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[This corrects the article DOI: 10.1177/11795484221119316.].
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BACKGROUND: Severe cases of coronavirus disease 2019 (COVID-19) are characterized by progressive respiratory failure and the development of acute respiratory distress syndrome (ARDS), with high mortality rates for patients requiring mechanical ventilation. Levels of the vascular growth factor Angiopoietin 2 (Ang2) in plasma have been strongly correlated with increased ARDS risk in patients with pneumonia or sepsis. The intent of this study was to determine whether LY3127804, an anti-Ang2 monoclonal antibody, could reduce the need for mechanical ventilation among patients admitted to the hospital with pneumonia and presumed or confirmed COVID-19. METHODS: Patients admitted to hospital with confirmed pneumonia, presumed or confirmed COVID-19, and infiltrates on chest imaging and/or oxygen saturation of ≤ 95% on room air were stratified by age group (< 65 years and ≥ 65 years), sex, and site and randomly assigned 1:1 within each stratum to receive either LY3127804 (20â mg/kg) or placebo on Day 1 and possibly on Day 15. The primary end point for this study was number of days in which a patient did not require a ventilator over the 28-day study period. RESULTS: Interim analysis assessed study futility after 95 randomized patients had 28-day data available and showed no benefit of LY3127804 in reducing the number of ventilator days over placebo. The study was subsequently terminated. CONCLUSION: LY3127804 treatment did not decrease the need for ventilator usage in patients hospitalized with pneumonia and presumed or confirmed COVID-19. ClinicalTrialsgov identifier: NCT04342897.
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CONTEXT: Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG. OBJECTIVE: This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients. METHODS: A double-blind, placebo-controlled, phase 2 crossover study was conducted with 2 active treatment periods of 28 days in 19 patients (aged 16-65 years; body mass index (BMI)â ≥â 28) with genetically confirmed PWS. The study took place in 7 hospital-based study centers in the United States and Canada. Patients received placebo or GLWL-01 (450 mg twice daily) orally after lead-in placebo and washout periods. The Hyperphagia Questionnaire for Clinical Trials and Caregiver Global Impression of Change were used to measure reductions in hyperphagia. Plasma concentrations of AG and UAG were evaluated as correlates. RESULTS: Treatment resulted in statistically significant differences compared to placebo in plasma AG (Pâ =â .0002), UAG (Pâ =â .0488), and AG/UAG (Pâ =â .0003). GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers. Anthropometric and clinical parameters correlated with obesity did not statistically significantly change in response to treatment. Less than half of patients reported a treatment-emergent adverse event (TEAE). No deaths, serious adverse events, or severe TEAEs were reported. CONCLUSION: GLWL-01 is safe and well tolerated. Pharmacological parameters confirmed the inhibition of GOAT following administration of GLWL-01. Patients' eating behaviors, BMI, blood glucose, and total cholesterol, among other similar measures, were not modified.
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Síndrome de Prader-Willi , Aciltransferasas , Estudios Cruzados , Método Doble Ciego , Ghrelina/uso terapéutico , Humanos , Hiperfagia , Síndrome de Prader-Willi/tratamiento farmacológicoRESUMEN
Background Aurora A kinase (AurA) overexpression likely contributes to tumorigenesis and therefore represents an attractive target for cancer therapeutics. This phase 1 study aimed to determine the safety, pharmacokinetics, and antitumor activity of LY3295668 erbumine, an AurA inhibitor, in patients with locally advanced or metastatic solid tumors. Methods Patients with locally advanced or metastatic solid tumors, Eastern Cooperative Oncology Group performance status 0-1, and disease progression after one to four prior treatment regimens were enrolled. Primary objective was to determine maximum tolerated dose (MTD); secondary objectives included evaluation of the tolerability and safety profile and pharmacokinetics of LY3295668. All patients received twice-daily (BID) oral LY3295668 in 21-day cycles in an ascending-dose schedule. Results Twelve patients were enrolled in phase 1 (25 mg, n = 8; 50 mg, n = 2; 75 mg, n = 2) and one patient was enrolled after. Overall, four patients experienced dose-limiting toxicities (DLTs) within the first cycle (75 mg: Grade 3 diarrhea [one patient], Grade 4 mucositis and Grade 3 corneal deposits [one patient]; 50 mg: mucositis and diarrhea [both Grade 3, one patient]; 25 mg: Grade 3 mucositis [one patient]). Patients exhibiting DLTs had the highest model-predicted exposures at steady state. Mucositis was the most common adverse event (67%), followed by diarrhea, fatigue, alopecia, anorexia, constipation, and nausea. Nine patients had best response of stable disease; the disease control rate was 69%. Conclusions MTD of LY3295668 was 25 mg BID. LY3295668 had a manageable toxicity profile and demonstrated activity in some patients with locally advanced or metastatic solid tumors.Trial registration ClinicalTrials.gov, NCT03092934. Registered March 22, 2017. https://clinicaltrials.gov/ct2/show/NCT03092934 .
