RESUMEN
Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development. The structural model that best described obicetrapib PK was a 3-compartment model with 4-compartment transit absorption and first-order elimination. Body weight was the only covariate found to significantly explain observed variability and was therefore included using allometric scaling on all disposition parameters. For a typical patient weighing 75 kg, the estimated apparent total body clearance and apparent volume of distribution of the central compartment was 0.81 L/h and 36.1 L, respectively. The final PK model parameters were estimated with good precision and were ultimately leveraged to sequentially inform 2 turnover models that describe obicetrapib's effect on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) concentrations. The maximum stimulatory effect of obicetrapib on LDL-C loss was estimated to be 1.046, while the maximum inhibitory effect of obicetrapib on HDL-C loss was 0.691. This corresponds to a predicted typical maximum percent change from baseline LDL-C and HDL-C of 51.1% and 224%, respectively. The final sequential model described obicetrapib PKPD well and was ultimately able to both demonstrate evidence of internal consistency and support decision-making throughout the development lifecycle.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol , Dislipidemias , Modelos Biológicos , Humanos , Dislipidemias/tratamiento farmacológico , Adulto , Masculino , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Femenino , Persona de Mediana Edad , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/farmacología , LDL-Colesterol/sangre , Adulto Joven , HDL-Colesterol/sangre , AncianoRESUMEN
BACKGROUND AND OBJECTIVE: This study aimed to assess and compare the pharmacokinetics, safety, and tolerability of a fixed-dose combination product (FDCP) comprising four different drugs (two antihypertensive drugs, amlodipine and losartan, and two lipid-lowering agents, ezetimibe and rosuvastatin) with their separate tablets. METHODS: A total of 60 participants were enrolled in this open-label, randomized, single-dose crossover study. Each participant received a single dose of FDCP and individual tablets during each period, with a 14-day washout period between the periods. The pharmacokinetic parameters of amlodipine, losartan, EXP3174 (an active metabolite of losartan), rosuvastatin, free ezetimibe, and total ezetimibe were evaluated and compared. RESULTS: The pharmacokinetic profiles of amlodipine, losartan, rosuvastatin, and ezetimibe after administration of the individual products were similar to those of FDCP. The geometric mean ratios and 90% confidence intervals for maximum concentration (Cmax) and area under the curve (AUC) of FDCP to individual tablets were within 0.8-1.25 for all six analytes. No clinically relevant changes were observed in the vital signs or physical, biochemical, hematological, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were reported. CONCLUSION: This study demonstrated that a newly developed FDCP containing amlodipine, losartan, ezetimibe, and rosuvastatin exhibited pharmacokinetic equivalence with the individual products and met the regulatory criteria. Both formulations were well tolerated. CLINICAL TRIAL REGISTRATION: This trial (NCT04322266) was retrospectively registered on 9 September 2019.
Asunto(s)
Amlodipino , Estudios Cruzados , Combinación de Medicamentos , Ezetimiba , Voluntarios Sanos , Losartán , Rosuvastatina Cálcica , Humanos , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/administración & dosificación , Amlodipino/farmacocinética , Amlodipino/administración & dosificación , Amlodipino/efectos adversos , Masculino , Ezetimiba/farmacocinética , Ezetimiba/administración & dosificación , Losartán/farmacocinética , Losartán/administración & dosificación , Adulto , Femenino , Adulto Joven , Persona de Mediana Edad , Antihipertensivos/farmacocinética , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Comprimidos , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/administración & dosificación , Área Bajo la CurvaRESUMEN
The current study aimed to evaluate the bioequivalence of a new generic combination of simvastatin and ezetimibe with the reference formulation. An open-label, randomized, 3-period, 3-sequence, crossover study, including 60 healthy volunteers, was implemented. Participants received the test and reference formulation, each containing 20 mg of simvastatin and 10 mg of ezetimibe as a single-dose tablet, separated by a minimum of 2-week washout periods. Blood samples were collected for 20 time points from predose to 72 hours after the dose. The total ezetimibe assay was carried out using a validated liquid chromatography-tandem mass spectrometry, while unconjugated ezetimibe, simvastatin, and simvastatin ß-hydroxy acid determination was done via a validated ultra-performance liquid chromatography-tandem mass spectrometry. Each assay was preceded by a liquid-liquid extraction step. The pharmacokinetic parameters were derived using noncompartmental analysis and then compared between the reference and test formulations via a multivariate analysis of variance. No statistical difference was found in under the concentration-time curve from time 0 to the last quantifiable concentration and maximum concentration of unconjugated ezetimibe, total ezetimibe, and simvastatin between the reference and test formulations. The 90% confidence intervals of unconjugated ezetimibe, total ezetimibe, and simvastatin natural log-transformed under the concentration-time curve from time 0 to the last quantifiable concentration, and maximum concentration were in the range of 80%-125% as per the bioequivalence acceptance criteria. Therefore, the test formulation was bioequivalent to the reference formulation.
