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Clinical Pharmacology in Drug... Jun 2023This phase I study compared pharmacokinetics and safety of maribavir in Japanese and White participants, and evaluated dose proportionality in Japanese participants....
This phase I study compared pharmacokinetics and safety of maribavir in Japanese and White participants, and evaluated dose proportionality in Japanese participants. Under fasting conditions, 12 healthy adult participants of Japanese descent and 12 matched White participants received a single 400-mg dose of maribavir. Japanese participants received 2 further doses of maribavir: 200 mg and 800 mg, or 800 mg and 200 mg, separated by a ≥72-hour washout period. Serial blood samples were collected up to 24 hours after dosing for pharmacokinetic assessments. Following the 400-mg dose, the geometric mean ratios (90% confidence interval) of Japanese versus White participants were 110% (91.7%-133%) for maximum plasma concentration, 122% (96.8%-155%) for area under the plasma concentration-time curve (AUC) from time of dosing to the last measurable concentration, and 125% (98.0%-160%) for AUC extrapolated to infinity. In Japanese participants, maribavir AUC extrapolated to infinity and AUC from time of dosing to the last measurable concentration increased in a dose-proportional fashion over 200-800 mg; maximum plasma concentration increased less than dose proportionally. Seven participants reported treatment-emergent adverse events (TEAEs; Japanese participants, 400 mg: 2 [16.7%], 200 mg: 1 [8.3%]; White participants, 400 mg: 4 [33.3%]), all mild and most commonly dysgeusia. No serious TEAEs or TEAEs leading to discontinuation were reported. This study demonstrated higher maribavir systemic exposure in Japanese than White participants and similar safety outcomes. This difference in exposure is not considered clinically important and its significance remains to be determined.
Topics: Adult; Humans; Area Under Curve; East Asian People; White People; Antiviral Agents; Dichlororibofuranosylbenzimidazole
PubMed: 37036111
DOI: 10.1002/cpdd.1247 -
Journal of Clinical Pharmacology Jan 2020Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug-drug interactions, we examined...
Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug-drug interactions, we examined the effects of multiple doses of maribavir on cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) activity using probe substrates in healthy volunteers. During this phase 1 open-label study (NCT02775240), participants received the probe substrates digoxin (0.5 mg) and dextromethorphan (30 mg) before and after maribavir (400 mg twice daily for 8 days). Serial plasma samples were analyzed for digoxin, dextromethorpha, dextrorphan, and maribavir concentrations. Pharmacokinetic parameters were calculated (noncompartmental analysis) and analyzed with a linear mixed-effects model for treatment comparison to estimate geometric mean ratios (GMRs) and 90% confidence intervals (CIs). CYP2D6 polymorphisms were genotyped using polymerase chain reaction. Overall, 17 of 18 participants (94.4%) completed the study. All participants were genotyped as CYP2D6 intermediate/extensive metabolizers. GMR (90%CI) of digoxin C , AUC , and AUC with and without maribavir was 1.257 (1.139-1.387), 1.187 (1.088-1.296), and 1.217 (1.110-1.335), respectively, outside the "no-effect" window (0.8-1.25). GMR (90%CI) of dextromethorphan AUC and AUC ratio of dextromethorphan/dextrorphan were 0.877 (0.692-1.112) and 0.901 (0.717-1.133), respectively, marginally outside the no-effect window, although large variability was observed in these pharmacokinetic parameters. Pharmacokinetic parameters of dextrorphan were unaffected. Maribavir inhibited P-gp activity but did not affect CYP2D6 activity. Maribavir's effect on the pharmacokinetics of P-gp substrates should be evaluated individually, and caution should be exercised with P-gp substrates with narrow therapeutic windows.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adult; Antiviral Agents; Benzimidazoles; Cytochrome P-450 CYP2D6; Cytomegalovirus Infections; Dextromethorphan; Digoxin; Drug Interactions; Female; Genotype; Healthy Volunteers; Humans; Male; Middle Aged; Ribonucleosides; Young Adult
PubMed: 31385617
DOI: 10.1002/jcph.1504 -
Drug Metabolism and Disposition: the... Nov 2021Maribavir is in phase 3 clinical development for treatment of cytomegalovirus infection/disease in transplant recipients. Previous research conducted using only intact...