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Aurora Quinasa A/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Piperidinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Baricitinib, an oral selective inhibitor of Janus kinase 1 and Janus kinase 2, modulates proinflammatory cytokine signaling. OBJECTIVES: The efficacy and safety of baricitinib were evaluated in patients with moderate-to-severe atopic dermatitis (AD). METHODS: In this phase 2, randomized, double-blind, placebo-controlled study, 124 patients with moderate-to-severe AD applied topical corticosteroids (TCSs) for 4 weeks before randomization to once-daily placebo, 2 mg of baricitinib, or 4 mg of baricitinib for 16 weeks. Use of TCSs was permitted during the study. The primary outcome was the proportion of patients achieving at least a 50% reduction in the Eczema Area and Severity Index (EASI-50) compared with placebo. RESULTS: Significantly more patients who received baricitinib, 4 mg, achieved EASI-50 than did patients receiving placebo (61% vs 37% [P = .027]) at 16 weeks. The difference between the proportion of patients receiving baricitinib, 2 or 4 mg, who achieved EASI-50 and the proportion of patients receiving placebo and achieving EASI-50 was significant as early as week 4. Baricitinib also improved pruritus and sleep loss. Treatment-emergent adverse events were reported in 24 of the patients receiving placebo (49%), 17 of those receiving 2 mg of baricitinib (46%), and 27 of those receiving 4 mg of baricitinib (71%). LIMITATIONS: A TCS standardization period before randomization reduced disease severity, limiting the ability to compare results with those of baricitinib monotherapy. Longer studies are required to confirm baricitinib's efficacy and safety in patients with AD. CONCLUSIONS: Baricitinib used with TCSs reduced inflammation and pruritus in patients with moderate-to-severe AD.
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Corticoesteroides/uso terapéutico , Azetidinas/efectos adversos , Azetidinas/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Fármacos Dermatológicos/efectos adversos , Fármacos Dermatológicos/uso terapéutico , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Administración Cutánea , Corticoesteroides/administración & dosificación , Adulto , Azetidinas/administración & dosificación , Fármacos Dermatológicos/administración & dosificación , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Purinas , Pirazoles , Índice de Severidad de la Enfermedad , Sulfonamidas/administración & dosificación , Resultado del TratamientoRESUMEN
Continuous glucose monitoring (CGM) systems allow patients with diabetes mellitus to closely track glucose concentrations over several days, identify trends in glucose levels, and avoid glucose excursions. This technology has not only advanced diabetes mellitus management but has increased patient safety through greater glycemic awareness. Due to these attributes, CGM is now being applied in therapeutic research as a pharmacodynamic tool to support early clinical drug development programs. However, to date only a handful of studies have utilized CGM in type 2 diabetes mellitus (T2DM) drug development. A potential barrier from fostering greater use of CGM in clinical development may be related to concerns over subject variability. Therefore, we investigated a key consideration when implementing CGM into early clinical research studies: daily variation within patients with T2DM from multiple clinical research units. From 24 patients with T2DM, we observed strong daily reproducibility (Pearson R = 0.86, P < .0001) in CGM results and found that this technique is practical for multisite studies. Altogether, with low daily variability, CGM is a powerful pharmacodynamic tool for drug efficacy and safety monitoring.
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Automonitorización de la Glucosa Sanguínea/instrumentación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacocinética , Metformina/farmacocinética , Adulto , Anciano , Tecnología Biomédica , Ensayos Clínicos Controlados como Asunto , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Seguridad del Paciente , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. METHODS: In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. RESULTS: Areas under the concentration-time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (C max) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80-1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max (t max) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INRmax); however, a 2% increase in area under the INR curve (AUCINR) was observed. CONCLUSIONS: Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen® are recommended when coadministered with dulaglutide. CLINICAL TRIAL REGISTRATION NUMBERS: NCT01458210, NCT01436201, NCT01432938, and NCT01250834.