Asunto(s)
Estudios Cruzados , Voluntarios Sanos , Simvastatina , Comprimidos , Equivalencia Terapéutica , Humanos , Masculino , Adulto , Simvastatina/farmacocinética , Simvastatina/administración & dosificación , Simvastatina/sangre , Adulto Joven , Femenino , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/sangre , Combinación Ezetimiba y Simvastatina/farmacocinética , Combinación Ezetimiba y Simvastatina/administración & dosificación , Ezetimiba/farmacocinética , Ezetimiba/administración & dosificación , Área Bajo la Curva , Espectrometría de Masas en Tándem/métodos , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/administración & dosificación , Persona de Mediana Edad , Combinación de MedicamentosRESUMEN
US Food and Drug Administration (FDA) guidance outlines how biosimilars can be developed based on pharmacokinetic (PK) and pharmacodynamic (PD) similarity study data in lieu of a comparative clinical efficacy study. There is a paucity of PD comparability studies in biosimilar development, leaving open questions about how best to plan these studies. To that end, we conducted a randomized, double-blinded, placebo-controlled, single-dose, parallel-arm clinical study in healthy participants to evaluate approaches to address information gaps, inform analysis best practices, and apply emerging technologies in biomarker characterization. Seventy-two healthy participants (n = 8 per arm) received either placebo or one of four doses of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab (15-100 mg) or evolocumab (21-140 mg) to evaluate the maximum change from baseline (ΔPDmax ) and the baseline-adjusted area under the effect curve (AUEC) for the biomarkers low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) in serum. We investigated approaches to minimize variability in PD measures. Coefficient of variation was lower for LDL-C than apoB at therapeutic doses. Modeling and simulation were used to establish the dose-response relationship and provided support that therapeutic doses for these products are adequately sensitive and are on the steep part of the dose-response curves. Similar dose-response relationships were observed for both biomarkers. ΔPDmax plateaued at lower doses than AUEC. In summary, this study illustrates how pilot study data can be leveraged to inform appropriate dosing and data analyses for a PK and PD similarity study.
Asunto(s)
Anticolesterolemiantes , Biosimilares Farmacéuticos , Humanos , Biosimilares Farmacéuticos/efectos adversos , Inhibidores de PCSK9 , LDL-Colesterol , Proproteína Convertasa 9 , Anticuerpos Monoclonales/farmacocinética , Proyectos Piloto , Apolipoproteínas B , Biomarcadores , Resultado del Tratamiento , Anticolesterolemiantes/farmacocinéticaRESUMEN
The analysis of parent drug is usually the design of choice for a bioequivalence (BE) study. However, there is a controversy regarding the choice of analytes between EMA and USFDA for the BE study of ezetimibe (EZE). The EMA recommends measuring the total form alone, that means the sum of the concentration of "parent" EZE and "metabolite" ezetimibe-glucuronide (EZEG), as the BE determination. On the other hand, the USFDA recommends measuring not only total form but also EZE. The aim of this study was to employ a simulation approach to determine which analyte (e.g., EZE alone, EZEG alone, total form alone, or combination of EZE and total form) was more appropriate for use as a BE indicator. The previously published pharmacokinetic model of EZE and EZEG with enterohepatic circulation was used to generate virtual BE studies. Eight different scenarios were performed with changes in the rate of absorption of EZE and EZEG. Five hundred virtual BE studies were generated for each scenario. In addition, the discriminatory ability of selected analytes for detecting differences in the rate of absorption of EZE and EZEG was evaluated based on power curve performance. The results obtained through simulations indicated that none of the single analytes (EZE alone, EZEG alone, and total form alone) could have clear advantages in terms of discriminatory ability. Therefore, it was recommended that a combination of EZE and total form should be used in the BE assessment.
