RESUMO
AIMS: Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion-transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive in vitro assessment of rifampicin inhibitory potential on statin transporters. METHODS: The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The in vitro transporter studies were performed using hepatocytes and recombinant expression systems. RESULTS: Rifampicin markedly increased exposures of both statins, with greater differential increases after POâ vs.â IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration-time curve were 5.7- and 7.6-fold for pitavastatin and 4.4- and 3.3-fold for rosuvastatin, after PO and IV rifampicin, respectively. In vitro studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3. CONCLUSIONS: The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose.
Assuntos
Fluorbenzenos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Pirimidinas/farmacocinética , Quinolinas/farmacocinética , Rifampina/farmacologia , Sulfonamidas/farmacocinética , Administração Intravenosa , Administração Oral , Adulto , Área Sob a Curva , Estudos Cross-Over , Interações Medicamentosas , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Rifampina/administração & dosagem , Rosuvastatina Cálcica , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Adulto JovemRESUMO
AIM: The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QT(c) in 131 healthy CYP2D6 poor metabolizer males were compared. METHODS: Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten second electrocardiograms were obtained for time-matched baseline on days -2 and -1, three time points after dosing on day 1 for moxifloxacin and five time points on day 7 for atomoxetine and placebo. Maximum mean placebo-subtracted change from baseline model-corrected QT (QT(c)M) on day 7 was the primary endpoint. RESULTS: QT(c)M differences for atomoxetine 20 and 60 mg twice daily were 0.5 ms (upper bound of the one-sided 95% confidence interval 2.2 ms) and 4.2 ms (upper bound of the one-sided 95% confidence interval 6.0 ms), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QT(c) was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QT(c)M for moxifloxacin was 4.8 ms and this difference was statistically significant. Moxifloxacin plasma concentrations were below the concentrations expected from the literature. However, the slope of the plasma concentration-QT(c) change observed was consistent with the literature. CONCLUSION: Atomoxetine was not associated with a clinically significant change in QT(c). However, a statistically significant increase in QT(c) was associated with increasing plasma concentrations.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Compostos Aza/farmacologia , Citocromo P-450 CYP2D6/metabolismo , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Propilaminas/farmacologia , Quinolinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Inibidores da Captação Adrenérgica/farmacocinética , Adulto , Cloridrato de Atomoxetina , Compostos Aza/farmacocinética , Estudos Cross-Over , Relação Dose-Resposta a Droga , Fluoroquinolonas , Humanos , Masculino , Moxifloxacina , Propilaminas/farmacocinética , Quinolinas/farmacocinética , Inibidores da Topoisomerase II/farmacocinética , Adulto JovemRESUMO
BACKGROUND: Consistent with its effect on gastric emptying, exenatide, an injectable treatment for type 2 diabetes, may slow the absorption rate of concomitantly administered oral drugs resulting in a decrease in maximum concentration (Cmax). This study evaluated the drug interaction potential of exenatide when administered adjunctively with oral contraceptives, given their potential concomitant use. METHODS: This trial evaluated the effect of exenatide co-administration on single- and multiple-dose pharmacokinetics of a combination oral contraceptive (ethinyl estradiol [EE] 30 µg, levonorgestrel [LV] 150 µg [Microgynon 30®]). Thirty-two healthy female subjects participated in an open-label, randomised, crossover trial with 3 treatment periods (oral contraceptive alone, 1 hour before exenatide, 30 minutes after exenatide). Subjects received a single dose of oral contraceptive on Day 8 of each period and QD doses on Days 10 through 28. During treatment periods of concomitant usage, exenatide was administered subcutaneously prior to morning and evening meals at 5 µg BID from Days 1 through 4 and at 10 µg BID from Days 5 through 22. Single- (Day 8) and multiple-dose (Day 22) pharmacokinetic profiles were assessed for each treatment period. RESULTS: Exenatide did not alter the bioavailability nor decrease daily trough concentrations for either oral contraceptive component. No substantive changes in oral contraceptive pharmacokinetics occurred when oral contraceptive was administered 1 hour before exenatide. Single-dose oral contraceptive administration 30 minutes after exenatide resulted in mean (90% CI) Cmax reductions of 46% (42-51%) and 41% (35-47%) for EE and LV, respectively. Repeated daily oral contraceptive administration 30 minutes after exenatide resulted in Cmax reductions of 45% (40-50%) and 27% (21-33%) for EE and LV, respectively. Peak oral contraceptive concentrations were delayed approximately 3 to 4 hours. Mild-to-moderate nausea and vomiting were the most common adverse events observed during the trial. CONCLUSIONS: The observed reduction in Cmax is likely of limited importance given the unaltered oral contraceptive bioavailability and trough concentrations; however, for oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before exenatide injection. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00254800.