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Atorvastatina/farmacocinética , Anticonceptivos Orales/administración & dosificación , Anticonceptivos Orales/farmacocinética , Digoxina/farmacocinética , Interacciones Farmacológicas , Péptidos Similares al Glucagón/análogos & derivados , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/farmacología , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/farmacología , Administración Oral , Adolescente , Adulto , Anciano , Atorvastatina/administración & dosificación , Atorvastatina/sangre , Anticonceptivos Orales/sangre , Digoxina/administración & dosificación , Digoxina/sangre , Femenino , Péptidos Similares al Glucagón/administración & dosificación , Péptidos Similares al Glucagón/farmacología , Voluntarios Sanos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Warfarina/administración & dosificación , Warfarina/sangre , Warfarina/farmacocinética , Adulto JovenRESUMEN
AIMS: To evaluate the effects of dulaglutide 1.5 mg on first- and second-phase insulin secretion in response to an intravenous (i.v.) glucose bolus challenge, in subjects with type 2 diabetes mellitus (T2DM; primary objective) and in healthy subjects. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled, 2-period crossover study, subjects received a single subcutaneous injection of dulaglutide 1.5 mg or placebo on day 1 of each period. On day 3, subjects underwent a 6-hour insulin infusion, followed by an i.v. glucose bolus and a glucagon challenge during hyperglycaemia. Areas under the concentration-time curve and maximum concentrations for first- (AUC0-10 and Cmax0-10 ) and second-phase secretion (AUC10-180 and Cmax10-180 ) were calculated for insulin and C-peptide. The glucose disappearance constant (Kg ) and homeostasis model assessment of ß-cell function (HOMA-ß) were assessed. RESULTS: In 20 subjects with T2DM, dulaglutide increased mean insulin AUC0-10 by 7.92-fold and Cmax0-10 by 5.40-fold vs placebo, and mean AUC10-180 and Cmax10-180 by 2.44- and 3.78- fold, respectively. In 10 healthy subjects, dulaglutide increased the mean insulin AUC0-10 by 3.09-fold and Cmax0-10 by 2.96-fold vs placebo, and mean AUC10-180 and Cmax10-180 by 2.04- and 4.15-fold, respectively. The corresponding C-peptide values also increased. Mean Kg and HOMA-ß were higher after dulaglutide compared with placebo. CONCLUSIONS: In subjects with T2DM, a single dulaglutide 1.5-mg dose restored the first-phase insulin secretion in response to an i.v. glucose bolus, increased the second-phase insulin response and enhanced ß-cell function.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Similares al Glucagón/análogos & derivados , Glucosa/administración & dosificación , Hipoglucemiantes/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Insulina/sangre , Proteínas Recombinantes de Fusión/administración & dosificación , Adulto , Área Bajo la Curva , Glucemia/efectos de los fármacos , Péptido C/sangre , Estudios Cruzados , Diabetes Mellitus Tipo 2/fisiopatología , Método Doble Ciego , Esquema de Medicación , Femenino , Glucagón , Péptidos Similares al Glucagón/administración & dosificación , Humanos , Hiperglucemia/tratamiento farmacológico , Infusiones Intravenosas , Inyecciones Subcutáneas , Células Secretoras de Insulina/efectos de los fármacos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Insulin lispro 200 U/mL (IL200) is a new strength formulation of insulin lispro (Humalog®, IL100), developed as an option for diabetic patients on higher daily mealtime insulin doses. This phase 1, open-label, 2-sequence, 4-period crossover, randomized, 8-hour euglycemic clamp study aimed to demonstrate the bioequivalence of IL200 and IL100 after subcutaneous administration of 20 U (U) to healthy subjects (n = 38). Pharmacokinetic (PK) and pharmacodynamic (PD) responses were similar in both formulations. All 90%CIs for the ratios of area under the concentration-versus-time curve from time zero to the time of the last measurable concentration (AUC0-tlast) and maximum observed drug concentration (Cmax), as well as the total glucose infused throughout the clamp (Gtot) and the maximum glucose infusion rate (Rmax), were contained within 0.80 and 1.25. Time of maximum observed drug concentration (tmax) was similar between formulations, with a median difference of 15 minutes and a 95%CI of the difference that included zero. Inter- and intrasubject variability estimates were similar for both formulations. Both formulations were well tolerated. IL200 was bioequivalent to IL100 after subcutaneous administration of 20-U single doses, and PD responses were comparable between formulation strengths.
