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1.
N Engl J Med ; 370(19): 1781-9, 2014 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-24806159

RESUMO

BACKGROUND: Cytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance. METHODS: In this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection, end-organ disease, or any other cause. Patients underwent weekly surveillance for CMV infection. RESULTS: The reduction in the incidence of all-cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P=0.32), 32% at a dose of 120 mg (P=0.01), and 29% at a dose of 240 mg (P=0.007). Kaplan-Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P=0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity. CONCLUSIONS: Letermovir, as compared with placebo, was effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants. The highest dose (240 mg per day) had the greatest anti-CMV activity, with an acceptable safety profile. (Funded by AiCuris; ClinicalTrials.gov number, NCT01063829.).


Assuntos
Acetatos/administração & dosagem , Antivirais/administração & dosagem , Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Hospedeiro Imunocomprometido , Infecções Oportunistas/prevenção & controle , Quinazolinas/administração & dosagem , Acetatos/efeitos adversos , Adulto , Antivirais/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Incidência , Estimativa de Kaplan-Meier , Quinazolinas/efeitos adversos , Transplante Homólogo , Falha de Tratamento
2.
Br J Clin Pharmacol ; 83(9): 1944-1953, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28345163

RESUMO

AIMS: Human cytomegalovirus remains a significant issue for immunocompromised patients and existing viral polymerase targeting therapies are associated with significant toxicity. Accordingly, the viral terminase complex inhibitor, letermovir, is in development. We assessed letermovir pharmacokinetics in renal impairment. METHODS: This was a Phase 1, open-label, nonrandomised trial. Estimated glomerular filtration rate based on the Modification of Diet Renal Disease equation was used to create three groups of eight subjects: healthy function (estimated glomerular filtration rate ≥ 90 ml min-1  1.73m-2 ), moderate (30-59 ml min-1  1.73m-2 ) and severe (<30 ml min-1  1.73m-2 ) impairment. Oral letermovir 120 mg was dosed once-daily for 8 days and blood collected for pharmacokinetic analyses. RESULTS: All 24 subjects enrolled completed the trial. Moderate and severe renal impairment increased mean unbound letermovir fractions by 11% and 26%, respectively, vs. healthy subjects. Exposure (AUCτ,ss and Css,max ) was increased with renal impairment [least square mean ratios (90% confidence intervals) total letermovir vs. healthy subjects, AUCτ,ss 192% (143-258%) and 142% (83-243%) for moderate and severe impairment, respectively; Css,max 125% (87-182%) and 106% (75-151%), respectively]. Clearance was decreased vs. healthy subjects. Correlation analyses indicated a correlation between decreasing renal function and increased unbound letermovir concentration (R2  = 0.5076, P < 0.0001). Correlations were identified between decreased clearance with both decreased renal function (R2  = 0.0662, P = 0.2249 and R2  = 0.1861, P = 0.0353 total and unbound clearance, respectively) and increased age (R2  = 0.3548, P = 0.0021 and R2  = 0.3166, P = 0.0042 total and unbound clearance, respectively). Multiple-dose letermovir 120 mg was well tolerated across groups. CONCLUSIONS: Renal impairment increased exposure to letermovir, although age was a confounding factor.


Assuntos
Acetatos/farmacocinética , Quinazolinas/farmacocinética , Insuficiência Renal/sangue , Acetatos/efeitos adversos , Acetatos/sangue , Idoso , Antivirais/efeitos adversos , Antivirais/sangue , Antivirais/farmacocinética , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Quinazolinas/efeitos adversos , Quinazolinas/sangue
3.
Br J Clin Pharmacol ; 83(12): 2678-2686, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28722153

RESUMO

AIMS: Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on letermovir pharmacokinetics. METHODS: Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral letermovir in female subjects with hepatic impairment and healthy matched controls. For 8 days, subjects with moderate hepatic impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg letermovir/day and those with severe hepatic impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg letermovir/day. Pharmacokinetic parameters were determined from blood samples. RESULTS: For subjects with moderate hepatic impairment, maximal observed concentration at steady state (Css,max ) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,ss ) for total letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, Css,max and AUCτ,ss values of total letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. CONCLUSIONS: Moderate hepatic impairment increased exposure to letermovir <2-fold, while severe hepatic impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment.