Asunto(s)
Anticolesterolemiantes , Anticolesterolemiantes/farmacocinética , Quimioterapia Combinada , Ezetimiba/farmacocinética , Equivalencia TerapéuticaRESUMEN
Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24S-hydroxycholesterol (24HC) for regulating brain cholesterol homeostasis. For the development of a novel and potent CH24H inhibitor, we designed and synthesized 3,4-disubstituted pyridine derivatives using a structure-based drug design approach starting from compounds 1 (soticlestat) and 2 (thioperamide). Optimization of this series by focusing on ligand-lipophilicity efficiency value resulted in the discovery of 4-(4-methyl-1-pyrazolyl)pyridine derivative 17 (IC50 = 8.5 nM) as a potent and highly selective CH24H inhibitor. The X-ray crystal structure of CH24H in complex with compound 17 revealed a unique binding mode. Both blood-brain barrier penetration and reduction of 24HC levels (26% reduction) in the mouse brain were confirmed by oral administration of 17 at 30 mg/kg, indicating that 17 is a promising tool for the novel and selective inhibition of CH24H.
Asunto(s)
Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacología , Colesterol 24-Hidroxilasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Animales , Anticolesterolemiantes/farmacocinética , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Colesterol/metabolismo , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Femenino , Hidroxicolesteroles , Lípidos/química , Ratones , Ratones Endogámicos C57BL , Relación Estructura-ActividadRESUMEN
INTRODUCTION: Fedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate). METHODS: In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25 mg, rosuvastatin 10 mg, and metformin 1000 mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600 mg 1 h before the cocktail on day 7 (period 2). An oral glucose tolerance test (OGTT) was performed to determine possible influences of fedratinib on the antihyperglycemic effect of metformin. RESULTS: Plasma exposure to the three probe drugs was generally comparable in the presence or absence of fedratinib. Reduced metformin renal clearance by 36% and slightly higher plasma glucose levels after OGTT were observed in the presence of fedratinib. Single oral doses of the cocktail ± fedratinib were generally well tolerated. CONCLUSIONS: These results suggest that fedratinib has minimal impact on the exposure of P-gp, BCRP, OATP1B1/1B3, OCT2, and MATE1/2-K substrates. Since renal clearance of metformin was decreased in the presence of fedratinib, caution should be exercised in using coadministered drugs that are renally excreted via OCT2 and MATEs. TRIAL REGISTRATION: Clinicaltrials.gov NCT04231435 on January 18, 2020.
Asunto(s)
Digoxina/farmacocinética , Interacciones Farmacológicas , Metformina/farmacocinética , Pirrolidinas/farmacología , Rosuvastatina Cálcica/farmacocinética , Sulfonamidas/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Administración Oral , Adolescente , Adulto , Anciano , Anticolesterolemiantes/farmacocinética , Transporte Biológico , Cardiotónicos/farmacocinética , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Voluntarios Sanos , Humanos , Hipoglucemiantes/farmacocinética , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Ensayos Clínicos Controlados no Aleatorios como Asunto , Transportadores de Anión Orgánico/antagonistas & inhibidores , Transportadores de Anión Orgánico/metabolismo , Distribución Tisular , Adulto JovenRESUMEN
Rotavirus is the most common cause of severe diarrhea among infants and young children and is responsible for more than 200,000 pediatric deaths per year. There is currently no pharmacological treatment for rotavirus infection in clinical activity. Although cholesterol synthesis has been proven to play a key role in the infections of multiple viruses, little is known about the relationship between cholesterol biosynthesis and rotavirus replication. The models of rotavirus infected two cell lines and a human small intestinal organoid were used. We investigated the effects of cholesterol biosynthesis, including inhibition, enhancement, and their combinations on rotavirus replication on these models. The knockdown of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was built by small hairpin RNAs in Caco2 cells. In all these models, inhibition of cholesterol synthesis by statins or HMGCR knockdown had a significant inhibitory effect on rotavirus replication. The result was further confirmed by the other inhibitors: 6-fluoromevalonate, Zaragozic acid A and U18666A, in the cholesterol biosynthesis pathway. Conversely, enhancement of cholesterol production increased rotavirus replication, suggesting that cholesterol homeostasis is relevant for rotavirus replication. The effects of all these compounds toward rotavirus were further confirmed with a clinical rotavirus isolate. We concluded that rotavirus replication is dependent on cholesterol biosynthesis. To be specific, inhibition of cholesterol synthesis can downregulate rotavirus replication; on the contrary, rotavirus replication is upregulated. Statin treatment is potentially an effective novel clinical anti-rotavirus strategy.