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Hipoglucemiantes/administración & dosificación , Insulina Lispro/administración & dosificación , Adulto , Área Bajo la Curva , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Insulina Lispro/farmacocinética , Insulina Lispro/farmacología , Masculino , Persona de Mediana Edad , Equivalencia Terapéutica , Adulto JovenRESUMEN
The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working group that greater focus be given to the analysis of uncontrolled ConMeds as part of a PopPK analysis of Phase 2/3 data to ensure that the resulting outcome in the PopPK analysis can be viewed as reliable. Other recommendations include: (1) collection of start and stop date and clock time, as well as dose and frequency, in Case Report Forms regarding ConMed administration schedule; (2) prespecification of goals and the methods of analysis, (3) consideration of alternate models, other than the binary covariate model, that might more fully characterize the interaction between perpetrator and victim drug, (4) analysts should consider whether the sample size, not the percent of subjects taking a ConMed, is sufficient to detect a ConMed effect if one is present and to consider the correlation with other covariates when the analysis is conducted, (5) grouping of ConMeds should be based on mechanism (e.g., PGP-inhibitor) and not drug class (e.g., beta-blocker), and (6) when reporting the results in a publication, all details related to the ConMed analysis should be presented allowing the reader to understand the methods and be able to appropriately interpret the results.
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Interacciones Farmacológicas , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/metabolismo , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Humanos , Tamaño de la MuestraRESUMEN
BACKGROUND AND OBJECTIVE: Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist administered as once-weekly subcutaneous injections for the treatment of type 2 diabetes (T2D). The clinical pharmacokinetics of dulaglutide were characterized in patients with T2D and healthy subjects. METHODS: The pharmacokinetics of dulaglutide were assessed throughout clinical development, including conventional pharmacokinetic analysis in clinical pharmacology studies and population pharmacokinetic analyses of data from combined phase 2 and phase 3 studies in patients with T2D. The effects of potential covariates on dulaglutide population pharmacokinetics were evaluated using nonlinear mixed-effects models. RESULTS: Dulaglutide gradually reached the maximum concentration in 48 h and had a terminal elimination half-life of 5 days. Steady state was achieved between the second and fourth doses. The accumulation ratio was 1.56 for the 1.5 mg dose. Intra-individual variability estimates for the area under the plasma concentration-time curve and the maximum concentration were both <17% [coefficient of variation (CV)]. There was no difference in pharmacokinetics between injection sites (arm, thigh or abdomen). Dulaglutide pharmacokinetics were well described by a two-compartment model with first-order absorption and elimination. The population clearance was estimated at 0.126 L/h [inter-individual variability (CV) 33.8%]. Age, body weight, sex, race and ethnicity did not influence dulaglutide pharmacokinetics to any clinically relevant degree. CONCLUSION: The pharmacokinetics of dulaglutide support once-weekly administration in patients with T2D. The pharmacokinetic findings suggest that dose adjustment is not necessary on the basis of body weight, sex, age, race or ethnicity or site of injection.
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Diabetes Mellitus Tipo 2/metabolismo , Péptidos Similares al Glucagón/análogos & derivados , Hipoglucemiantes/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Vías de Administración de Medicamentos , Femenino , Péptidos Similares al Glucagón/administración & dosificación , Péptidos Similares al Glucagón/sangre , Péptidos Similares al Glucagón/farmacocinética , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/sangre , Masculino , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/sangre , Adulto JovenRESUMEN
BACKGROUND: An 8-mm needle length is commonly used for insulin injections; however, recent recommendations suggest shorter needles may help patients avoid intramuscular injections and reduce pain, while maintaining adequate glucose control. The goal of these analyses was to compare the pharmacokinetics (PK) and glucodynamics (GD) of insulin lispro after a 5-mm or an 8-mm injection depth administration in 2 populations: normal weight (study 1) or obese (study 2). METHODS: In both open-label, randomized, 2-period crossover euglycemic clamp studies, subjects received single 0.25 U/kg insulin lispro doses on 2 occasions (at 5-mm and 8-mm injection depths); samples for PK and GD analyses were collected up to 6 hours postdose. Noncompartmental PK parameters AUC0-tlast, AUC0-∞, Cmax and GD parameters Gtot, Rmax, tRmax were log-transformed prior to analysis using a mixed effects model. RESULTS: There were no apparent differences between PK profiles at the 5-mm or 8-mm injection depth in either study, demonstrated by the ratios of geometric means of AUC0-tlast, AUC0-∞, and Cmax being close to 1, with 90% confidence intervals (CI) within (0.80, 1.25). There were no apparent differences between GD profiles at either injection depth with the ratios of Gtot and Rmax near unity and 90% CIs that included 1. In both studies, the tRmax values were similar between injection depths, with a small median of pairwise differences and a 90% CI that included zero. CONCLUSIONS: Injection depths in the 5-8 mm range did not affect the PK or GD of insulin lispro in normal weight or obese subjects.