Assuntos
Acetatos/farmacocinética , Antivirais/farmacocinética , Infecções por Citomegalovirus/tratamento farmacológico , Hepatopatias/metabolismo , Fígado/metabolismo , Quinazolinas/farmacocinética , Acetatos/administração & dosagem , Acetatos/efeitos adversos , Acetatos/sangue , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/sangue , Área Sob a Curva , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Fígado/fisiopatologia , Hepatopatias/diagnóstico , Hepatopatias/fisiopatologia , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/sangue , Federação Russa , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
5.
Transpl Int ; 27(1): 77-86, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24164420

RESUMO

Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in transplant recipients. Letermovir (AIC246), is a novel anti-HCMV drug in development, acting via a novel mechanism of action. In this proof-of-concept trial with first administration of letermovir to patients, 27 transplant recipients with active CMV replication were randomly assigned to a 14-day oral treatment regimen of either letermovir 40 mg twice a day, letermovir 80 mg once a day, or local standard of care (SOC) in a multicenter, open-label trial. Efficacy, safety, and limited pharmacokinetic parameters were assessed. All groups had a statistically significant decrease in CMV-DNA copy number from baseline (40 mg BID: P = 0.031; 80 mg QD: P = 0.018; SOC: P = 0.001), and comparison of viral load reduction between treatment groups showed no statistically significant differences. Viral clearance was achieved for 6 of 12 patients (50%) in the letermovir groups versus two of seven SOC patients (28.6%). Letermovir treatment was generally well tolerated, no patient developed CMV disease during the trial. Both letermovir treatment regimens resulted in equally high trough level plasma concentrations. The efficacy, safety, and pharmacokinetics observed in these viremic transplant recipients indicate that letermovir is a promising new anti-CMV drug.


Assuntos
Acetatos/administração & dosagem , Infecções por Citomegalovirus/tratamento farmacológico , Transplante de Rim , Quinazolinas/administração & dosagem , Acetatos/farmacocinética , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/farmacocinética , Citomegalovirus/genética , Infecções por Citomegalovirus/virologia , DNA Viral/sangue , Feminino , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/virologia , Quinazolinas/farmacocinética , Carga Viral , Viremia/virologia
6.
Clin Pharmacol Drug Dev ; 12(7): 749-760, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36860173

RESUMO

The pharmacokinetics and safety of the novel herpes simplex virus helicase-primase inhibitor pritelivir were evaluated in 5 phase 1 trials: a single-ascending-dose trial, 2 multiple-ascending-dose trials, a food-effect trial, and an absolute bioavailability trial in healthy male subjects. One cohort of healthy female subjects was included in the single-ascending-dose trial. Pritelivir pharmacokinetics were linear up to 480 mg following single and up to 400 mg following multiple once-daily doses. The half-life ranged from 52 to 83 hours, and steady state was reached between 8 and 13 days. Maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration were 1.5- and 1.1-fold higher in female compared to male subjects. Absolute bioavailability was 72% under fasted conditions. Following a fatty diet, pritelivir time to maximum concentration was 1.5 hour delayed and maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration were 33% and 16% higher, respectively. Pritelivir was safe and well tolerated up to 600 mg following single and up to 200 mg following multiple once-daily doses. Considering a therapeutic dose of 100 mg once-daily, pritelivir demonstrated a favorable safety and tolerability and pharmacokinetic profile in healthy subjects to support further development.


Assuntos
DNA Primase , Simplexvirus , Feminino , Humanos , Masculino , Disponibilidade Biológica , Voluntários Saudáveis
7.
Clin Pharmacol Drug Dev ; 11(1): 16-24, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34714967

RESUMO

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection and disease in allogeneic hematopoietic stem-cell transplant recipients. In vitro studies have identified letermovir as a potential cytochrome P450 (CYP) 3A inhibitor. Thus, the effect of letermovir on the CYP3A isoenzyme-specific probe drug midazolam was investigated in a phase 1 trial. Healthy female subjects received single-dose intravenous (IV; 1 mg) and oral (2 mg) midazolam on days -4 and -2, respectively. Letermovir 240 mg once daily was administered on days 1 to 6, and further single doses of midazolam 1 mg IV and oral midazolam 2 mg were administered on days 4 and 6, respectively. Pharmacokinetics, tolerability, and safety were monitored throughout the trial. Following coadministration with letermovir, the least square means ratio for maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last measurable concentration was 172.4% and 225.3%, respectively, for oral midazolam, and 105.2% and 146.6%, respectively, for midazolam IV. The area under the plasma concentration-time curve from time 0 to the last measurable concentration ratio of midazolam to 1-hydroxymidazolam increased slightly in the presence of letermovir following IV (8.8-13.1; 49% increase) and oral (3.3-5.3; 59% increase) midazolam. Letermovir reached steady state, on average, by days 5 to 6. All treatments were generally well tolerated. Letermovir demonstrated moderate CYP3A inhibition.