Assuntos
Anticoncepcionais Orais Combinados/farmacocinética , Etinilestradiol/farmacocinética , Hipoglicemiantes/administração & dosagem , Levanogestrel/farmacocinética , Peptídeos/administração & dosagem , Peçonhas/administração & dosagem , Adulto , Anticoncepcionais Orais Combinados/sangue , Estudos Cross-Over , Interações Medicamentosas , Etinilestradiol/sangue , Exenatida , Feminino , Humanos , Levanogestrel/sangue , Adulto JovemRESUMO
Ubrogepant (MK-1602) is a novel, oral, calcitonin gene-related peptide receptor antagonist in clinical development with positive phase III outcomes for acute treatment of migraine. This paper describes the population exposure-response (E-R) modeling and simulations, which were used to inform the phase III dose-selection rationale, based on ~ 800 participants pooled across two phase IIb randomized dose-finding clinical trials. The E-R model describes the placebo and ubrogepant treatment effects based on migraine pain end points (2-hour pain relief and 2-hour pain freedom) at various dose levels. Sensitivity analyses were conducted to evaluate various assumptions of placebo response in light of the high placebo response observed in one phase II trial. A population pharmacokinetic model describing the effect of formulations was included in the E-R simulation framework to assess potential dose implications of a formulation switch from phase II to phase III. Model-based simulations predict that a dose of 25 mg or higher is likely to achieve significantly better efficacy than placebo with desirable efficacy levels. The understanding of E-R helped support the dose selection for the phase III clinical trials.
Assuntos
Tomada de Decisão Clínica/métodos , Transtornos de Enxaqueca/tratamento farmacológico , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Adolescente , Adulto , Idoso , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/diagnóstico , Modelos Biológicos , Medição da Dor , Piridinas/efeitos adversos , Piridinas/farmacocinética , Pirróis/efeitos adversos , Pirróis/farmacocinética , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
This randomized, placebo-controlled, double-blind, parallel study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of exenatide once weekly (QW) in 30 Japanese patients with type 2 diabetes (T2D) suboptimally controlled by diet and exercise alone or combined with biguanide, sulfonylurea, thiazolidinedione, or combinations of these agents (58.6% male; 58+/-9 years; body mass index 26.3+/-2.9 kg/m(2); hemoglobin A(1c) [HbA(1c)] 7.4+/-0.8%; fasting plasma glucose [FPG] 156.1+/-29.1 mg/dL; duration of T2D 6+/-5 years; means +/- SD). Patients were randomized in a 1:1:1 ratio to subcutaneous placebo QW, exenatide QW 0.8 mg, or exenatide QW 2.0 mg for 10 weeks. All evaluable patients were analyzed (placebo QW, n=10; exenatide QW 0.8 mg, n=10; exenatide QW 2.0 mg, n=9), unless otherwise stated. Steady-state plasma exenatide concentrations were observed by Week 8 of the study. For the evaluable pharmacokinetic population, geometric mean (90% confidence interval) steady-state plasma concentrations (pg/mL) were 81.2 (68.3-96.4) and 344.5 (256.5-462.7) with exenatide QW 0.8 mg (n=8) and exenatide QW 2.0 mg (n=5), respectively. Baseline-to-Week 10 glycemic improvements with placebo QW, exenatide QW 0.8 mg, and exenatide QW 2.0 mg, respectively, were: HbA(1c) (%): -0.4+/-0.3, -1.0+/-0.7, and -1.5+/-0.7; FPG (mg/dL): -20.5+/-20.4, -25.2+/-10.9, and -50.8+/-27.8; and 2-hour postprandial plasma glucose excursions (mg/dL): -8.8+/-26.9, -50.0+/-41.1, and -59.7+/-26.8 (means +/- SD). No serious adverse events (AEs) were reported and no AEs led to study discontinuation in any group. The most frequent AE observed was mild-to-moderate injection site induration. No serious hypoglycemia was reported. Exenatide QW for 10 weeks was well tolerated and improved short-term glycemic control in Japanese patients with suboptimally controlled T2D.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Peptídeos/farmacocinética , Peçonhas/administração & dosagem , Peçonhas/efeitos adversos , Peçonhas/farmacocinética , Idoso , Algoritmos , Povo Asiático , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Exenatida , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Injeções , Masculino , Pessoa de Meia-Idade , PlacebosRESUMO
Merck & Co, Inc (Kenilworth, NJ) is investing in approaches to enrich clinical trial data and augment decision making through use of digital health technologies, outpatient sampling, and real-time data access. As part of this strategy, a phase I study was conducted to explore a few technologies of interest. In this fixed-sequence two-period trial, 16 healthy subjects were administered 50-mg once-daily sitagliptin packaged in a bottle that electronically captured the date and time study medication was dispensed (period 1) and in a traditional pharmacy bottle (period 2). Dried blood spot samples were collected for sitagliptin concentration analysis on select study days, both in clinic and at home, with collection time recorded using an electronic diary in period 1 and by clinic staff in period 2. Study results demonstrated the feasibility and subject acceptance of collecting digital adherence data and outpatient dried blood spot samples in clinical trials and highlighted areas for future improvements.