Asunto(s)
Colesterol/biosíntesis , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Infecciones por Rotavirus/tratamiento farmacológico , Rotavirus/efectos de los fármacos , Rotavirus/crecimiento & desarrollo , Replicación Viral/efectos de los fármacos , Animales , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/uso terapéutico , Células CACO-2/efectos de los fármacos , Células CACO-2/virología , Células Cultivadas/efectos de los fármacos , Células Cultivadas/virología , Chlorocebus aethiops/crecimiento & desarrollo , Chlorocebus aethiops/virología , Modelos Animales de Enfermedad , Células HEK293/efectos de los fármacos , Células HEK293/virología , HumanosRESUMEN
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.
Asunto(s)
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
This phase 1, 2-part, 2-period, open-label, drug-drug interaction study evaluated the potential for pharmacokinetic interactions between upadacitinib and rosuvastatin, an organic anion transporting polypeptide (OATP) 1B1 and breast cancer resistance protein substrate, or atorvastatin, a cytochrome P450 3A, OATP1B1, and OATP1B3 substrate, in 36 healthy volunteers. During period 1, a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered on day 1, followed by a washout period of 5 days. During period 2, once-daily doses of upadacitinib extended-release (30 mg) were administered on days 1 to 10, and a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered 1 hour after the upadacitinib dose on day 7. Serial blood samples were collected for assays of drug concentrations. In Part 1, rosuvastatin maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to infinity (AUCinf ) were 23% and 33% lower, respectively, when administered with upadacitinib relative to when administered alone. In part 2, atorvastatin Cmax and AUCinf was 11% and 23% lower, respectively, when administered with upadacitinib relative to when administered alone. The Cmax and AUCinf of the active metabolite ortho-hydroxyatorvastatin remained unchanged. Administration of a single 5-mg dose of rosuvastatin or a single 10-mg dose of atorvastatin had no relevant effect on upadacitinib Cmax or area under the plasma concentration-time curve. These results demonstrated that upadacitinib has no clinically relevant effect on the pharmacokinetics of rosuvastatin and atorvastatin or on substrates transported by OATP1B or breast cancer resistance protein.
Asunto(s)
Anticolesterolemiantes/farmacocinética , Atorvastatina/farmacocinética , Interacciones Farmacológicas , Compuestos Heterocíclicos con 3 Anillos/farmacología , Inhibidores de las Cinasas Janus/farmacología , Rosuvastatina Cálcica/farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/efectos de los fármacos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Adulto , Femenino , Voluntarios Sanos , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/efectos de los fármacos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Adulto JovenRESUMEN
CSL112 (apolipoprotein A-I, apo AI [human]) is an investigational drug in Phase 3 development for risk reduction of early recurrent cardiovascular events following an acute myocardial infarction (AMI). Although CSL112 is known to be well tolerated with a regimen of four weekly 6 g intravenous infusions after AMI, high doses of reconstituted apo AI preparations can transiently elevate liver enzymes in rats, raising the possibility of additive liver toxicity and toxicokinetic (TK) effects upon co-administration with cholesterol-lowering drugs, i.e., HMG-CoA reductase and proprotein convertase subtilisin/kexin type 9 inhibitors. We performed a toxicity and TK study in CD rats assigned to eleven treatment groups, including two dose levels of intravenous (IV) CSL112 (140 mg/kg, low-dose; 600 mg/kg, high-dose) administered as a single dose, alone or with intravenous alirocumab 50 mg/kg/week and/or oral atorvastatin 10 mg/kg/day. In addition, control groups of atorvastatin and alirocumab alone and in combination were investigated. Results showed some liver enzyme elevations (remaining <2-fold of baseline) related to administration of CSL112 alone. There was limited evidence of an additive effect of CSL112 on liver enzymes when combined, at either dose level, with alirocumab and/or atorvastatin, and histology revealed no evidence of an increased incidence or severity of hepatocyte vacuolation compared to the control treatments. Co-administration of the study drugs had minimal effect on their respective exposure levels, and on levels of total cholesterol and high-density lipoprotein cholesterol. These data support concomitant use of CSL112 with alirocumab and/or atorvastatin with no anticipated negative impact on liver safety and TK.
