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1.
Clin Transl Sci ; 16(10): 1947-1956, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37526305

RESUMO

Molnupiravir is an orally administered, small-molecule ribonucleoside prodrug of ß-D-N4-hydroxycytidine (NHC) that has demonstrated potent, broad-spectrum preclinical activity against RNA viruses and has a high barrier to the development of resistance. A double-blind, placebo-controlled, phase I trial was conducted to evaluate the pharmacokinetics (PKs), safety, and tolerability of 10.5-day administration of multiple doses of molnupiravir and its metabolites in healthy, adult participants. Participants were randomly assigned (3:1) to receive molnupiravir (400 mg [n = 6], 600 mg [n = 6], and 800 mg [n = 12]) or matching placebo (n = 8) every 12 h (q12h) for 10.5 days. Blood was collected to evaluate the PKs of NHC in plasma and of its active metabolite, NHC-triphosphate (NHC-TP), in peripheral blood mononuclear cells (PBMCs). Molnupiravir was generally well-tolerated. All adverse events were mild or moderate in severity and none led to treatment discontinuation. No clinically meaningful dose-related safety findings were observed. Mean time to maximal concentration was ~1.50 to 1.98 h for plasma NHC and ~4.00 to 8.06 h for PBMC NHC-TP. Accumulation was minimal (<1.2) for NHC and ~2- to 2.5-fold for NHC-TP. Plasma NHC PKs was generally dose proportional, and PBMC NHC-TP PKs was less than dose proportional over the dose range studied. NHC and NHC-TP PK support twice-daily administration. Overall, molnupiravir administered at up to 800 mg q12h for 10.5 days was generally well-tolerated in healthy participants with dose-linear PKs, supporting the evaluation of longer molnupiravir dosing up to 10 days in future clinical trials.


Assuntos
Leucócitos Mononucleares , Adulto , Humanos , Voluntários Saudáveis , Meia-Vida , Método Duplo-Cego , Relação Dose-Resposta a Droga
2.
Clin Transl Sci ; 15(11): 2697-2708, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36053806

RESUMO

Molnupiravir (MK-4482) is an oral prodrug of the antiviral ribonucleoside analog, N-hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in healthy Japanese adult participants. A sample size larger than typically used in pharmacokinetic studies was implemented to collect additional safety data in the Japanese population to support special approval for emergency use in Japan. Single doses of molnupiravir up to 1600 mg and multiple doses of 400 and 800 mg administered every 12 h (q12h) for 5.5 days were generally well-tolerated. NHC appeared rapidly in plasma and reached maximum concentration (Cmax ), with a median time to Cmax (Tmax ) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC0-inf ), area under the concentration versus time curve from zero to 12 h (AUC0-12 ), and Cmax of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC0-12 and Cmax were ~1 for 400 and 800 mg. Pharmacokinetics of NHC triphosphate (NHC-TP), the active metabolite of NHC was assessed in peripheral blood mononuclear cells and also demonstrated roughly dose proportional pharmacokinetics. The GM accumulation ratios for NHC-TP AUC0-12 and Cmax were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC Cmax with comparable AUC0-inf was seen, supporting administration without regard to food.


Assuntos
Tratamento Farmacológico da COVID-19 , Adulto , Humanos , Japão/epidemiologia , Leucócitos Mononucleares , SARS-CoV-2 , Voluntários Saudáveis
3.
Thromb Haemost ; 113(4): 719-27, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25566930

RESUMO

Edoxaban is an oral, direct, once-daily, factor Xa inhibitor developed for stroke prevention in patients with atrial fibrillation and for the treatment and secondary prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism. Among elderly patients who require anticoagulation therapies, some may have end-stage renal disease (ESRD). This open-label, phase 1, randomised, two-way crossover study was conducted to evaluate the pharmacokinetics of edoxaban in 10 subjects on haemodialysis. Eligible subjects with ESRD on chronic haemodialysis received a single, oral dose of edoxaban 15 mg 2 hours (h) prior to (on-dialysis) or in between (off-dialysis) haemodialysis sessions. Haemodialysis resulted in a minor decrease in mean total exposure (AUC0-∞; 676.2 ng·h/ml) as compared with that observed in subjects off-dialysis (691.7 ng·h/ml). Mean maximum observed plasma concentration (Cmax) values were comparable between on-dialysis and off-dialysis treatments (53.3 vs 56.3 ng/ml, respectively). Mean apparent total body clearance (CL/F) values were 24.1 and 22.5 l/h during the on-dialysis and off-dialysis treatment periods, respectively. Dialyser clearance was 5.7 l/h and haemodialysis clearance was 6.1 l/h. Haemodialysis clearance was only 6.1 l/h, suggesting that it only accounts for one-fourth of the total clearance in these subjects. A single, oral dose of 15 mg of edoxaban was well tolerated by subjects with ESRD. In conclusion, based on these single-dose PK data, a supplementary dose of edoxaban may not be required following a haemodialysis session. Importantly, haemodialysis is not an effective mechanism for removal of edoxaban from the blood.


Assuntos
Inibidores do Fator Xa/farmacocinética , Falência Renal Crônica/terapia , Piridinas/farmacocinética , Diálise Renal , Tiazóis/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Estudos Cross-Over , Esquema de Medicação , Monitoramento de Medicamentos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Meia-Vida , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Resultado do Tratamento
4.
J Clin Pharmacol ; 49(10): 1185-95, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19783712

RESUMO

Quantitative structure-property relationship (QSPR) models were developed to correlate physicochemical properties of structurally unrelated drugs with extent of in vitro binding to colesevelam, and predicted values were compared with drug exposure changes in vivo following coadministration. The binding of 17 drugs to colesevelam was determined by an in vitro dissolution drug-binding assay. Data from several clinical studies in healthy volunteers to support administration of colesevelam in diabetic patients were also collected along with existing in vivo literature data and compared with in vitro results. Steric, electronic, and hydrophobic descriptors were calculated for test compounds, and univariate and partial least squares regression approaches were used to derive QSPR models to evaluate which of the molecular descriptors correlated best with in vitro binding. A quadrant analysis evaluated the correlation between predicted/actual in vitro binding results and the in vivo data. The in vitro binding assay exhibited high sensitivity, identifying those compounds with a low probability of producing relevant in vivo drug interactions. Drug lipophilicity was identified as the primary determinant of in vitro binding to colesevelam by the final univariate and partial least squares models (R(2) = 0.69 and 0.98; Q(2) = 0.48 and 0.59). The in vitro assay and in silico models represent predictive tools that may allow investigators to conduct only informative clinical drug interaction studies with colesevelam.


Assuntos
Alilamina/análogos & derivados , Anticolesterolemiantes/farmacocinética , Hipoglicemiantes/farmacocinética , Modelos Moleculares , Medicamentos sob Prescrição/farmacocinética , Relação Quantitativa Estrutura-Atividade , Alilamina/química , Alilamina/farmacocinética , Anticolesterolemiantes/química , Ácidos e Sais Biliares/metabolismo , Resina de Colestiramina/química , Resina de Colestiramina/farmacocinética , Ensaios Clínicos como Assunto , Cloridrato de Colesevelam , Interações Medicamentosas , Humanos , Hipoglicemiantes/química , Técnicas In Vitro , Medicamentos sob Prescrição/química
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