Assuntos
Teste em Amostras de Sangue Seco/métodos , Desenvolvimento de Medicamentos/métodos , Hipoglicemiantes/sangue , Fosfato de Sitagliptina/sangue , Telemedicina/métodos , Adulto , Teste em Amostras de Sangue Seco/normas , Desenvolvimento de Medicamentos/normas , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fosfato de Sitagliptina/administração & dosagem , Manejo de Espécimes/métodos , Manejo de Espécimes/normas , Inquéritos e Questionários/normas , Telemedicina/normas , Adulto JovemRESUMO
A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development. This multicenter, open-label study explored D(2) receptor occupancy of a fixed dose of olanzapine pamoate (OP) depot given every 4 weeks. Patients (nine male, five female) with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine were switched to OP depot 300 mg by intramuscular injection every 4 weeks for 6 months. No visitwise within-group significant changes were found in Brief Psychiatric Rating Scale Total or Clinical Global Impressions-Severity of Illness scores, although seven patients received oral olanzapine supplementation during the first four injection cycles. To minimize impact on D(2) occupancy, positron emission tomography (PET) scans were not completed during injection cycles that required supplemental oral olanzapine. Two patients reported transient injection site adverse events, which did not result in discontinuation. The most frequently reported treatment-emergent adverse events were insomnia, aggravated psychosis, and anxiety. Mean striatal D(2) receptor occupancy, as measured by [(11)C]-raclopride PET, was 69% on oral olanzapine (5-20 mg/day) and 50% (trough) on OP depot at steady state. Following an initial decline, occupancy returned to 84% of baseline oral olanzapine occupancy after six injections. Over the study period, D(2) receptor occupancy and plasma olanzapine concentrations were significantly correlated (r=0.76, P=0.001). OP depot resulted in mean D(2) receptor occupancy of approximately 60% or higher at the end of the 6-month study period, a level consistent with antipsychotic efficacy and found during treatment with oral olanzapine. However, supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles.
Assuntos
Antipsicóticos/farmacocinética , Benzodiazepinas/farmacocinética , Receptores de Dopamina D2/metabolismo , Esquizofrenia/metabolismo , Adulto , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Benzodiazepinas/sangue , Benzodiazepinas/uso terapêutico , Feminino , Humanos , Masculino , Olanzapina , Tomografia por Emissão de Pósitrons/métodos , Receptores de Dopamina D2/efeitos dos fármacos , Esquizofrenia/diagnóstico por imagem , Fatores de TempoRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos/farmacocinética , Peçonhas/farmacocinética , Área Sob a Curva , Povo Asiático , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Ensaio de Imunoadsorção Enzimática , Exenatida , Feminino , Glucagon/sangue , Meia-Vida , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Injeções Subcutâneas , Insulina/sangue , Japão , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Peptídeos/efeitos adversos , Peptídeos/uso terapêutico , Método Simples-Cego , Fatores de Tempo , Resultado do Tratamento , Peçonhas/efeitos adversos , Peçonhas/uso terapêutico , Vômito/induzido quimicamenteRESUMO
OBJECTIVES: To evaluate the effect of exenatide on gastric emptying (GE) in type 2 diabetes using scintigraphy. METHODS: Seventeen subjects with type 2 diabetes participated in a randomized, single-blind, 3-period, crossover study. In each 5-day period, 5 or 10 microg exenatide or placebo was administered subcutaneously BID. Oral antidiabetic treatments were continued. The presence of cardiac autonomic neuropathy was assessed during screening. On day 5, after the morning dose, subjects consumed a 450-kcal breakfast containing (99m)Tc-labeled eggs and (111)In-labeled water, and GE was measured by scintigraphy. Plasma glucose and insulin, perceptions of appetite, and plasma exenatide were also quantified. RESULTS: Exenatide slowed GE of both solid and liquid meal components [solid (T(50)(90% confidence interval [CI]); placebo, 60(50-70) min; 5 microg exenatide, 111(94-132) min; 10 microg exenatide, 169(143-201) min; both P<0.01); liquid (T(50)(90% CI), placebo, 34(25-46) min; 5 microg exenatide, 87(65-117) min; 10 microg exenatide, 114(85-154) min; both P<0.01)]. GE was not different between subjects with cardiac autonomic neuropathy (n=7), compared with those without (n=10) (P>/=0.68). Exenatide reduced postprandial glucose (area under the curve [AUC((0-6 h))]) by 69-76% and peak insulin (C(max)) by 84-86% compared with placebo. There was an inverse relationship between the postprandial rise in glucose (AUC((0-3 h))) and GE (solid T(50), r=-0.49, P<0.001). CONCLUSIONS: Exenatide slows GE substantially in type 2 diabetes, which could be an important mechanism contributing to the beneficial effect of exenatide on postprandial glycemia.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Esvaziamento Gástrico/efeitos dos fármacos , Hiperglicemia/prevenção & controle , Hipoglicemiantes/farmacologia , Peptídeos/farmacologia , Peçonhas/farmacologia , Idoso , Apetite/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Tolerância a Medicamentos , Exenatida , Feminino , Humanos , Hiperglicemia/sangue , Hipoglicemiantes/farmacocinética , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Peptídeos/farmacocinética , Período Pós-Prandial , Segurança , Método Simples-Cego , Peçonhas/farmacocinéticaRESUMO