Asunto(s)
Anticuerpos Monoclonales Humanizados/toxicidad , Anticolesterolemiantes/toxicidad , Atorvastatina/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Lipoproteínas HDL/toxicidad , Hígado/efectos de los fármacos , Animales , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticolesterolemiantes/farmacocinética , Atorvastatina/farmacocinética , Biomarcadores/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Colesterol/sangre , Interacciones Farmacológicas , Femenino , Lipoproteínas HDL/farmacocinética , Hígado/metabolismo , Hígado/patología , Masculino , Ratas Sprague-Dawley , Medición de Riesgo , Pruebas de Toxicidad , ToxicocinéticaRESUMEN
PURPOSE: Comorbid conditions of heart and liver disorders added to HCV-induced hepatic steatosis make co-administration of statins, and direct-acting antivirals is common in clinical practice. This study aimed to evaluate the pharmacokinetic interaction of atorvastatin and fixed-dose combination of sofosbuvir/ledipasvir "FDCSL" with rationalization to the underlying mechanism. METHODS: A randomized, three-phase crossover study that involves 12 healthy volunteers was performed. Participants received a single-dose of atorvastatin 80 mg alone, atorvastatin 80-mg plus tablets containing 400/90 mg FDCSL, or tablets containing 400/90 mg FDCSL alone. Plasma samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for atorvastatin, sofosbuvir, ledipasvir, and sofosbuvir metabolite "GS-331007," and their pharmacokinetics parameters were determined. RESULTS: Compared to atorvastatin alone, the administration of FDCSL caused a significant increase in both areas under the concentration-time curve from time zero to infinity (AUC0-∞) and maximum plasma concentration (Cmax) of atorvastatin by 65.5% and 156.0%, respectively. Also, atorvastatin caused a significant increase in the AUC0-∞ and Cmax of sofosbuvir by 32.0% and 11.0%, respectively. Similarly, AUC0-∞ and Cmax of sofosbuvir metabolite significantly increased by 84.0% and 74.0%, respectively. However, ledipasvir AUC0-∞ showed no significant change after atorvastatin intake. The elimination rate in all drugs revealed no significant changes. CONCLUSION: After concurrent administration of FDCSL with atorvastatin, the AUC0-∞ of both atorvastatin and sofosbuvir were increased. Caution should be taken with close monitoring for possible side effects after co-administration of atorvastatin and FDCSL in clinical practice.
Asunto(s)
Anticolesterolemiantes/farmacología , Antivirales/farmacología , Atorvastatina/farmacología , Bencimidazoles/farmacología , Fluorenos/farmacología , Sofosbuvir/farmacología , Adulto , Anticolesterolemiantes/farmacocinética , Antivirales/farmacocinética , Área Bajo la Curva , Atorvastatina/farmacocinética , Bencimidazoles/farmacocinética , Estudios Cruzados , Egipto , Fluorenos/farmacocinética , Voluntarios Sanos , Humanos , Masculino , Tasa de Depuración Metabólica , Método Simple Ciego , Sofosbuvir/farmacocinéticaRESUMEN
This open-label, repeat-dose, fixed-sequence study in healthy subjects examined pharmacokinetic drug-drug interactions between the components of a novel fixed-dose combination product containing ramipril, amlodipine, and atorvastatin. Sequential 5-day monotreatments (MTs) of ramipril (5 mg/d) and atorvastatin (40 mg/d) were followed by a 9-day amlodipine MT (5 mg/d), separated by 96 hours washout intervals. After amlodipine MT, all 3 single-entity drugs were coadministered for 5 days. Blood samples were taken over the dosing intervals and drug concentrations quantified by high-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were assessed and compared between the MTs and combination treatments by analysis of variance. Eighteen healthy subjects were enrolled and completed the study. No significant difference in maximum concentration (Cmax ) and area under the plasma concentration-time curve over the dosing interval (AUC0-τ ) for amlodipine and AUC0-τ of atorvastatin was observed upon combination treatments versus MTs. Cmax of atorvastatin was slightly decreased (Cmax ratio, 89.3%) when given in combination. Increased exposure of ramipril and less pronounced exposure of ramiprilat were observed in the presence of amlodipine and atorvastatin, with Cmax ratios for ramipril and ramiprilat of 182.6% and 155.9%, and corresponding AUC0-τ ratios of 150.0% and 112.1%, respectively. These ramiprilat increases are unlikely of clinical relevance, because complete angiotensin-converting enzyme occupation is achieved with ≥5-mg ramipril doses, and free ramiprilat is rapidly eliminated. As ramipril is known to be subject to a site-dependent absorption in the upper small intestine, it is hypothesized that slowing of intestinal motility by atorvastatin or amlodipine or a combined effect of both, increased the residence time of ramipril in its "absorption window," thereby enhancing its bioavailability.
