RESUMO
Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.
Assuntos
Amidas/farmacologia , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Piridinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Redução de Peso/efeitos dos fármacos , Adulto , Idoso , Amidas/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Gorduras/metabolismo , Humanos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Piridinas/uso terapêuticoRESUMO
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: ⢠Inhibition of cholesteryl ester transfer protein (CETP) is a potential new mechanism for the treatment of dyslipidaemia. Anacetrapib is a novel CETP inhibitor in development. Warfarin is a commonly prescribed anticoagulant that has a narrow therapeutic index. A drug interaction study for warfarin with a novel CETP inhibitor is expected to be helpful in defining dosing regimens. WHAT THIS STUDY: ADDS ⢠This is the first study to show that there is no clinically meaningful pharmacokinetic interaction between anacetrapib and warfarin. The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib. AIM: Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted. METHODS: In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 × 10 mg Coumadin(TM) ) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of anacetrapib (1 × 100 mg) beginning on day -14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 × 10 mg) on day 1. All anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied. RESULTS: Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC((0-∞)) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(-) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin C(max) were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(-) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC((0-168 h)) was 0.93 (0.89, 0.96). CONCLUSION: The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib.
Assuntos
Anticoagulantes/farmacologia , Anticoagulantes/farmacocinética , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Oxazolidinonas/farmacologia , Varfarina/farmacologia , Varfarina/farmacocinética , Administração Oral , Adolescente , Adulto , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina , Adulto JovemRESUMO
BACKGROUND: Vaccines against COVID-19 are needed to overcome challenges associated with mitigating the global pandemic. We report the safety and immunogenicity of V590, a live recombinant vesicular stomatitis virus-based COVID-19 vaccine candidate. METHODS: In this placebo-controlled, double-blind, three-part phase 1 study, healthy adults were randomised to receive a single intramuscular dose of vaccine or placebo. In Part 1, younger (18-54 years) and, in Part 2, older (≥55 years) adults seronegative for SARS-CoV-2 nucleocapsid received one of four V590 dose levels (5.00 × 105; 2.40 × 106; 1.15 × 107; or 5.55 × 107 plaque-forming units [pfu]) or placebo. In Part 3, a single V590 dose level (5.55 × 107 pfu) or placebo was administered to younger SARS-CoV-2 seropositive adults. Primary endpoints included adverse events (AEs) and for Parts 1 and 2 anti-SARS-CoV-2 serum neutralising antibody responses measured by 50% plaque reduction neutralisation (PRNT50) assay at Day 28. Registration NCT04569786 [P001-02]. FINDINGS: 232 participants were randomised and 219 completed the study. In seronegative participants, anti-SARS-CoV-2 spike-specific antibody responses to V590 were low and comparable to placebo across the lower dose levels. At the highest dose level (5.55 × 107 pfu), anti-SARS-CoV-2 spike-specific PRNT50 was 2.3-fold higher than placebo. The most frequently reported AEs were injection-site pain (38.4%), headache (15.1%) and fatigue (13.4%). INTERPRETATION: V590 was generally well-tolerated. However, Day 28 anti-SARS-Cov-2 spike-specific antibody responses in seronegative participants following a single intramuscular administration of V590 were not sufficient to warrant continued development. FUNDING: The study was funded by Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Adulto , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Método Duplo-Cego , Humanos , Pandemias/prevenção & controle , SARS-CoV-2 , VacinasRESUMO
Neuropeptide Y (NPY) is a potent orexigenic neuropeptide, and antagonism of NPY Y1 and NPY Y5 receptors (NPYxR) is considered a potentially important anti-obesity drug target. We tested the hypothesis that blockade of the NPY5R will lead to weight loss in humans using MK-0557, a potent, highly selective, orally active NPY5R antagonist. The initial series of experiments reported herein, including a multiple-dose positron-emission tomography study and a 12 week proof-of concept/dose-ranging study, suggested an optimal MK-0557 dose of 1 mg/day. The hypothesis was then tested in a 52 week, multicenter, randomized, double-blind, placebo-controlled trial involving 1661 overweight and obese patients. Although statistically significant at 52 weeks, the magnitude of induced weight loss was not clinically meaningful. These observations provide the first clinical insight into the human NPY-energy homeostatic pathway and suggest that solely targeting the NPY5R in future drug development programs is unlikely to produce therapeutic efficacy.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Cicloexanos/uso terapêutico , Obesidade/tratamento farmacológico , Pirazóis/uso terapêutico , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Compostos de Espiro/uso terapêutico , Administração Oral , Adolescente , Adulto , Idoso , Fármacos Antiobesidade/administração & dosagem , Peso Corporal , Cicloexanos/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Estrutura Molecular , Placebos , Tomografia por Emissão de Pósitrons/métodos , Pirazóis/administração & dosagem , Receptores de Neuropeptídeo Y/metabolismo , Sensibilidade e Especificidade , Compostos de Espiro/administração & dosagem , Relação Estrutura-Atividade , Resultado do TratamentoRESUMO
Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.