Advances in emerging innovative technologies have led to optimistic outlooks on their transformative potential for healthcare and clinical trials.1 Given the increased attention, this white paper by the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) presents perspectives on pharmaceutical and biotechnology industry trends for innovative digital health, adherence, and outpatient sampling technologies. As stimulus for cross-company scientific dialog points to consider for adoption, implementation, and recommendations to broaden uptake are proposed.
Assuntos
Biomarcadores Farmacológicos/análise , Desenvolvimento de Medicamentos/métodos , Monitoramento de Medicamentos/métodos , Preparações Farmacêuticas/administração & dosagem , Telemedicina/métodos , Tomada de Decisão Clínica , Difusão de Inovações , Desenvolvimento de Medicamentos/instrumentação , Desenvolvimento de Medicamentos/tendências , Monitoramento de Medicamentos/instrumentação , Monitoramento de Medicamentos/tendências , Previsões , Humanos , Adesão à Medicação , Aplicativos Móveis , Valor Preditivo dos Testes , Smartphone , Telemedicina/instrumentação , Telemedicina/tendências , Dispositivos Eletrônicos VestíveisRESUMO
Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late-stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late-stage clinical program: ubrogepant (MK-1602), a novel oral calcitonin gene-related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure-response modeling. The clinical endpoint was a spontaneous event, which generally occurs outside a clinic visit. Thus, an innovative feature of this trial was facilitating DBS in an outpatient setting. In vitro and bioanalytical tests established initial method feasibility and suitability for further evaluations in the clinic. A quantitative relationship was developed between blood and plasma concentrations from concurrently collected samples in a phase 1 (healthy subjects) and phase 2 (target patient population) study using graphical and population PK approaches. This integrated information was presented to the Food and Drug Administration for regulatory input. Following regulatory concurrence, DBS was poised for use in further clinical studies. Population PK modeling was used to dissect sources of variability contributing to DBS collection in the outpatient setting. What has been learned from this program has informed the broader integrated strategy of Merck & Co., Inc. (Kenilworth, NJ) for DBS implementation in clinical trials and research to improve the precision of PK data collected in an outpatient setting.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/sangue , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacocinética , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/tratamento farmacológico , Piridinas/sangue , Piridinas/farmacocinética , Pirróis/sangue , Pirróis/farmacocinética , Adulto , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Relação Dose-Resposta a Droga , Teste em Amostras de Sangue Seco , Feminino , Humanos , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Inquéritos e QuestionáriosRESUMO
Exenatide, a treatment for type 2 diabetes, slows gastric emptying as part of its pharmacologic action and may alter the absorption of concomitant oral drugs. This open-label, 2-period, fixed-sequence study evaluated the influence of exenatide coadministration on the pharmacokinetics and pharmacodynamics of warfarin, a narrow therapeutic index drug, in healthy men (N = 16). A single, 25-mg oral dose of warfarin, with a standardized breakfast, was administered alone in period 1 and concomitantly with 10 microg exenatide subcutaneous twice daily in period 2. Exenatide did not produce significant changes in R- or S-warfarin pharmacokinetics. Although there were minor reductions in warfarin anticoagulant effect, the ratios of geometric means for the area under the international normalized ratio (INR)-time curve from dosing until the time of the last measurable INR value or maximum-observed INR response being 0.94 (0.93-0.96) and 0.88 (0.84-0.92), respectively, the magnitude and direction of these changes do not suggest a safety concern from this interaction.