Assuntos
Midazolam , Acetatos , Área Sob a Curva , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Midazolam/farmacocinética , Quinazolinas
8.
Clin Pharmacol Drug Dev ; 11(1): 6-15, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34812580

RESUMO

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor approved in the United States, Canada, Japan, and the European Union for prophylaxis of CMV infection and disease in CMV-seropositive, allogeneic, hematopoietic stem-cell transplant recipients. In vitro, letermovir is a substrate and potential modulator of P-glycoprotein. The potential of letermovir to alter the pharmacokinetics of digoxin (a P-glycoprotein substrate) upon coadministration in healthy subjects was therefore investigated in a phase 1 trial (EudraCT: 2011-004516-39). Oral letermovir 240 mg was administered twice daily for 12 days with a single oral digoxin 0.5-mg dose on day 7; after a washout period, oral digoxin 0.5 mg was administered on day 35 (sequence 1). The period order was reversed after a 28-day washout for sequence 2. Pharmacokinetics and safety were evaluated. The presence of steady-state letermovir reduced digoxin area under the plasma concentration-time curve from administration until last quantifiable measurement by 12% and maximum plasma concentration by 22% compared with digoxin alone; digoxin half-life and elimination rate remained similar in both conditions. The between-subject variability of digoxin maximum plasma concentration was higher with letermovir than without (42% vs 31%) and similar for digoxin area under the plasma concentration-time curve in both periods. No specific safety or tolerability concerns were identified. Overall, letermovir had no clinically relevant effect on concomitant administration with digoxin.


Assuntos
Acetatos , Digoxina , Quinazolinas , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Acetatos/administração & dosagem , Acetatos/efeitos adversos , Administração Oral , Ensaios Clínicos Fase I como Assunto , Digoxina/administração & dosagem , Digoxina/farmacocinética , Voluntários Saudáveis , Humanos , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Estados Unidos
9.
Clin Pharmacol Drug Dev ; 7(1): 9-21, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28967706

RESUMO

Letermovir is being developed for human cytomegalovirus infection treatment and prophylaxis. In patients receiving transplants, antivirals are coadministered with cyclosporine A (CsA) or tacrolimus (TAC) immunosuppressants. Therefore, we investigated the potential for letermovir-immunosuppressant interactions. In 2 phase 1 clinical trials either CsA 50 mg or TAC 5 mg was administered to healthy males. Following washout, letermovir 80 mg was dosed twice daily for 7 and 11 days in the CsA and TAC trials, respectively, with a second dose of immunosuppressant coadministered with letermovir at steady state. In addition, letermovir 40 mg twice daily was administered for 14 days, and either CsA 50 or 200 mg administered on days 7 and 14. Pharmacokinetics and tolerability were assessed. Letermovir increased CsA and TAC Cmax by 37% and 70%, respectively, and exposure by 70% and 78%, respectively, compared with immunosuppressant alone; t½ was also increased from 10.7 to 17.9 hours for CsA. CsA (50/200 mg) increased letermovir Cmax,ss (109%/167%) and AUCss,τ (126%/237%) and decreased t½ (4.33 to 3.68/3.04 hours) versus letermovir alone. TAC did not significantly affect letermovir pharmacokinetics. All treatments were well tolerated. Concomitant letermovir increased TAC and CsA exposure. CsA altered letermovir pharmacokinetics, whereas TAC did not.


