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Transplant Infectious Disease : An... Jun 2023
Topics: Humans; Cytomegalovirus Infections; Antiviral Agents
PubMed: 37053091
DOI: 10.1111/tid.14063 -
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 -
Clinical Microbiology and Infection :... Sep 2023Cytomegalovirus (CMV) is an opportunistic pathogen responsible for substantial morbidity after solid organ transplantation and haematopoietic stem cell transplantation.... (Review)
Review
BACKGROUND
Cytomegalovirus (CMV) is an opportunistic pathogen responsible for substantial morbidity after solid organ transplantation and haematopoietic stem cell transplantation. Treatment of CMV disease involves a two-pronged approach with antiviral drug treatment coupled with strategies to minimize the intensity of immune suppression.
OBJECTIVES
This narrative review examines the evidence for the current treatment of CMV disease in transplant recipients, including the use of oral antiviral drugs.
SOURCES
Literature search was performed on PubMed with keywords cytomegalovirus, transplantation, ganciclovir, valganciclovir, maribavir, letermovir, cidofovir, and foscarnet.
CONTENT
Intravenous and oral valganciclovir are the standard first-line treatment of cytomegalovirus disease after transplantation. Oral maribavir has demonstrated superior efficacy and safety over CMV DNA polymerase inhibitors for the treatment of refractory or resistant CMV infection. Transplant patients with severe and life-threatening CMV disease, those with very high viral load, and patients with impaired gastrointestinal absorption should still be treated initially with intravenous antiviral drugs, including ganciclovir and foscarnet. Criteria for the safe transition from intravenous therapies to oral antiviral drugs include achieving clinical improvement and satisfactory decline in viral load. Recurrence of CMV viremia and disease is common, particularly among transplant patients who are lymphopenic and have impaired CMV-specific immunity.
IMPLICATIONS
Oral antiviral drugs for the treatment of CMV infection and disease in transplant recipients have improved the CMV landscape, because they reduce the cost and mitigate the inconvenience and risks related to prolonged hospitalization and the need for long-term intravascular access. However, their antiviral efficacy should be complemented by an intentional strategy of reducing the degree of immune suppression to allow for immunologic recovery that ensures durable control of CMV infection.
Topics: Humans; Antiviral Agents; Cytomegalovirus; Valganciclovir; Foscarnet; Transplant Recipients; Ganciclovir; Cytomegalovirus Infections
PubMed: 36963566
DOI: 10.1016/j.cmi.2023.03.020 -
Computational Biology and Chemistry Jun 2023Nucleoside analogs/derivatives (NAs/NDs) with potent antiviral activities are now deemed very convenient choices for the treatment of coronavirus disease 2019 (COVID-19)...
Nucleoside analogs/derivatives (NAs/NDs) with potent antiviral activities are now deemed very convenient choices for the treatment of coronavirus disease 2019 (COVID-19) arisen by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. At the same time, the appearance of a new strain of SARS-CoV-2, the Omicron variant, necessitates multiplied efforts in fighting COVID-19. Counteracting the crucial SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) jointly altogether using the same inhibitor is a quite successful new plan to demultiplicate SARS-CoV-2 particles and eliminate COVID-19 whatever the SARS-CoV-2 subtype is (due to the significant conservation nature of RdRps and ExoNs in the different SARS-CoV-2 strains). Successive in silico screening of known NAs finally disclosed six different promising NAs, which are riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir, respectively, that predictably can act through the planned dual-action mode. Further in vitro evaluations affirmed the anti-SARS-CoV-2/anti-COVID-19 potentials of these NAs, with riboprine and forodesine being at the top. The two NAs are able to effectively antagonize the replication of the new virulent SARS-CoV-2 strains with considerably minute in vitro anti-RdRp and anti-SARS-CoV-2 EC values of 189 and 408 nM for riboprine and 207 and 657 nM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. Furthermore, the favorable structural characteristics of the two molecules qualify them for varied types of isosteric and analogistic chemical derivatization. In one word, the present important outcomes of this comprehensive dual study revealed the anticipating repurposing potentials of some known nucleosides, led by the two NAs riboprine and forodesine, to successfully discontinue the coronaviral-2 polymerase/exoribonuclease interactions with RNA nucleotides in the SARS-CoV-2 Omicron variant (BA.5 sublineage) and accordingly alleviate COVID-19 infections, motivating us to initiate the two drugs' diverse anti-COVID-19 pharmacological evaluations to add both of them betimes in the COVID-19 therapeutic protocols.