Maribavir is in phase 3 clinical development for treatment of cytomegalovirus infection/disease in transplant recipients. Previous research conducted using only intact cynomolgus monkeys indicated biliary secretion as the primary elimination pathway for maribavir and that maribavir undergoes enterohepatic recirculation (EHR). To clarify the exact mechanisms of maribavir's EHR behavior, we studied its clearance pathways using intravenously administered C-labeled maribavir in intact and bile duct-cannulated (BDC) monkeys and constructed a semi-physiologically based pharmacokinetic (PBPK) model. Total radioactivity metabolite profiles in plasma and excreta were quantitatively determined along with plasma maribavir concentrations. Intact animals showed significantly lower clearance and longer half-lives in both total radioactivity and parent concentration in plasma than BDC monkeys. The primary in vitro and in vivo metabolic pathway for maribavir in monkey is direct glucuronidation; -dealkylation and renal clearance are minor pathways. In BDC monkeys, 73% of dose was recovered as maribavir glucuronides in bile, and 3% of dose was recovered as parent in bile and feces; in intact animals' feces, 58% of dose was recovered as parent, and no glucuronides were detected. Therefore, EHR of maribavir occurs through biliary secretion of maribavir glucuronides, and this is followed by hydrolysis of glucuronides in the gut lumen and subsequent reabsorption of parent. A semi-PBPK model constructed from physiologic, in vitro, and in vivo BDC monkey data is capable of projecting maribavir's pharmacokinetic and EHR behavior in intact animals after intravenous or oral dosing and could be applied to modeling other xenobiotics that are subject to similar EHR processes. SIGNIFICANCE STATEMENT: Through both mass balance and semi-physiologically based pharmacokinetic (semi-PBPK) modeling approaches, this study mechanistically and quantitatively elucidates maribavir's enterohepatic recirculation (EHR) behavior in monkeys, which occurs via extensive direct glucuronidation, biliary secretion of these glucuronides, luminal hydrolysis of glucuronides to parent, and subsequent reabsorption of the parent. The study also identifies important drug- and animal-specific parameters that determine the EHR kinetics, and the semi-PBPK model is readily applicable to other drugs that undergo similar metabolic and recirculation mechanisms.
Topics: Animals; Antiviral Agents; Benzimidazoles; Bile; Biotransformation; Caco-2 Cells; Dealkylation; Feces; Gastrointestinal Transit; Glucuronides; Half-Life; Humans; Hydrolysis; Kidney; Macaca fascicularis; Male; Models, Biological; Ribonucleosides
PubMed: 34462268
DOI: 10.1124/dmd.121.000493 -
Current Opinion in Pulmonary Medicine Jul 2024Infections in lung transplant recipients remain a major challenge and can affect lung allograft function and cause significant morbidity and mortality. New strategies... (Review)
Review
PURPOSE OF REVIEW
Infections in lung transplant recipients remain a major challenge and can affect lung allograft function and cause significant morbidity and mortality. New strategies for the prevention and treatment of infection in lung transplantation have emerged and are reviewed.
RECENT FINDINGS
For important vaccine preventable infections (VPIs), guidance has been updated for at risk solid organ transplant (SOT) recipients. However, data on the efficacy of newer vaccines in lung transplant, including the respiratory syncytial virus (RSV) vaccine, are limited. Studies demonstrate improved vaccination rate with Infectious Diseases consultation during pretransplant evaluation. Two new antiviral agents for the treatment and prevention of cytomegalovirus (CMV) in SOT, letermovir and maribavir, are being incorporated into clinical care. CMV-specific cell-mediated immune function assays are more widely available. Antibiotics for the management of multidrug resistant pathogens and Burkholderia cepacia complex have been described in case series and case reports in lung transplant.
SUMMARY
Although new vaccines and novel therapies for preventing and treating infections are available, larger studies evaluating efficacy in lung transplant recipients are needed.
Topics: Humans; Lung Transplantation; Antiviral Agents; Transplant Recipients; Cytomegalovirus Infections; Anti-Bacterial Agents
PubMed: 38411211
DOI: 10.1097/MCP.0000000000001060 -
Journal of Clinical Virology : the... Jul 2019The natural history of cytomegalovirus (CMV) infection in transplant patients has been well established. This virus may originate from the recipient, the donor or both.... (Review)
Review
The natural history of cytomegalovirus (CMV) infection in transplant patients has been well established. This virus may originate from the recipient, the donor or both. When pre-transplant IgG antibodies in the recipient are taken into account, three types of infection are possible: primary, reactivation or reinfection. The risks of high viral load and end-organ disease are highest after primary infection and lowest after reactivation. Serial monitoring of patients by quantitative polymerase chain reaction for CMV DNA allows antiviral drugs to be deployed for pre-emptive therapy or an antiviral drug may be given prophylactically. Both of these strategies are effective, but pre-emptive therapy has the advantage that randomised allocation of a new drug or placebo given prophylactically may show a reduced need for pre-emptive valganciclovir. In this review, I will consider what has been learned from use of ganciclovir and valganciclovir and apply this information to clinical trials that have evaluated maribavir, brincidofovir and letermovir. In addition, pre-emptive therapy has the advantage of facilitating the discovery of vaccines against CMV using a pharmacodynamic approach. Briefly, patients awaiting transplantation are given vaccine or placebo pre-transplant. When they proceed to transplantation, various parameters of viral load can be compared to determine if the vaccine has an effect against CMV when compared to patients randomised to receive placebo. If there is evidence of control of CMV, this can be related to immune responses induced by the vaccine to define a correlate of protection. This review will summarise the published evidence available.
