RESUMO
Pilocarpine-induced salivary secretion could serve as a nontherapeutic target engagement biomarker in a clinical setting to test the activity of an M3 positive allosteric modulator (PAM). The potentiating effect on the reactivity of the M3 receptor to the agonistic effect of pilocarpine would support the mechanism of action of an M3 PAM in a variety of therapeutic areas. The aim of this study was to determine the optimal pilocarpine dose needed for evaluation of this potentiating effect. Therefore, the effects of pilocarpine on salivary secretion rate and its pharmacokinetics were explored at single doses of 2.5, 5, and 10 mg of pilocarpine or placebo. The study also explored the test-retest variability of the pilocarpine-induced effects on salivary secretion. Pilocarpine caused a reproducible, dose-related increase in overall and maximum salivary secretion rate, in line with pilocarpine exposure. Oral doses of pilocarpine from 2.5 to 10 mg were safe and well tolerated, consistent with the published safety profile. These results support the use of pilocarpine in single-dose pharmacological challenge studies. The recommended dose for evaluating M3 PAM activity would be between 2.5 and 5 mg, showing a small increase in salivary secretion rate with room for further increase due to PAM activation.
Assuntos
Biomarcadores Farmacológicos , Pilocarpina , Humanos , Agonistas Muscarínicos/farmacologia , Pilocarpina/farmacologia , Receptor Muscarínico M3 , SalivaçãoRESUMO
BACKGROUND: The calcineurin inhibitor tacrolimus is a narrow therapeutic index medication, which requires therapeutic drug monitoring to optimize dose on the basis of systemic exposure. MITRA microsampling offers a minimally invasive approach for the collection of capillary blood samples from a fingerprick as an alternative to conventional venous blood sampling for quantitation of tacrolimus concentrations. METHODS: A bioanalytical method for the quantitation of tacrolimus in human whole blood samples collected on MITRA tips was developed, using liquid-liquid extraction followed by liquid chromatography with tandem mass spectrometry detection. Validation experiments were performed according to the current Food and Drug Administration and European Medicines Agency guidelines on validation of bioanalytical methods. Validation criteria included assay specificity and sensitivity, interference, carryover, accuracy, precision, dilution integrity, matrix effect, extraction recovery, effect of hematocrit and hyperlipidemia, and stability. RESULTS: All assay validation results were within the required acceptance criteria, indicating a precise and accurate tacrolimus quantitation method. The validated assay range was 1.00-50.0 ng/mL. No interference, carryover or matrix effect was observed. Extraction recovery was acceptable across the assay range. Samples were stable for up to 96 days at -20°C and 20°C, and 28 days at 40°C. Hematocrit, hyperlipidemia, and lot-to-lot differences in the nominal absorption volume of the 10-µL MITRA tips were shown not to influence tacrolimus quantitation by this assay method. CONCLUSIONS: The bioanalytical method validated in this study is appropriate and practical for the quantitation of tacrolimus in human whole blood samples collected using the MITRA microsampling device.
Assuntos
Coleta de Amostras Sanguíneas/instrumentação , Monitoramento de Medicamentos , Tacrolimo , Cromatografia Líquida , Humanos , Reprodutibilidade dos Testes , Tacrolimo/sangue , Tacrolimo/farmacocinética , Espectrometria de Massas em TandemRESUMO
The aim of this investigation was to characterize and compare the pharmacokinetics (PK) of the antimuscarinic drug solifenacin in pediatric patients with overactive bladder (OAB) or neurogenic detrusor overactivity (NDO) utilizing data from three phase III trials. LION was a placebo-controlled, 12-week trial in children (5-<12 years) and adolescents (12-<18 years) with OAB. MONKEY and MARMOSET were open-label, 52-week trials in children and adolescents or younger children (6 months-<5 years), respectively, with NDO. During the trials, solifenacin doses could be titrated to weight-adjusted pediatric equivalent doses (PEDs) of 2.5, 5, 7.5, or 10 mg day-1 . Nonlinear mixed effects modeling was used to develop population PK models to characterize the PK in patients with either OAB or NDO. Overall, 194 children and adolescents received solifenacin. At the time of PK sampling, the majority (119/164 [72.6%] patients) were receiving PED10 once daily. All population models included first-order oral absorption, a lag time, and interindividual variability. PK analysis showed that apparent clearance was similar in both patient populations. Mean apparent oral plasma clearance (CL/F), apparent volume of distribution during the terminal phase (Vz /F), and terminal half-life (t1/2 ) were higher in adolescents than in children, but median time to maximum plasma concentration (tmax ) was similar. Dose-normalized exposure results were similar for both younger and older patients with OAB or NDO. In conclusion, population PK modeling was used to successfully characterize solifenacin PK in pediatric patients with OAB or NDO. Similar solifenacin PK characteristics were observed in both populations.
