RESUMEN
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.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Adulto , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Método Doble Ciego , Humanos , Pandemias/prevención & control , SARS-CoV-2 , VacunasRESUMEN
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.
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Anticolesterolemiantes/uso terapéutico , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Enfermedad Coronaria/tratamiento farmacológico , Oxazolidinonas/uso terapéutico , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/toxicidad , Perros , Humanos , Macaca mulatta , Ratones Endogámicos C57BL , Estructura Molecular , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacocinética , Oxazolidinonas/toxicidad , Ratas Wistar , Relación Estructura-ActividadRESUMEN
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.
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Anticolesterolemiantes/farmacocinética , Oxazolidinonas/farmacocinética , Grupos Raciales , Adulto , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/sangre , Área Bajo la Curva , Esquema de Medicación , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Oxazolidinonas/administración & dosificación , Oxazolidinonas/efectos adversos , Oxazolidinonas/sangre , Adulto JovenRESUMEN
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.
Asunto(s)
Anticolesterolemiantes/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Oxazolidinonas/farmacología , Adulto , Anticolesterolemiantes/sangre , Pueblo Asiatico , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Citocromo P-450 CYP3A/metabolismo , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Oxazolidinonas/sangre , Población Blanca , Adulto JovenRESUMEN
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.
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Anticolesterolemiantes/farmacocinética , Enfermedades Renales/metabolismo , Hepatopatías/metabolismo , Oxazolidinonas/farmacocinética , Adulto , Anciano , Anticolesterolemiantes/sangre , Área Bajo la Curva , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , Oxazolidinonas/sangreRESUMEN
Anacetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor in development for treatment of dyslipidemia. This open-label, fixed-sequence, 3-period study was intended to evaluate the potential of anacetrapib to be a victim of OATP1B1/3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin, respectively, as a probe. In this study, 16 healthy subjects received 100 mg anacetrapib administered without rifampin (Day 1, Period 1), with single-dose (SD) 600 mg rifampin (Day 1, Period 2), and with multiple-dose (MD) 600 mg rifampin for 20 days (Day 14, Period 3). Log-transformed anacetrapib AUC0-∞ and Cmax were analyzed by a linear mixed effects model. The GMRs and 90% CIs for anacetrapib AUC0-∞ and Cmax were 1.25 (1.04, 1.51) and 1.43 (1.13, 1.82) for SD rifampin (Period 2/Period 1) and 0.35 (0.29, 0.42) and 0.26 (0.21, 0.32) for MD rifampin (Period 3/Period 1), respectively. Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin. In conclusion, treatment with SD rifampin, which inhibits the OATP1B1/3 transporter system, did not substantially influence the SD pharmacokinetics of anacetrapib, while chronic (20 days) administration of rifampin, which strongly induces CYP3A isozymes, reduced mean systemic exposure to SD anacetrapib by 65%.
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Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Transportadores de Anión Orgánico/antagonistas & inhibidores , Oxazolidinonas/administración & dosificación , Oxazolidinonas/farmacocinética , Rifampin/farmacología , Adulto , Área Bajo la Curva , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Femenino , Humanos , Inactivación Metabólica , Transportador 1 de Anión Orgánico Específico del Hígado , Masculino , Persona de Mediana Edad , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Rifampin/efectos adversos , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos , Adulto JovenAsunto(s)
Conducta Cooperativa , Conducta Alimentaria/psicología , Trastornos de Alimentación y de la Ingestión de Alimentos/enfermería , Trastornos de Alimentación y de la Ingestión de Alimentos/prevención & control , Comunicación Interdisciplinaria , Trastornos Mentales/enfermería , Adulto , Obstrucción de las Vías Aéreas/enfermería , Obstrucción de las Vías Aéreas/prevención & control , Obstrucción de las Vías Aéreas/psicología , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Conducta Alimentaria/efectos de los fármacos , Humanos , Masculino , Trastornos Mentales/psicología , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/enfermería , Trastornos Psicóticos/psicología , Quebec , Factores de RiesgoRESUMEN
UNLABELLED: The End-Stage Renal Disease population is aging. Considering that hemodialysis is a treatment that maintains and prolongs life, this descriptive-comparative study looks at the perceptions of patients according to age group -< 65 years, n = 121 and ≥ 65 years, n = 123, as it pertains to dialysis treatment cessation and life-sustaining treatments. RESULTS: Older patients are more indecisive as to what dialysis treatment cessation may actually represent for them (p = 0,01). They expressed a greater need for support from the health care team if they decided to stop dialysis treatments (p = 0,02); a greater involvement from the physician (p = 0,04); and, in the event patients could not take part in end-of-life decision-making, they would give priority to the wishes of loved ones instead of their own wishes (p = 0,01). CONCLUSION: Advanced care planning is necessary to demystify hemodialysis withdrawal and to support patients and their loved ones through this process.
Asunto(s)
Actitud Frente a la Salud , Cuidados para Prolongación de la Vida , Diálisis Renal , Privación de Tratamiento , Factores de Edad , Anciano , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , QuebecRESUMEN
Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D2, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.
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Ácidos Grasos/metabolismo , Niacina/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Ácidos Grasos/sangre , Humanos , Lipólisis/efectos de los fármacos , Lipoproteínas/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Niacina/administración & dosificación , Pirazoles/farmacología , Receptores Acoplados a Proteínas G/agonistasRESUMEN
G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.