Asunto(s)
Amlodipino/farmacocinética , Anticolesterolemiantes/farmacocinética , Antihipertensivos/farmacocinética , Atorvastatina/farmacocinética , Interacciones Farmacológicas , Motilidad Gastrointestinal/efectos de los fármacos , Absorción Intestinal/efectos de los fármacos , Ramipril/farmacocinética , Adulto , Amlodipino/farmacología , Anticolesterolemiantes/farmacología , Antihipertensivos/farmacología , Atorvastatina/farmacología , Disponibilidad Biológica , Combinación de Medicamentos , Voluntarios Sanos , Humanos , Masculino , Adulto JovenRESUMEN
To evaluate the pharmacokinetic interactions among rosuvastatin, ezetimibe, and telmisartan, a randomized, open-label, 3-period, 6-sequence crossover study was conducted in healthy subjects. Subjects received one of the following treatments once daily for 7 days in each period with a 1-week washout: a fixed-dose combination of ezetimibe/rosuvastatin 10/20 mg, telmisartan 80 mg, combination therapy of ezetimibe/rosuvastatin 10/20 mg, or telmisartan 80 mg. Blood samples were collected up to 24 hours postdose at steady state. Geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) of the combination therapy to monotherapy for the maximum plasma concentration (Cmax,ss ), and the area under the time-concentration curve within a dosing interval at steady state (AUCtau,ss ) were estimated. Among the 36 randomized subjects, 31 subjects completed the study. The GMRs and 90%CIs of Cmax,ss and AUCtau,ss of total ezetimibe were not significantly altered. The Cmax,ss of free ezetimibe was increased (GMR, 1.85; 90%CI, 1.56-2.19) but not for the AUCtau,ss (GMR, 1.16; 90%CI, 1.06-1.26). Similarly, the Cmax,ss of rosuvastatin was increased (GMR, 2.13; 90%CI, 1.88-2.43) without a change in the AUCtau,ss (GMR, 1.09; 90%CI, 1.03-1.15). The Cmax,ss (GMR, 1.16; 90%CI, 1.01-1.32) and AUCtau,ss (GMR, 1.26; 90%CI, 1.17-1.37) of telmisartan were slightly increased. Considering the therapeutic range of the components, the interaction would have limited clinical impact.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Anticolesterolemiantes/farmacocinética , Interacciones Farmacológicas , Ezetimiba/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Telmisartán/farmacocinética , Adulto , Estudios Cruzados , Voluntarios Sanos , Humanos , Masculino , Adulto JovenRESUMEN
We investigated the influence of multiple oral administration on the accumulation of dalcetrapib (JTT-705/RO4607381), a novel cholesteryl ester transfer protein inhibitor, in rats. It is well known that orally administered dalcetrapib is rapidly hydrolysed to its active form, which has a sulfhydryl group, in the body. The active form then binds covalently to endogenous thiols via mixed disulfide bonds. Following multiple once daily oral administration of 14C-dalcetrapib for seven days to rats, the concentration of radioactivity in the plasma and almost all tissues reached the steady state by day 4. At 24 h after the last dose, there was a relatively high concentration of radioactivity in the mesenteric lymph nodes, liver, adrenal glands and fat. After the last dose to rats, the radioactivity was almost completely recovered in the urine and faeces, indicating that dalcetrapib is not retained in the body, probably due to the reversibility of the disulfide bonds despite being covalent bonds.