Assuntos
Povo Asiático , Peptídeos/farmacocinética , Peçonhas/farmacocinética , Varfarina/farmacocinética , Administração Oral , Adulto , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Área Sob a Curva , Hidrocarboneto de Aril Hidroxilases/genética , Cromatografia Líquida/métodos , Citocromo P-450 CYP2C9 , Relação Dose-Resposta a Droga , Interações Medicamentosas , Exenatida , Genótipo , Haplótipos/genética , Cefaleia/induzido quimicamente , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Injeções Subcutâneas , Coeficiente Internacional Normatizado/métodos , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Peçonhas/administração & dosagem , Peçonhas/efeitos adversos , Varfarina/administração & dosagem , Varfarina/efeitos adversosRESUMO
Dried blood spot (DBS) sample collection has gained increased interest across the pharmaceutical industry as a potential alternative to plasma for pharmacokinetic (PK) evaluations. However, regulatory guidelines and examples of late-stage clinical trial applications in the literature are lacking. This paper communicates Merck's strategy for the implementation of DBS exemplified by experience on a late-stage program (MK-8931). In this program, DBS was proposed as the sole matrix for phase 3 studies to decrease logistical burden in an aging target patient population (Alzheimer's disease). In vitro and bioanalytical tests demonstrated initial method feasibility and suitability for further evaluations in the clinic. An in vivo dataset was developed initially in healthy subjects (phase 1 study) and then in patients (phase 2/3 study) to establish a quantitative relationship between the blood and plasma concentrations (bridging dataset) using descriptive and population PK analyses. This allowed for PK conclusions to be seamlessly drawn across the clinical program without impact from the choice of matrix. This integrated information package (in vitro, bioanalytical and clinical) was presented to major regulatory agencies (FDA and EMA) for regulatory input. Based on this package, regulatory concurrence was gained on accepting DBS as the sole matrix in late-stage clinical trials.
Assuntos
Teste em Amostras de Sangue Seco/métodos , Teste em Amostras de Sangue Seco/tendências , Indústria Farmacêutica/métodos , Indústria Farmacêutica/tendências , HumanosRESUMO
This open-label study investigated the effect of exenatide coadministration on the steady-state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2-12, 0.25 mg once daily) and exenatide (days 8-12, 10 microg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24-hour steady-state digoxin exposure (AUCtau,ss) and Cmin,ss but caused a 17% decrease in mean plasma digoxin Cmax,ss (1.40 to 1.16 ng/mL) and an increase in digoxin tmax,ss (median increase, 2.5 hours). Although the decrease in digoxin Cmax,ss was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.