Assuntos
Anticolesterolemiantes/uso terapêutico , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Doença das Coronárias/tratamento farmacológico , Oxazolidinonas/uso terapêutico , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/toxicidade , Cães , Humanos , Macaca mulatta , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazolidinonas/síntese química , Oxazolidinonas/farmacocinética , Oxazolidinonas/toxicidade , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Sistema Enzimático do Citocromo P-450/fisiologia , Oxazolidinonas/farmacologia , Adolescente , Adulto , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Interações Medicamentosas , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Cetoconazol/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Midazolam/farmacologia , Pessoa de Meia-Idade , Oxazolidinonas/efeitos adversos , Adulto JovemRESUMO
AIMS: Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. METHODS: Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. RESULTS: Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. CONCLUSIONS: Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Dislipidemias/tratamento farmacológico , Oxazolidinonas/farmacocinética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Método Duplo-Cego , Jejum , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade , Oxazolidinonas/administração & dosagem , Oxazolidinonas/farmacologia , Fatores Sexuais , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for treatment of dyslipidaemia. Anacetrapib (MK-0859) is a CETP inhibitor currently under development. We aimed to assess anacetrapib's effects as monotherapy on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and on 24-h ambulatory blood pressure. METHODS: We did two double-blind, randomised, placebo-controlled phase I studies. In the first study, 50 patients with dyslipidaemia (LDL-C 100-190 mg/dL; 40 active, 10 placebo) aged 18-75 years received anacetrapib doses of 0, 10, 40, 150, or 300 mg orally once a day with a meal for 28 days. Standard lipid and lipoprotein monitoring, safety monitoring, and anacetrapib concentrations for pharmacokinetics were done. In the second study, 22 healthy participants aged 45-75 years received either 150 mg of anacetrapib once a day or matching placebo with a meal for 10 days in each crossover period, in a randomised sequence, with at least a 14-day washout between the treatment periods. Continuous 24-h ambulatory blood pressure monitoring was done on day -1 and day 10 of each treatment period in this study. The primary or secondary endpoints of safety and tolerability were assessed in both studies by monitoring clinical adverse experiences, physical examinations, vital signs, 12-lead electrocardiogram, and laboratory safety. Analysis was per protocol. These trials are registered with ClinicalTrials.gov, number NCT00565292 and NCT00565006. FINDINGS: In the dyslipidaemia study, one patient withdrew consent and one was excluded from the data analysis for HDL-C and LDL-C because complete pre-dose measurements were not available. Anacetrapib produced dose-dependent lipid-altering effects with peak lipid-altering effects of 129% (mean 51.1 [SD 3.8]-114.9 [7.9] mg/dL) increase in HDL-C and a 38% (138.2 [11.4]-77.6 [7.9] mg/dL) decrease in LDL-C in patients with dyslipidaemia. In the 24-h ambulatory blood pressure study in healthy individuals, least squares difference between anacetrapib and placebo groups on day 10 were 0.60 (90% CI -1.54 to 2.74; p=0.634) mm Hg for systolic blood pressure and 0.47 (90% CI -0.90 to 1.84; p=0.561) mm Hg for diastolic blood pressure. INTERPRETATION: Anacetrapib seems to exhibit HDL-C increases greater than those seen with other investigational drugs in this class and LDL-C lowering effects similar to statins. Despite greater lipid-altering effects relative to other members of this class, anacetrapib seems not to increase blood pressure, suggesting that potent CETP inhibition by itself might not lead to increased blood pressure.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Dislipidemias/tratamento farmacológico , Oxazolidinonas/uso terapêutico , Adolescente , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Dislipidemias/sangue , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