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Glucemia/análisis , Inyecciones Subcutáneas , Insulina Lispro/administración & dosificación , Insulina Lispro/farmacocinética , Adulto , Área Bajo la Curva , Índice de Masa Corporal , Peso Corporal , Estudios Cruzados , Femenino , Técnica de Clampeo de la Glucosa , Voluntarios Sanos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Masculino , Persona de Mediana Edad , Obesidad , Proyectos de Investigación , Adulto JovenRESUMEN
Pharmacokinetic/pharmacodynamic (PK/PD) studies of human regular U-500 insulin (U-500R) at high doses commonly used in clinical practice (>100 units) have not been performed. The current analysis applied PK/PD modeling/simulation to fit the data and simulate single-dose and steady-state PK/PD of U-500R high-dose regimens. Data from 3 single-dose euglycemic clamp studies in healthy obese and normal-weight patients, and normal-weight patients with type 1 diabetes were used to build the model. The model was sequential (PK inputs fed into PD component). PK was described using a 1-compartment model with first-order absorption and elimination. The model estimated separate absorption rate constants for U-500R and human regular U-100 insulin. The PD component used an effect compartment model, parameterized in terms of maximum pharmacologic effect (E(max)) and concentration to achieve 50% of E(max). The model described the data well. Steady-state PK for once-daily (QD), twice-daily (BID), or thrice-daily (TID) administration appeared to be reached 24 hours after the first dose. At steady-state, QD dosing showed the greatest fluctuations in PK/PD. BID dosing showed a gradual increase in insulin action with each dose and a fairly stable basal insulin effect. For TID dosing, activity was maintained throughout the dosing interval. PK/PD modeling/simulation of high U-500R doses supports BID or TID administration with an extended duration of activity relative to QD. TID dosing may provide slightly better full-day insulin effect. Additional PK/PD studies and randomized controlled trials of U-500R are needed to validate model predictions in patients with insulin-resistant diabetes requiring high-dose insulin.
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Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Insulina/administración & dosificación , Insulina/farmacocinética , Adulto , Algoritmos , Simulación por Computador , Estudios Cruzados , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Masculino , Modelos Estadísticos , Obesidad/metabolismo , Reproducibilidad de los ResultadosRESUMEN
Ketoconazole is recognized as the prototypical CYP3A inhibitor and is often used to determine the metabolic CYP3A liabilities of new chemical entities in preclinical and clinical studies. Ketoconazole has been commercially available for approximately 30 years and was marketed before drug-metabolizing enzymes were well characterized; consequently, little is known about its metabolic profile. Semagacestat, a γ-secretase inhibitor investigated as a potential therapy for Alzheimer's disease, was determined to be a potent CYP3A autoinducer in human hepatocytes. Two human studies were conducted to assess the induction potential of semagacestat. In the first study (study 1, n = 20), semagacestat increased the mean apparent clearance (CL/F) of oral midazolam (76-324 l/h) and nifedipine (63-229 l/h) as predicted from hepatocytes. In a second (steady-state) study (study 2, n = 20), semagacestat CL/F increased from 22 after a single dose to 31 l/h. Ketoconazole decreased semagacestat CL/F by 32% after a single dose of semagacestat [geometric means ratio estimate, 0.68; 90% confidence interval (CI). 0.64, 0.73] and 46% at steady state (geometric means ratio estimate. 0.54; 90% CI, 0.51, 0.58). Ketoconazole area under the concentration-time curve over 8 h decreased 49% from first to last day of semagacestat dosing. Semagacestat significantly increases the oral clearance of CYP3A substrates, confirming its inducer designation. More importantly, when administered with a potent CYP3A inducer at steady state, ketoconazole's plasma exposure decreased, indicating that it may also be cleared by CYP3A, other inducible enzymes or transporters, or both.