Topics: Humans; COVID-19; SARS-CoV-2; Nucleosides; Exoribonucleases; RNA-Dependent RNA Polymerase; Antiviral Agents
PubMed: 36842392
DOI: 10.1016/j.compbiolchem.2022.107768 -
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 -
Clinical Transplantation Apr 2023
Topics: Humans; Cytomegalovirus; Cytomegalovirus Infections; Antiviral Agents; Transplant Recipients; Organ Transplantation
PubMed: 36740886
DOI: 10.1111/ctr.14929 -
Retinal Cases & Brief Reports Mar 2024To determine whether maribavir is effective at treating ganciclovir-resistant cytomegalovirus retinitis.
PURPOSE
To determine whether maribavir is effective at treating ganciclovir-resistant cytomegalovirus retinitis.
METHODS
Retrospective case report of a lung-transplant patient with bilateral cytomegalovirus retinitis documented with serum and aqueous humor studies and color fundus photographs.
RESULTS
A 72-year-old lung-transplant patient with active ganciclovir-resistant cytomegalovirus was treated with intravitreal foscarnet therapy in one eye. Retinitis developed in the contralateral eye and was managed with systemic maribavir alone. Active retinitis regressed in both the eye treated with intravitreal foscarnet and the uninjected eye.
CONCLUSION
This patient's results suggest that systemic maribavir is an effective treatment for treatment-resistant cytomegalovirus retinitis.
Topics: Humans; Aged; Cytomegalovirus Retinitis; Valganciclovir; Foscarnet; Retrospective Studies; Ganciclovir; Antiviral Agents; Dichlororibofuranosylbenzimidazole
PubMed: 36730596
DOI: 10.1097/ICB.0000000000001372 -
ChemistrySelect Dec 2022Given the rapid progression of the coronavirus disease 2019 (COVID-19) pandemic, an ultrafast response was urgently required to handle this major public crisis. To...
Given the rapid progression of the coronavirus disease 2019 (COVID-19) pandemic, an ultrafast response was urgently required to handle this major public crisis. To contain the pandemic, investments are required to develop diagnostic tests, prophylactic vaccines, and novel therapies. Lately, nucleoside analog (NA) antivirals topped the scene as top options for the treatment of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Meanwhile, the continuous generation of new lineages of the SARS-CoV-2 Omicron variant caused a new challenge in the persistent COVID-19 battle. Hitting the two crucial SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) collectively together using only one single ligand is a very successful new approach to stop SARS-CoV-2 multiplication and combat COVID-19 irrespective of the SARS-CoV-2 variant type because RdRps and ExoNs are broadly conserved among all SARS-CoV-2 strains. Herein, the current comprehensive study investigated most NAs libraries, searching for the most ideal drug candidates expectedly able to perfectly act through this double tactic. Gradual computational filtration gave rise to six different promising NAs, which are riboprine, forodesine, tecadenoson, nelarabine, vidarabine, and maribavir, respectively. Further biological assessment proved for the first time, using the anti-RdRp/ExoN and anti-SARS-CoV-2 bioassays, that riboprine and forodesine, among all the six tested NAs, are able to powerfully inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute anti-RdRp and anti-SARS-CoV-2 EC values of about 0.22 and 0.49 μM for riboprine and about 0.25 and 0.73 μM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. The prior data supported these biochemical findings, suggesting that riboprine and forodesine molecules strongly hit the key catalytic pockets of the SARS-CoV-2 (Omicron variant) RdRp's and ExoN's main active sites. Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading, with their relatively flexible structures open for diverse types of chemical derivatization. In Brief, the current important results of this comprehensive study revealed the interesting repurposing potentials of, mainly, the two nucleosides riboprine and forodesine to effectively shut down the polymerase/exoribonuclease-RNA nucleotides interactions of the SARS-CoV-2 Omicron variant and consequently treat COVID-19 infections, motivating us to rapidly begin the two drugs' broad preclinical/clinical anti-COVID-19 bioevaluations, hoping to combine both drugs soon in the COVID-19 treatment protocols.
PubMed: 36718467
DOI: 10.1002/slct.202201912 -
Transplant Infectious Disease : An... Jun 2023
Topics: Humans; Cytomegalovirus Infections; Cytomegalovirus; Renal Insufficiency
PubMed: 36715583
DOI: 10.1111/tid.14017 -
Open Forum Infectious Diseases Jan 2023
PubMed: 36632422
DOI: 10.1093/ofid/ofac686