UNLABELLED: The cannabinoid type-1 (CB1) receptor is one of the most abundant G-coupled protein receptors in the human body and is responsible for signal transduction of both endogenous and exogenous cannabinoids. The endocannabinoid system is strongly implicated in regulation of homeostasis and several neuropsychiatric disorders, obesity, and associated comorbidities, such as dyslipidemia and metabolic syndrome. We have used whole-body PET/CT to characterize the biodistribution and dosimetry of a novel high-affinity, subtype-selective radioligand, (18)F-MK-9470, in healthy male and female subjects. METHODS: Eight nonobese subjects (5 men, 3 women; age, 22-54 y) underwent serial whole-body PET/CT for 6 h after a bolus injection of 251 +/- 25 MBq (18)F-MK-9470 (N-[2-(3-cyano-phenyl)-3-(4-(2-(18)F-fluorethoxy)phenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylproponamide). Source organs were delineated 3-dimensionally using the combined morphologic and functional data. Residence times were derived from time-activity profiles using both the trapezoid rule and curve fitting. Individual organ doses and effective doses were determined using the OLINDA software package, with different approaches for gastrointestinal and urinary excretion modeling. RESULTS: (18)F-MK-9470 is taken up slowly in the brain, reaching a plateau at approximately 90-120 min after bolus injection and is excreted predominantly through the hepatobiliary system. The gallbladder, upper large intestine, small intestine, and liver are the organs with the highest absorbed dose (average: 159, 98, 87, and 86 microGy/MBq, respectively). The mean effective dose (ED) was 22.8 +/- 4.3 microSv/MBq, indicating relatively low intersubject variability and a mean value in the range of many commercially available (18)F-labeled radiopharmaceuticals. Brain uptake was relatively high compared with that of existing central nervous system ligands for other receptors, between 3.2% and 4.9% of the injected dose. CONCLUSION: The estimated radiation burden of (18)F-MK-9470 for PET CB1 receptor imaging shows relatively low variability between subjects and has an acceptable ED, which allows multiple serial cerebral scans of good image quality, while remaining within the risk category class II-b defined by the World Health Organization and the International Commission for Radiation Protection for a standard injected activity (185-370 MBq).
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Piridinas/farmacocinética , Receptor CB1 de Canabinoide/metabolismo , Contagem Corporal Total , Adulto , Carga Corporal (Radioterapia) , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Especificidade de Órgãos , Doses de Radiação , Cintilografia , Compostos Radiofarmacêuticos/análise , Compostos Radiofarmacêuticos/farmacocinética , Valores de Referência , Eficiência Biológica Relativa , Distribuição TecidualRESUMO
Taranabant is a novel cannabinoid CB-1 receptor (CB1R) inverse agonist in clinical development for the treatment of obesity. This double-blind, randomized, placebo-controlled, single oral dose study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of taranabant (0.5-600 mg) in 24 healthy male volunteers. Single-dose AUC(0-infinity) and C(max) values for taranabant increased approximately linearly with dose up to 200 mg, with slightly less than dose-proportional increases in AUC(0-infinity) and C(max) values for doses >200 mg. Plasma taranabant had a biphasic disposition, with a median t(max) of 1 to 2.5 hours and a terminal elimination t((1/2)) of 38 to 69 hours. Coadministration of taranabant with a high-fat meal led to a 14% increase in C(max) and a 74% increase in AUC(0-infinity). Clinical adverse experiences associated with single doses of taranabant were generally mild and transient. Of the 198 clinical adverse experiences reported, the most common drug-related ones were nausea (36), headache (22), drowsiness (14), abdominal discomfort/abdominal pain/stomachache (14), hiccups (9), dizziness (8), decreased appetite (7), increased bowel movement (7), mood change (6), tiredness (4), vomiting (4), and sweating increased (4). Taranabant has pharmacokinetic characteristics suitable for a once-daily dosing regimen.