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Alanina/análogos & derivados , Azepinas/farmacología , Inhibidores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A/biosíntesis , Inhibidores Enzimáticos/farmacología , Hepatocitos/efectos de los fármacos , Cetoconazol/farmacología , Administración Oral , Adulto , Anciano , Alanina/administración & dosificación , Alanina/farmacocinética , Alanina/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Área Bajo la Curva , Azepinas/administración & dosificación , Azepinas/farmacocinética , Células Cultivadas , Interacciones Farmacológicas , Inducción Enzimática , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Femenino , Semivida , Hepatocitos/enzimología , Humanos , Hidroxilación , Cetoconazol/administración & dosificación , Cetoconazol/farmacocinética , Masculino , Tasa de Depuración Metabólica , Midazolam/administración & dosificación , Midazolam/farmacocinética , Persona de Mediana Edad , Modelos Biológicos , Nifedipino/administración & dosificación , Nifedipino/farmacocinética , Testosterona/metabolismo , Adulto JovenRESUMEN
Semagacestat, a γ-secretase inhibitor, reduces formation of amyloid beta peptide. Two single-dose (140 mg), open-label, randomized, 3-period, crossover studies evaluated the effect of formulation, food, and time of dosing on the pharmacokinetics and pharmacodynamics of semagacestat in healthy participants. The first study (n = 14) compared tablet to capsules. For all formulations, the median time to maximum plasma concentration (t(max)) was generally 1.0 hour. Plasma elimination was rapid, with a half-life of approximately 2.5 hours. Tablet form II bioavailability (F) relative to capsule was approximately 100% (F = 1.03 [90% confidence interval (CI), 0.96-1.10]). In the second study, participants (n = 27) received semagacestat either fed or fasting in the morning or fasting in the evening. No significant change in exposure (AUC(0-∞) [area under the concentration-time curve from 0 to infinity] ratio = 1.02, [90% CI, 0.990-1.05]) occurred with food, whereas maximum plasma concentration (C(max)) declined approximately 15%, and median t(max) was delayed to 1.5 hours. Time of dosing made no significant difference in AUC(0-∞), C(max), or t(max) (AUC(0-∞) ratio 1.01, [90% CI, 0.975-1.04]). No clinically significant safety concerns occurred in either study. Accordingly, semagacestat may be dosed without regard to formulation, food, or time of administration.
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Alanina/análogos & derivados , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Azepinas/administración & dosificación , Interacciones Alimento-Droga , Nootrópicos/administración & dosificación , Anciano , Alanina/administración & dosificación , Alanina/sangre , Alanina/farmacocinética , Alanina/farmacología , Péptidos beta-Amiloides/sangre , Azepinas/sangre , Azepinas/farmacocinética , Azepinas/farmacología , Disponibilidad Biológica , Cápsulas , Química Farmacéutica , Estudios Cruzados , Esquema de Medicación , Femenino , Semivida , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Nootrópicos/sangre , Nootrópicos/farmacocinética , Nootrópicos/farmacología , Pacientes Desistentes del Tratamiento , Fragmentos de Péptidos/sangre , ComprimidosRESUMEN
OBJECTIVE: Human regular U-500 (U-500R) insulin (500 units/mL) is increasingly being used clinically, yet its pharmacokinetics (PK) and pharmacodynamics (PD) have not been well studied. Therefore, we compared PK and PD of clinically relevant doses of U-500R with the same doses of human regular U-100 (U-100R) insulin (100 units/mL). RESEARCH DESIGN AND METHODS: This was a single-site, randomized, double-blind, crossover euglycemic clamp study. Single subcutaneous injections of 50- and 100-unit doses of U-500R and U-100R were administered to 24 healthy obese subjects. RESULTS: Both overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC(0-)(t)(')]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tR(max50), tR(last)) were prolonged for U-500R versus U-100R at both doses (P < 0.05). CONCLUSIONS: Overall exposure to and action of U-500R insulin after subcutaneous injection were no different from those of U-100R insulin. For U-500R, peaks of concentration and action profiles were blunted and the effect after the peak was prolonged. These findings may help guide therapy with U-500R insulin for highly insulin-resistant patients with diabetes.
