of 4173 patients were included for review. Prophylactic strategies included use of acyclovir, valacyclovir, ganciclovir, maribavir, brincidofovir, and letermovir compared with placebo or a comparator antiviral. Fourteen trials that compared antiviral prophylaxis with placebo demonstrated overall effectiveness in reducing incidence of CMV infection (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.42-0.58), CMV disease (OR, 0.56; 95% CI, 0.40-0.80), and use of preemptive therapy (OR, 0.51; 95% CI, 0.42-0.62; 6 trials); however, none demonstrated reduction in all-cause mortality (OR, 0.96; 95% CI, 0.78-1.18) except the phase 3 trial of letermovir (week-24 OR, 0.59; 95% CI, 0.38-0.98). Additional research is warranted to determine patient groups most likely to benefit from antiviral prophylaxis and its optimal deployment after allogeneic HCT.
Topics: Allografts; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Humans
PubMed: 30154125
DOI: 10.1182/bloodadvances.2018016493