Assuntos
Amidas/efeitos adversos , Amidas/farmacocinética , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Receptor CB1 de Canabinoide/agonistas , Adolescente , Adulto , Amidas/farmacologia , Análise de Variância , Fármacos Antiobesidade/farmacologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Masculino , Piridinas/farmacologiaRESUMO
Taranabant is a cannabinoid-1 receptor inverse agonist for the treatment of obesity. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of taranabant (5, 7.5, 10, or 25 mg once daily for 14 days) in 60 healthy male subjects. Taranabant was rapidly absorbed, with a median t(max) of 1.0 to 2.0 hours and a t(1/2) of approximately 74 to 104 hours. Moderate accumulation was observed in C(max) (1.18- to 1.40-fold) and AUC(0-24 h) (1.5- to 1.8-fold) over 14 days for the 5-, 7.5-, and 10-mg doses, with an accumulation half-life ranging from 15 to 21 hours. Steady state was reached after 13 days. After multiple-dose administration, plasma AUC(0-24 h) and C(max) of taranabant increased dose proportionally (5-10 mg) and increased somewhat less than dose proportionally for 25 mg. Taranabant was generally well tolerated up to doses of 10 mg and exhibited multiple-dose pharmacokinetics consistent with once-daily dosing.
Assuntos
Amidas/farmacocinética , Fármacos Antiobesidade/farmacocinética , Piridinas/farmacocinética , Receptor CB1 de Canabinoide/efeitos dos fármacos , Adulto , Amidas/administração & dosagem , Amidas/efeitos adversos , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Agonismo Inverso de Drogas , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Piridinas/administração & dosagem , Piridinas/efeitos adversosAssuntos
Comportamento Cooperativo , Comportamento Alimentar/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/enfermagem , Transtornos da Alimentação e da Ingestão de Alimentos/prevenção & controle , Comunicação Interdisciplinar , Transtornos Mentais/enfermagem , Adulto , Obstrução das Vias Respiratórias/enfermagem , Obstrução das Vias Respiratórias/prevenção & controle , Obstrução das Vias Respiratórias/psicologia , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Comportamento Alimentar/efeitos dos fármacos , Humanos , Masculino , Transtornos Mentais/psicologia , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/enfermagem , Transtornos Psicóticos/psicologia , Quebeque , Fatores de RiscoRESUMO
Anacetrapib is a cholesteryl ester transfer protein inhibitor intended for the treatment of dyslipidemia. A phase 1 study was conducted to examine the pharmacokinetics and pharmacodynamics of multiple doses of anacetrapib in black compared to white healthy subjects. Although there was no apparent race-related pharmacokinetic effect, attenuation of the lipid response was observed in black subjects. Specifically, high-density lipoprotein cholesterol percentage increased 18.1% (absolute percentage points) less in black subjects (89.9%) when compared to increases in white subjects (108.0%). Similarly, the decrease in low-density lipoprotein cholesterol was 17.8% (absolute percentage points) less in blacks (-21.2%) relative to whites (-39.0%). In contrast, there were no apparent race-related differences in cholesteryl ester transfer protein mass or activity. Anacetrapib was generally well tolerated in this study. The results of this study suggest that there may be race-related differences in pharmacodynamics of anacetrapib independent of pharmacokinetics.