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Anticolesterolemiantes/farmacocinética , Compuestos de Sulfhidrilo/farmacocinética , Administración Oral , Amidas , Animales , Anticolesterolemiantes/administración & dosificación , Proteínas de Transferencia de Ésteres de Colesterol , Ésteres , Humanos , Masculino , Ratas , Compuestos de Sulfhidrilo/administración & dosificaciónRESUMEN
AIM: Coronary plaque regression is weak in acute coronary syndrome (ACS) patients with diabetes mellitus (DM). We evaluated whether dual lipid-lowering therapy (DLLT) with ezetimibe and atorvastatin attenuates coronary plaques in ACS patients with DM. METHODS: The prospective, randomized controlled, multicenter PRECISE-IVUS (Plaque Regression with Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial assigned 246 patients undergoing percutaneous coronary intervention to DLLT or atorvastatin monotherapy and evaluated IVUS-derived changes in percent atheroma volume (ΔPAV), at baseline and 9-12-month follow-up, in 126 ACS cases, including 25 DM patients. The atorvastatin dose was up-titrated to achieve low-density lipoprotein cholesterol (LDL-C) ï¼70 mg/dL. RESULTS: In DM patients, the monotherapy group (n=13) and the DLLT group (n=12) showed a similar prevalence of coronary risks and baseline lipid profiles. During the study, the change in LDL-C level was similar between DM and non-DM patients. Compared with non-DM patients, DM patients showed weaker regression of ΔPAV by DLLT than those who underwent monotherapy (DM: -2.77±3.47% vs. -0.77±2.51%, P=0.11; non-DM: -2.01±3.36% vs. -0.08±2.66%, P=0.008). The change in LDL-C level was not correlated with ΔPAV in non-DM patients, but there was significant correlation between the change in LDL-C level and ΔPAV in DM patients (r=0.52, P=0.008). CONCLUSIONS: ACS patients with DM showed weaker coronary plaque regression than their counterparts. A significant correlation between the change in LDL-C level and ΔPAV in DM patients suggested that more intensive lipid-lowering therapy is required in ACS patients with DM.
Asunto(s)
Síndrome Coronario Agudo , Atorvastatina , Vasos Coronarios/patología , Diabetes Mellitus Tipo 2/complicaciones , Ezetimiba , Placa Aterosclerótica , Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/etiología , Anciano , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/farmacocinética , Atorvastatina/administración & dosificación , Atorvastatina/farmacocinética , LDL-Colesterol/sangre , Monitoreo de Drogas/métodos , Ezetimiba/administración & dosificación , Ezetimiba/farmacocinética , Femenino , Humanos , Masculino , Placa Aterosclerótica/complicaciones , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/tratamiento farmacológico , Resultado del Tratamiento , Ultrasonografía Intervencional/métodosRESUMEN
The aim of this project was to improve the Aspergillus terreus strain and pretreatment of sugarcane bagasse as carrier substrate for bulk production of lovastatin, a cholesterol-lowering drug, in solid state fermentation. Sugarcane bagasse was treated with alkali (1-3% NaOH) for the conversion of complex polysaccharides into simple sugars for better utilization of carrier substrate by microorganism for maximum lovastatin production. Ethidium bromide (time of exposure 30-180 min) was used to induce mutation in Aspergillus terreus and the best mutant was selected on the basis of inhibition zone appeared on petri plates. Fermented lovastatin was quantified by high-performance liquid chromatography. The fermented lovastatin, produced by parent and mutant Aspergillus terreus strain, was checked on body weight, blood glucose and serum cholesterol, ALT, AST, HDL-C, LDL-C, TG and TC levels of rats for their cholesterol lowering capacity. Our results indicate that selected strain along with 2% NaOH treated sugar cane bagasse was best suitable for bulk production of lovastatin by fermentation and fermented lovastatin effectively lower the cholesterol level of rats.
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Anticolesterolemiantes , Aspergillus , Colesterol/sangre , Lovastatina , Animales , Anticolesterolemiantes/aislamiento & purificación , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/farmacología , Aspergillus/genética , Aspergillus/crecimiento & desarrollo , Celulosa/química , Evaluación Preclínica de Medicamentos , Lovastatina/biosíntesis , Lovastatina/aislamiento & purificación , Lovastatina/farmacocinética , Lovastatina/farmacología , Masculino , Ratas , Saccharum/químicaRESUMEN
INTRODUCTION: While atherosclerotic cardiovascular disease is affecting growing numbers of patients, lipid-lowering therapies have been continuously improving to achieve prevention of cardiovascular events. Thus, the appearance of a novel therapeutic class, PCSK9 inhibitors, has raised both high expectations as well as concern over possible adverse effects. AREAS COVERED: This current review aims to analyze adverse events of special interest linked to PCSK9 inhibitors and give recommendations regarding further conduct when dealing with patients on this therapy. The most stringent adverse effect, neurocognitive impairment has been investigated in several studies, concluding that PCSK9 inhibitors neither improved nor worsened cognitive function. While new onset diabetes mellitus has also been a cause of concern due to its possible association with lipid lowering therapies, studies conducted so far have dispelled this possibility by showing that PCSK9 inhibitors do not increase this risk. Also, statin-associated muscle symptoms have not been proven to arise after the use of PCSK9 inhibitors, even in statin-intolerant patients. EXPERT OPINION: In conclusion, it can be safely stated that so far, no compelling evidence links PCSK9 inhibitors to these adverse events; however, long-term trials are always welcome to further assess potential adverse effects.