Assuntos
Antiarrítmicos/farmacocinética , Cardiotônicos/farmacocinética , Digoxina/farmacocinética , Peptídeos/farmacologia , Peçonhas/farmacologia , Adulto , Antiarrítmicos/administração & dosagem , Antiarrítmicos/sangue , Cardiotônicos/administração & dosagem , Cardiotônicos/sangue , Digoxina/administração & dosagem , Digoxina/sangue , Interações Medicamentosas , Exenatida , Humanos , Masculino , Náusea/induzido quimicamente , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Peçonhas/administração & dosagem , Peçonhas/efeitos adversosAssuntos
Pesquisa Biomédica/organização & administração , Prática Clínica Baseada em Evidências/organização & administração , Sistemas de Informação , Projetos de Pesquisa , Biomarcadores , Pesquisa Biomédica/normas , Coleta de Dados/métodos , Tomada de Decisões , Indústria Farmacêutica/organização & administração , Registros Eletrônicos de Saúde/organização & administração , Prática Clínica Baseada em Evidências/normas , Humanos , Dispositivos Eletrônicos VestíveisRESUMO
OBJECTIVE: In patients with type 2 diabetes, exenatide reduces A1C, postprandial and fasting glucose, and weight. In this study we investigated the effects of continuous exenatide administration from a long-acting release (LAR) formulation. RESEARCH DESIGN AND METHODS: In this randomized, placebo-controlled phase 2 study, exenatide LAR (0.8 or 2.0 mg) was administered subcutaneously once weekly for 15 weeks to subjects with type 2 diabetes (n = 45) suboptimally controlled with metformin (60%) and/or diet and exercise (40%): 40% female, A1C (mean +/- SD) 8.5 +/- 1.2%, fasting plasma glucose 9.9 +/- 2.3 mmol/l, weight 106 +/- 20 kg, and diabetes duration 5 +/- 4 years. RESULTS: From baseline to week 15, exenatide LAR reduced mean +/- SE A1C by -1.4 +/- 0.3% (0.8 mg) and -1.7 +/- 0.3% (2.0 mg), compared with +0.4 +/- 0.3% with placebo LAR (P < 0.0001 for both). A1C of < or =7% was achieved by 36 and 86% of subjects receiving 0.8 and 2.0 mg exenatide LAR, respectively, compared with 0% of subjects receiving placebo LAR. Fasting plasma glucose was reduced by -2.4 +/- 0.9 mmol/l (0.8 mg) and -2.2 +/- 0.5 mmol/l (2.0 mg) compared with +1.0 +/- 0.7 mmol/l with placebo LAR (P < 0.001 for both). Exenatide LAR reduced self-monitored postprandial hyperglycemia. Subjects receiving 2.0 mg exenatide LAR had body weight reductions (-3.8 +/- 1.4 kg) (P < 0.05), whereas body weight was unchanged with both placebo LAR and the 0.8-mg dose. Mild nausea was the most frequent adverse event. No subjects treated with exenatide LAR withdrew from the study. CONCLUSIONS: Exenatide LAR offers the potential of 24-h glycemic control and weight reduction with a novel once-weekly treatment for type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Peptídeos/uso terapêutico , Peçonhas/uso terapêutico , Adulto , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Automonitorização da Glicemia , Peso Corporal/efeitos dos fármacos , Preparações de Ação Retardada , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Esquema de Medicação , Exenatida , Humanos , Hipoglicemiantes/administração & dosagem , Pessoa de Meia-Idade , Peptídeos/administração & dosagem , Peçonhas/administração & dosagem , Redução de PesoRESUMO
AIMS: To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI). METHODS: Exenatide (5 or 10 microg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft-Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min(-1), n = 8), mild RI (51-80 ml min(-1), n = 8), moderate RI (31-50 ml min(-1), n = 7) or end-stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single-dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL. RESULTS: Mean half-life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h(-1), respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 microg q.d.). CONCLUSIONS: Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 microg) unsuitable in severe RI or ESRD.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Hipoglicemiantes/farmacocinética , Peptídeos/farmacocinética , Peçonhas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Creatinina/sangue , Estudos Cross-Over , Método Duplo-Cego , Exenatida , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Peptídeos/sangue , Método Simples-Cego , Peçonhas/efeitos adversos , Peçonhas/sangueRESUMO
The influence of enzyme localization and blood flow on intestinal elimination was evaluated in rats. Phenol was administered vascularly (approximately 1400 and 2500 microg) and luminally (intrajejunal bolus doses of approximately 100 and 1000 microg) to the recirculating in situ perfused intestine. The portal effluent and the reservoir were sampled. The intestinal extraction ratios for phenol at the low and high vascular doses were (mean +/- S.D., n = 3) 0.09 +/- 0.02 and 0.11 +/- 0.01, respectively. The perfusion flow rate was also varied from 5 to 12 ml/min at a vascular dose of approximately 2500 microg of phenol. The organ clearance at the lowest flow rate significantly exceeded those at the higher flow rates. The presence of a diffusional barrier at the mucosa-serosa interface was suggested. The calculated mean diffusional clearance of phenol was 1.11 ml/min. Sulfation was the predominant metabolic pathway after vascular administration of phenol. After luminal dosing, the intestinal intrinsic clearances of phenol at the low and high doses were 7.29 +/- 1.39 (n = 4) and 3.55 +/- 1.16 ml/min (n = 3), respectively, indicating saturation at the higher dose. Moreover, there was a decrease in the area under the curve ratio (metabolite/phenol) at the high luminal dose. Luminal administration, in general, produced greater glucuronidation. These data and STELLA simulations suggest that enzyme localization at both the cellular and tissue levels has a significant influence on intestinal metabolism.