Assuntos
Anticolesterolemiantes/farmacocinética , Oxazolidinonas/farmacocinética , Grupos Raciais , Adulto , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/sangue , Área Sob a Curva , Esquema de Medicação , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Oxazolidinonas/administração & dosagem , Oxazolidinonas/efeitos adversos , Oxazolidinonas/sangue , Adulto JovemRESUMO
Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary anacetrapib levels were all below quantitation limits. Plasma concentrations of anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects.
Assuntos
Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Oxazolidinonas/farmacologia , Adulto , Anticolesterolemiantes/sangue , Povo Asiático , Proteínas de Transferência de Ésteres de Colesterol/sangue , Citocromo P-450 CYP3A/metabolismo , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Masculino , Oxazolidinonas/sangue , População Branca , Adulto JovemRESUMO
The effects of etoricoxib on pharmacodynamic and pharmacokinetic parameters of warfarin were determined in healthy men and women. Subjects titrated with warfarin to an international normalized ratio for prothrombin time of 1.4 to 1.7 during a 28-day prestudy period were randomly assigned in crossover fashion to be coadministered etoricoxib (120 mg) or matching placebo over two 21-day continuous periods. On day 21, a 24-hour pharmacokinetic profile of both S(-) and R(+) warfarin, as well as international normalized ratio values, were determined. Etoricoxib increased the international normalized ratio by 13% (90% confidence interval: 8%, 19%; P = .001). Etoricoxib had no effect on the pharmacokinetics of S(-) warfarin but led to a modest increase in the AUC(24 h) ( approximately 10%) of R(+) warfarin. This increase in the international normalized ratio is not likely to be clinically important in most patients; however, the international normalized ratio of patients coadministered oral anticoagulants and etoricoxib should be closely monitored, particularly during initiation of therapy.
Assuntos
Anticoagulantes/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Piridinas/farmacologia , Sulfonas/farmacologia , Varfarina/farmacologia , Adulto , Anticoagulantes/farmacocinética , Estudos Cross-Over , Método Duplo-Cego , Etoricoxib , Feminino , Humanos , Coeficiente Internacional Normatizado , Masculino , Tempo de Protrombina , Varfarina/farmacocinéticaRESUMO
Sitagliptin (MK-0431) is an orally active, potent, and selective dipeptidyl peptidase-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P-glycoprotein in preclinical studies. Cyclosporine was used as a probe P-glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P-glycoprotein inhibition on single-dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600-mg dose of cyclosporine with a single 100-mg oral sitagliptin dose and a single oral 100-mg sitagliptin dose alone in an open-label, randomized, 2-period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC(0-infinity) geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin Cmax geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t(1/2), or C(24 h), suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Ciclosporina/farmacologia , Pirazinas/farmacocinética , Triazóis/farmacocinética , Inibidores de Adenosina Desaminase , Adulto , Estudos Cross-Over , Ciclosporina/efeitos adversos , Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV , Interações Medicamentosas , Glicoproteínas/antagonistas & inibidores , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Rim/metabolismo , Masculino , Pirazinas/efeitos adversos , Pirazinas/sangue , Fosfato de Sitagliptina , Triazóis/efeitos adversos , Triazóis/sangueRESUMO
The effect of hepatic insufficiency on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, was investigated following administration of single and multiple oral doses to mild hepatic insufficiency patients (Child-Pugh score of 5 to 6), multiple oral doses to moderate hepatic insufficiency patients (Child-Pugh score of 7 to 9), and single intravenous doses to both mild and moderate hepatic insufficiency patients. A trend of decreasing systemic clearance with increasing hepatic impairment was observed. Absorption of etoricoxib was unaffected by hepatic impairment. Binding of etoricoxib to plasma proteins was also found to be unaffected by hepatic disease. Etoricoxib was generally well tolerated by patients with mild and moderate hepatic insufficiency. Together, these results support a 60-mg once-daily dosing regimen for mild hepatic insufficiency patients and a 60-mg every-other-day dosing regimen for moderate hepatic insufficiency patients. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score > 9).