Asunto(s)
Ácidos Grasos no Esterificados/sangre , Pirazoles/uso terapéutico , Receptores Acoplados a Proteínas G/agonistas , Animales , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/uso terapéutico , Masculino , Niacina/farmacología , Pirazoles/síntesis química , Pirazoles/farmacocinética , Ratas , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacos , Estereoisomerismo , Vasodilatadores/farmacologíaRESUMEN
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.
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Anticoagulantes/farmacología , Anticoagulantes/farmacocinética , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Oxazolidinonas/farmacología , Warfarina/farmacología , Warfarina/farmacocinética , Administración Oral , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Humanos , Masculino , Persona de Mediana Edad , Tiempo de Protrombina , Adulto JovenRESUMEN
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.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Dislipidemias/tratamiento farmacológico , Oxazolidinonas/farmacocinética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios Cruzados , Método Doble Ciego , Ayuno , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad , Oxazolidinonas/administración & dosificación , Oxazolidinonas/farmacología , Factores Sexuales , Resultado del Tratamiento , Adulto JovenRESUMEN
Laropiprant, an antagonist of the PGD(2) receptor, DP1, is effective in reducing the flushing symptoms associated with extended-release (ER) niacin and thereby improves the tolerability of niacin therapy for dyslipidemia. Because PGD(2) has been reported to inhibit platelet aggregation in vitro, it has been speculated that antagonism of DP1 may enhance platelet reactivity. Three clinical studies evaluated the potential effect of laropiprant, with or without coadministration of ER niacin, on in vivo platelet function in healthy subjects and hypercholesterolemic or diabetic subjects by measuring urinary levels of 11-dehydrothromboxane B(2) (11-dTxB(2)), a marker of in vivo platelet activation. Following 7 days of multiple-dose administration, coadministration of laropiprant with ER niacin did not increase urinary 11-dTxB(2) levels compared to ER niacin alone in healthy, hypercholesterolemic, or diabetic subjects. In hypercholesterolemic and diabetic subjects, laropiprant did not increase urinary 11-dTxB(2) levels compared to placebo. These results demonstrate that laropiprant does not enhance in vivo platelet reactivity, either alone or in combination with niacin.
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Plaquetas/efectos de los fármacos , Diabetes Mellitus/sangre , Hipercolesterolemia/sangre , Indoles/farmacología , Niacina/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Tromboxano B2/análogos & derivados , Adolescente , Adulto , Anciano , Biomarcadores/orina , Plaquetas/metabolismo , Estudios Cruzados , Preparaciones de Acción Retardada , Método Doble Ciego , Epoprostenol/metabolismo , Femenino , Humanos , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Niacina/administración & dosificación , Niacina/efectos adversos , Activación Plaquetaria , Prostaglandina D2/metabolismo , Tromboxano B2/metabolismo , Tromboxano B2/orina , Adulto JovenAsunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Hipolipemiantes/administración & dosificación , Hipolipemiantes/farmacocinética , Pirazinas/farmacología , Simvastatina/farmacocinética , Triazoles/farmacología , Adulto , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Pirazinas/administración & dosificación , Simvastatina/administración & dosificación , Fosfato de Sitagliptina , Factores de Tiempo , Triazoles/administración & dosificaciónRESUMEN
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.
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Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Sistema Enzimático del Citocromo P-450/fisiología , Oxazolidinonas/farmacología , Adolescente , Adulto , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Interacciones Farmacológicas , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Cetoconazol/farmacología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Midazolam/farmacología , Persona de Mediana Edad , Oxazolidinonas/efectos adversos , Adulto JovenRESUMEN
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.
Asunto(s)
Amidas/farmacocinética , Fármacos Antiobesidad/farmacocinética , Piridinas/farmacocinética , Receptor Cannabinoide CB1/efectos de los fármacos , Adulto , Amidas/administración & dosificación , Amidas/efectos adversos , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/efectos adversos , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Agonismo Inverso de Drogas , Semivida , Humanos , Masculino , Persona de Mediana Edad , Obesidad/tratamiento farmacológico , Piridinas/administración & dosificación , Piridinas/efectos adversosRESUMEN
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).
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Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Piridinas/farmacocinética , Receptor Cannabinoide CB1/metabolismo , Recuento Corporal Total , Adulto , Carga Corporal (Radioterapia) , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Especificidad de Órganos , Dosis de Radiación , Cintigrafía , Radiofármacos/análisis , Radiofármacos/farmacocinética , Valores de Referencia , Efectividad Biológica Relativa , Distribución TisularRESUMEN
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.
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Amidas/efectos adversos , Amidas/farmacocinética , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/farmacocinética , Piridinas/efectos adversos , Piridinas/farmacocinética , Receptor Cannabinoide CB1/agonistas , Adolescente , Adulto , Amidas/farmacología , Análisis de Varianza , Fármacos Antiobesidad/farmacología , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Semivida , Humanos , Masculino , Piridinas/farmacologíaRESUMEN
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.
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Amidas/farmacología , Ingestión de Energía/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Piridinas/farmacología , Receptor Cannabinoide CB1/agonistas , Pérdida de Peso/efectos de los fármacos , Adulto , Anciano , Amidas/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Grasas/metabolismo , Humanos , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Piridinas/uso terapéuticoRESUMEN
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.