Assuntos
Acetatos/farmacocinética , Antivirais/farmacocinética , Ciclosporina/farmacocinética , Imunossupressores/farmacocinética , Quinazolinas/farmacocinética , Tacrolimo/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Acetatos/efeitos adversos , Acetatos/sangue , Adulto , Antivirais/efeitos adversos , Ciclosporina/efeitos adversos , Ciclosporina/sangue , Sistema Enzimático do Citocromo P-450/genética , Interações Medicamentosas , Genótipo , Voluntários Saudáveis , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Masculino , Quinazolinas/efeitos adversos , Quinazolinas/sangue , Tacrolimo/efeitos adversos , Tacrolimo/sangue , Adulto Jovem
10.
J Neuroimmunol ; 282: 63-72, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25903730

RESUMO

Targeting regulatory T cells (Treg cells) with interleukin-2 (IL-2) constitutes a novel therapeutic approach for autoimmunity. As anti-cancer therapy with IL-2 has revealed substantial toxicities a mutated human IL-2 molecule, termed AIC284 (formerly BAY 50-4798), has been developed to reduce these side effects. To assess whether AIC284 is efficacious in autoimmunity, we studied its therapeutic potential in an animal model for Multiple Sclerosis. Treatment of Lewis rats with AIC284 increased Treg cell numbers and protected the rats from Experimental Autoimmune Encephalomyelitis (EAE). AIC284 might, thus, also efficiently prevent progression of autoimmune diseases in humans.


Assuntos
Antineoplásicos/uso terapêutico , Interleucina-2/análogos & derivados , Esclerose Múltipla , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Anexina A5/metabolismo , Antígenos CD/metabolismo , Autoimunidade/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Interleucina-2/farmacologia , Interleucina-2/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Esclerose Múltipla/prevenção & controle , Edema Pulmonar/etiologia , Edema Pulmonar/prevenção & controle , Ratos , Ratos Endogâmicos Lew , Proteínas Recombinantes/uso terapêutico
11.
Nat Commun ; 6: 6320, 2015 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-25695750

RESUMO

The Clp protease complex degrades a multitude of substrates, which are engaged by a AAA+ chaperone such as ClpX and subsequently digested by the dynamic, barrel-shaped ClpP protease. Acyldepsipeptides (ADEPs) are natural product-derived antibiotics that activate ClpP for chaperone-independent protein digestion. Here we show that both protein and small-molecule activators of ClpP allosterically control the ClpP barrel conformation. We dissect the catalytic mechanism with chemical probes and show that ADEP in addition to opening the axial pore directly stimulates ClpP activity through cooperative binding. ClpP activation thus reaches beyond active site accessibility and also involves conformational control of the catalytic residues. Moreover, we demonstrate that substoichiometric amounts of ADEP potently prevent binding of ClpX to ClpP and, at the same time, partially inhibit ClpP through conformational perturbance. Collectively, our results establish the hydrophobic binding pocket as a major conformational regulatory site with implications for both ClpXP proteolysis and ADEP-based anti-bacterial activity.


Assuntos
Proteínas de Bactérias/química , Depsipeptídeos/química , Endopeptidase Clp/química , Chaperonas Moleculares/química , Sítio Alostérico , Sítios de Ligação , Calorimetria , Catálise , Domínio Catalítico , Cromatografia , Escherichia coli/química , Fluoresceína-5-Isotiocianato , Interações Hidrofóbicas e Hidrofílicas , Cinética , Luz , Listeria monocytogenes/química , Espectrometria de Massas , Mutação , Ligação Proteica , Conformação Proteica , Estrutura Secundária de Proteína , Staphylococcus aureus/química , Especificidade por Substrato
12.
Nat Struct Mol Biol ; 17(4): 471-8, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20305655

RESUMO

Clp-family proteins are prototypes for studying the mechanism of ATP-dependent proteases because the proteolytic activity of the ClpP core is tightly regulated by activating Clp-ATPases. Nonetheless, the proteolytic activation mechanism has remained elusive because of the lack of a complex structure. Acyldepsipeptides (ADEPs), a recently discovered class of antibiotics, activate and disregulate ClpP. Here we have elucidated the structural changes underlying the ClpP activation process by ADEPs. We present the structures of Bacillus subtilis ClpP alone and in complex with ADEP1 and ADEP2. The structures show the closed-to-open-gate transition of the ClpP N-terminal segments upon activation as well as conformational changes restricted to the upper portion of ClpP. The direction of the conformational movement and the hydrophobic clustering that stabilizes the closed structure are markedly different from those of other ATP-dependent proteases, providing unprecedented insights into the activation of ClpP.


Assuntos
Antibacterianos/química , Bacillus subtilis/química , Endopeptidase Clp/química , Proteínas de Escherichia coli/química , Peptídeos/química , Endopeptidase Clp/metabolismo , Proteínas de Escherichia coli/metabolismo , Conformação Proteica
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