Assuntos
Hepatopatias/tratamento farmacológico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Sulfonas/farmacocinética , Sulfonas/uso terapêutico , Administração Oral , Idoso , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Relação Dose-Resposta a Droga , Esquema de Medicação , Etoricoxib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/sangue , Sulfonas/sangueAssuntos
Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipolipemiantes/administração & dosagem , Hipolipemiantes/farmacocinética , Pirazinas/farmacologia , Sinvastatina/farmacocinética , Triazóis/farmacologia , Adulto , Estudos Cross-Over , Interações Medicamentosas , Feminino , Humanos , Masculino , Pirazinas/administração & dosagem , Sinvastatina/administração & dosagem , Fosfato de Sitagliptina , Fatores de Tempo , Triazóis/administração & dosagemRESUMO
The effect of renal insufficiency on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, was examined in 23 patients with varying degrees of renal impairment (12 moderate [creatinine clearance between 30 and 50 mL/min/1.73 m2], 5 severe [creatinine clearance below 30 mL/min/1.73 m2], and 6 with end-stage renal disease requiring hemodialysis) following administration of single 120-mg oral doses of etoricoxib. Even the most severe renal impairment was found to have little effect on etoricoxib pharmacokinetics. The low recovery of etoricoxib in dialysate (less than 6% of the dose) supports that hemodialysis also has little effect on etoricoxib pharmacokinetics, and binding of etoricoxib to plasma proteins was generally unaffected by renal disease. Single doses of etoricoxib were generally well tolerated by patients with renal impairment. Based on pharmacokinetic considerations, dosing adjustments are not necessary for patients with any degree of renal impairment. However, because patients with advanced renal disease (creatinine clearance below 30 mL/min/1.73 m2) are likely to be very sensitive to any further compromise of renal function, and there is no long-term clinical experience in these patients, the use of etoricoxib is not recommended in patients with advanced renal disease.
Assuntos
Inibidores de Ciclo-Oxigenase/farmacocinética , Falência Renal Crônica/metabolismo , Piridinas/farmacocinética , Sulfonas/farmacocinética , Administração Oral , Adulto , Idoso , Área Sob a Curva , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Etoricoxib , Feminino , Meia-Vida , Humanos , Falência Renal Crônica/terapia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Ligação Proteica , Diálise RenalRESUMO
Two open-label, parallel-group studies evaluated the influence of renal and hepatic insufficiency on the pharmacokinetics of a single-dose anacetrapib 100 mg. Eligible participants included adult men and women with moderate hepatic impairment (assessed by Child-Pugh criteria) or severe renal impairment (CrCl <30 mL/min/1.73 m(2)). In both studies, patients were matched (race, age, sex, BMI) with healthy control subjects. Twenty-four subjects were randomized in each study (12 with either moderate hepatic or severe renal impairment and 12 matched healthy controls). In the hepatic insufficiency study, the geometric mean ratio (GMR; mean value for the group with moderate hepatic insufficiency/mean value for the healthy controls) and 90% CIs for the area under the concentration-time curve from time zero to infinity (AUC(0-∞)) and the maximum concentration of drug in plasma (C(max)) were 1.16 (0.84, 1.60) and 1.02 (0.71, 1.49), respectively. In the renal insufficiency study, the GMRs (mean value for the group with severe renal insufficiency/mean value for the healthy controls) and 90% CIs for AUC(0-∞) and Cmax were 1.14 (0.80, 1.63) and 1.31 (0.93, 1.83), respectively. Anacetrapib was generally well tolerated and there was no clinically meaningful effect of moderate hepatic or severe renal insufficiency on the pharmacokinetics of anacetrapib.