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Hipoglucemiantes/farmacocinética , Insulina Regular Humana/farmacología , Insulina Regular Humana/farmacocinética , Obesidad/tratamiento farmacológico , Adulto , Anciano , Área Bajo la Curva , Glucemia/efectos de los fármacos , Estudios Cruzados , Método Doble Ciego , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Insulina Regular Humana/administración & dosificación , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: In order to assess pharmacokinetic (PK) and glucodynamic (GD) attributes relevant to the end user of an inhaled insulin, this study examined the exposure and GD effect of doses of AIR inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) by combining capsules of different strengths in healthy subjects. METHODS: Fifty-nine healthy, nonsmoking, male or female subjects with normal pulmonary function were enrolled in an open-label, randomized, crossover study. Subjects underwent up to five euglycemic glucose clamp procedures, separated by 5-18 days. The five AIR insulin treatments tested included one 6 unit-equivalent (U-eq) capsule containing 2.6 mg of insulin, three 2 U-eq (0.9 mg) capsules (2.7 mg total), one 10 U-eq (3.9 mg) capsule, one 6 U-eq capsule plus two 2 U-eq capsules (4.4 mg total), and two 10 U-eq capsules (7.8 mg total). Samples for PK and GD assessments were taken up to 10 h post-dose. RESULTS: Based on both PK (area under the curve from time 0 to time of return to baseline and maximum concentration) and GD (total amount of glucose infused and maximum glucose infusion rate) responses, administration of a 6 U-eq capsule was equivalent to three 2 U-eq capsules; 90% confidence intervals for the ratios were contained within the interval (0.8, 1.25). Similarly, both overall exposure and glucodynamic response after administration of a 10 U-eq capsule were comparable to the 6 U-eq plus two 2 U-eq capsule combination. AIR insulin exhibited PK dose proportionality and dose-dependent increases in GD responses over the 2.6-7.8 mg dose range. CONCLUSIONS: AIR insulin exhibited dose strength interchangeability and dose proportionality after single-dose administration in healthy subjects.
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Administración por Inhalación , Insulina/farmacología , Insulina/farmacocinética , Área Bajo la Curva , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Estudios Cruzados , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Insulina/administración & dosificación , Insulina/sangre , Cinética , Masculino , Valores de Referencia , Capacidad Vital/efectos de los fármacosRESUMEN
BACKGROUND: Delivery of GH via inhalation is a potential alternative to injection. Previous studies of inhaled GH in adults have demonstrated safety and tolerability. OBJECTIVE: We sought to assess safety and tolerability of inhaled GH in children and to estimate relative bioavailability and biopotency between inhaled GH and sc GH. DESIGN/METHODS: This pediatric multicenter, randomized, double-blind, placebo-controlled, crossover trial had two 7-d treatment phases. Patients received inhaled GH and sc GH in the alternate phase. Placebo was administered by the route opposite from active drug. GH and IGF-I levels were measured at multiple time points. Pharmacokinetics were assessed using noncompartmental methods. RESULTS: Twenty-two GH-deficient children aged 6-16 yr were treated. Absorption of GH appeared to be faster after inhalation with maximum serum concentrations measured at 1-4 h compared with 2-8 h for sc GH. Mean relative bioavailability for inhaled GH was 3.5% (90% confidence interval 2.7-4.4%). Mean relative biopotency, based on IGF-I response, was 5.5% (confidence interval 5.2-5.8%). Similar dose-dependent increases in mean serum GH area under the curve and IGF-I changes from baseline were seen after inhaled and sc GH doses. Inhaled GH was well tolerated and preferred to injection. No significant changes in pulmonary function tests were seen. CONCLUSIONS: In this first pediatric trial of GH delivered by inhalation, it was well tolerated and resulted in dose-dependent increases in serum GH and IGF-I levels. This study establishes that delivery of GH via the deep lung is feasible in children.
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Trastornos del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/administración & dosificación , Hormona de Crecimiento Humana/efectos adversos , Hormona de Crecimiento Humana/farmacocinética , Administración Cutánea , Administración por Inhalación , Adolescente , Niño , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Trastornos del Crecimiento/sangre , Hormona de Crecimiento Humana/deficiencia , Humanos , Masculino , Satisfacción del Paciente , PlacebosRESUMEN
In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 microg [group A] or 5 microg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 microg bid; groups C and D received 10 and 15 microg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.