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Anticolesterolemiantes/administración & dosificación , Aterosclerosis/tratamiento farmacológico , Inhibidores de PCSK9 , Animales , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/farmacocinética , Aterosclerosis/complicaciones , Enfermedades Cardiovasculares/prevención & control , Cognición/efectos de los fármacos , Interacciones Farmacológicas , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversosRESUMEN
PURPOSE: Obesity affecting drug pharmacokinetics results in the risk of the therapeutic failure or toxic side effects of drugs increasing. Unfortunately, the pharmacokinetic data in obese patients still lack for majority of drugs. Therefore, our study principally investigated the effect of obesity induced by high fat-diet (HFD) on the pharmacokinetics of rosuvastatin and explored the underlying mechanism via the hepatic pregnane X receptor (Pxr)- organic anion transporting polypeptide 2 (Oatp2) signaling pathway and multidrug resistance-associated protein 2 (Mrp2) in rats. MAIN METHODS: Rats with obesity was induced by HFD for 4 weeks, and subsequently, the effect of obesity on the blood concentration, pharmacokinetic parameters and biliary excretion of rosuvastatin administrated intravenously and the hepatic uptake of rosuvastatin in the rat primary hepatocytes were evaluated. Additionally, in order to illuminate the underlying mechanism, the alterations of the mRNA expressions of Oatp2, Mrp2 and Pxr and the concentrations of lithocholic acid (LCA), glycine-LCA (GLCA) and taurine-LCA (TLCA) in liver were determined. KEY FINDINGS: The blood concentration of rosuvastatin that has great relationship with the muscle toxicity increased in rats with HFD-induced obesity, which could be principally ascribed to the decreased hepatic uptake of rosuvastatin that was mainly resulted from the inhibition of hepatic Pxr-Oatp2 pathway. SIGNIFICANCE: The decreased hepatic uptake of rosuvastatin causing the increase of the rosuvastatin concentration in blood under the condition of HFD-induced obesity provides a cue for clinicians to reduce the rosuvastatin dose for obese patients to avoid the occurrence risk of the muscle toxicity of rosuvastatin.
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Hígado/metabolismo , Obesidad/metabolismo , Transportadores de Anión Orgánico/metabolismo , Receptor X de Pregnano/metabolismo , Rosuvastatina Cálcica/farmacocinética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Anticolesterolemiantes/farmacocinética , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas WistarRESUMEN
Aprocitentan is an investigational, orally active, dual, endothelin receptor antagonist that targets a novel pathway in the treatment of difficult-to-control (resistant) hypertension. The drug-drug interaction potential of aprocitentan on the breast cancer resistance protein (BCRP) transporter substrate rosuvastatin was investigated in this single-center, open-label, single-sequence study. Twenty healthy male subjects received a single dose of 10-mg rosuvastatin on days 1 and 13 followed by pharmacokinetic and tolerability assessments for up to 120 hours. From day 5 to day 17, subjects received 25 mg of aprocitentan once daily. Seventeen of 20 enrolled subjects completed the treatment. At steady state, aprocitentan did not affect the pharmacokinetics of rosuvastatin in a clinically relevant way. The maximum plasma concentration was increased by 40% with a 90% confidence interval of 1.19 to 1.65. However, the ratio of the geometric means for both area under the plasma concentration-time curve from time 0 to time t and area under the plasma concentration-time curve from time 0 to infinity was close to 1 with the 90% confidence interval within a reference interval of 0.80 to 1.25. Adverse events leading to study discontinuation were reported in 2 subjects. Overall, the combination of rosuvastatin and aprocitentan was well tolerated. Based on these data, aprocitentan does not affect BCRP and can be administered concomitantly with drugs dependent on BCRP transport.