Topics: Antiviral Agents; Clinical Trials as Topic; Combined Modality Therapy; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Humans; Transplantation; Viral Load
PubMed: 31132546
DOI: 10.1016/j.jcv.2019.04.007 -
The Annals of Pharmacotherapy Mar 2024The article reviews the safety and efficacy of treatments for cytomegalovirus (CMV) in solid organ transplantation. (Review)
Review
OBJECTIVE
The article reviews the safety and efficacy of treatments for cytomegalovirus (CMV) in solid organ transplantation.
DATA SOURCES
A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from database inception through January 2024, using terms CMV, therapy, and solid organ transplantation.
STUDY SELECTION AND DATA EXTRACTION
Clinical trials, meta-analyses, cohort studies, case reports, and guidelines were included. Letters to the editor, reviews, and commentaries were excluded.
DATA SYNTHESIS
After abstract screening and full-text review of 728 citations for eligibility, 53 were included. Valganciclovir and intravenous ganciclovir are drugs of choice for CMV management and, until recently, the availability of alternative options has been restricted due to toxicity. For instance, foscarnet and cidofovir serve as second-line agents due to potential bone marrow and renal toxicity. In patients with refractory or resistant CMV, maribavir, a novel oral agent, has proven efficacy and a lower adverse effect profile. However, in refractory or resistant CMV, foscarnet and cidofovir are preferred in invasive disease (CMV gastritis, CMV retinitis, and CMV encephalitis), high viral loads, and inability to tolerate oral preparations.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Consensus guidelines have not been revised since approval of novel antivirals in solid organ transplantation. Valganciclovir and ganciclovir remain drugs of choice for initial CMV therapy. Foscarnet, cidofovir, and maribavir are treatments for refractory or resistant-CMV.
CONCLUSIONS
Selection of CMV antiviral treatment should be determined by patient-specific factors, including severity of illness, resistant or refractory disease, dose-limiting adverse effects, and the preferred route of administration.
PubMed: 38501850
DOI: 10.1177/10600280241237534 -
Current Opinion in Infectious Diseases Aug 2015The purpose of this study is to provide updated information on diagnosis of cytomegalovirus (CMV) drug resistance, treatments for drug-resistant infection and potential... (Review)
Review
PURPOSE OF REVIEW
The purpose of this study is to provide updated information on diagnosis of cytomegalovirus (CMV) drug resistance, treatments for drug-resistant infection and potential uses of experimental antiviral compounds.
RECENT FINDINGS
For established CMV antivirals, uncommon viral UL97 kinase and UL54 DNA polymerase drug resistance mutations are sporadically described that expand an extensive existing database. Some novel mutations reported from treated patients have no drug-resistant phenotype and may be genotyping artefacts. Next-generation sequencing technology may enable earlier detection of emerging resistance mutations in treated patients. Management options for drug-resistant infection include optimization of host defenses, antiviral dose escalation, substitutions or combinations of standard or experimental antivirals. Maribavir and letermovir have antiviral targets distinct from the classic DNA polymerase. UL97 mutations elicited by ganciclovir and maribavir are different, although a single p-loop mutation can confer significant cross-resistance. High-grade resistance mutations in the UL56 terminase gene are readily selected in vitro under letermovir and await clinical correlation.
SUMMARY
Technical advancements can enhance the accurate and timely genotypic detection of drug resistance. Antivirals undergoing clinical trial offer the prospect of new viral targets and drug combinations, but unresolved issues exist with regard to their therapeutic potential for drug-resistant CMV and their genetic barriers to resistance.
Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Genotype; Genotyping Techniques; Humans; Immunocompromised Host; Molecular Diagnostic Techniques; Transplant Recipients; Transplantation
PubMed: 26098499
DOI: 10.1097/QCO.0000000000000170 -
Transplant Infectious Disease : An... Jun 2023
Topics: Humans; Cytomegalovirus Infections; Antiviral Agents
PubMed: 37053091
DOI: 10.1111/tid.14063 -
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 -
The Medical Letter on Drugs and... Nov 2022
Topics: Humans; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole
PubMed: 36397194
DOI: No ID Found