Assuntos
Antagonistas Muscarínicos/farmacocinética , Succinato de Solifenacina/farmacocinética , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/metabolismo , Agentes Urológicos/farmacocinética , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Lactente , Masculino , Antagonistas Muscarínicos/administração & dosagem , Método Simples-Cego , Succinato de Solifenacina/administração & dosagem , Bexiga Urinária Hiperativa/diagnóstico , Agentes Urológicos/administração & dosagemRESUMO
INTRODUCTION: Inhibitors of fatty acid amide hydrolase (FAAH) increase the levels of endocannabinoids and have shown analgesic and anti-inflammatory activity in animal models. ASP3652 is a peripherally acting FAAH inhibitor in development for the treatment of chronic bladder and pelvic pain disorders. Here we describe the safety, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of ASP3652 administered in healthy non-elderly and elderly male and female volunteers. METHODS: Study 1 was a combined single-ascending dose and food-effect study in which ASP3652 was given as single doses (1-600 mg) or matching placebo in healthy subjects. Study 2 was a multiple ascending dose study in which ASP3652 or matching placebo was administered in multiple oral doses (10-300 mg bid and 600 mg qd for 14 days) to healthy subjects. In both studies, the levels of ASP3652, FAAH, endocannabinoids (eCBs) and safety were evaluated. RESULTS: ASP3652 was readily absorbed to reach Cmax at 1 h after a single dose. Steady state was reached within 3 days after the start of multiple dosing. The Cmax and AUC of ASP3652 increased in a slightly more than dose-proportional manner after a single dose of ASP3652 at 30-600 mg. There was some accumulation (15-38%) based on Cmax and AUC12h upon multiple doses. Cmax was 47% lower in combination with food. There was no significant effect of gender or age on the pharmacokinetics of ASP3652. FAAH activity was inhibited in a dose-dependent manner in all dose groups after single and multiple doses of ASP3652, paralleled by an increase in plasma levels of anandamide (AEA). The incidence of adverse events following multiple doses was similar across all treatment groups including the placebo group. CONCLUSIONS: Single and multiple doses of ASP3652 were safe and well tolerated and increased endogenous cannabinoid plasma levels.
Assuntos
Amidoidrolases/uso terapêutico , Analgésicos/uso terapêutico , Cistite Intersticial/tratamento farmacológico , Voluntários Saudáveis/estatística & dados numéricos , Dor Pélvica/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Amidoidrolases/administração & dosagem , Analgésicos/administração & dosagem , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: The studies described here were conducted to investigate the central nervous system (CNS) transfer of ASP3652, a peripherally acting inhibitor of fatty acid amide hydrolase, after multiple doses at around the anticipated therapeutic dose and the safety, tolerability, and pharmacokinetics after single doses at corresponding supratherapeutic doses in healthy subjects. METHODS: Study 1 was an open-label multiple dose study in which ASP3652 (300 mg bid) or matching placebo was administered in multiple doses to healthy subjects. Study 2 was a placebo-controlled, randomized 4 × 4 crossover study in which ASP3652 was given as three single ascending doses of ASP3652 (600-1800 mg) or matching placebo to healthy subjects. Levels of ASP3652 and endocannabinoids (eCBs) in plasma, cerebrospinal fluid (CSF) (study 1 only), and safety were evaluated. RESULTS: In study 1, ASP3652 was readily absorbed to reach Cmax at 1 h after dosing. AUCtau and Cmax of ASP3652 in CSF were approximately 0.2% and 0.06% of the AUCtau and Cmax in plasma after multiple doses of ASP3652 300 mg bid. At steady state the area under the response-time curve (AURC) from 0 to 12 h and the maximum response for anandamide in plasma were approximately 550-fold and 230-fold higher than those in CSF. In study 2, the Cmax and AUC of ASP3652 increased higher than dose proportionally in subjects receiving 600-1800 mg ASP3652. For eCBs, although the AURC increased less than dose proportionally, maximum plasma levels were comparable across all treatment groups. The incidence of adverse events (AEs) was similar across all treatment groups including the placebo group. There was no evidence of CNS-related side effects. CONCLUSIONS: ASP3652 showed low CNS penetration at the anticipated therapeutic dose and was well tolerable without any CNS-related AEs at supratherapeutic doses, supporting that the drug can be safely tested at the anticipated therapeutic dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02034734 for study 1, NCT01815684 for study 2.
Assuntos
Amidoidrolases/antagonistas & inibidores , Amidoidrolases/uso terapêutico , Cérebro/metabolismo , Relação Dose-Resposta a Droga , Adolescente , Adulto , Amidoidrolases/sangue , Amidoidrolases/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Adulto JovemRESUMO
Mirabegron is the first registered ß3-adrenoceptor agonist for treatment of overactive bladder as an alternative to antimuscarinics. Previously four liquid chromatography-tandem mass spectrometry assays were published to determine mirabegron and eight metabolites (M5, M8, M11-M16) in human plasma. In order to support paediatric development, the assays were further optimized to reduce the required blood volume and increase the sensitivity. The assays were miniaturized by using 96-well supported liquid extraction plates (mirabegron, M5, M16) or 96-well mixed-mode cation exchange solid phase extraction plates (M8, M11-M15) and a more sensitive MS-system was used. For the analytes, up to fivefold increase in assay sensitivity was achieved. The required blood sample volume was reduced from 10 to 2 mL for each timepoint. Validation demonstrated that the assays were accurate, precise and selective in the determination of mirabegron and metabolites. The assays were successfully applied to evaluate the pharmacokinetics of mirabegron in a paediatric population.
Assuntos
Acetanilidas/sangue , Agonistas de Receptores Adrenérgicos beta 3/sangue , Tiazóis/sangue , Acetanilidas/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/metabolismo , Criança , Cromatografia Líquida , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Extração em Fase Sólida , Espectrometria de Massas em Tandem , Tiazóis/metabolismoRESUMO
The aim of this work was to assess the influence of preanalytical variables on the stability of two endogenous opioid peptides (Methionine-Enkephalin and Leucine-Enkephalin) in human plasma. For this purpose, first a sensitive LC-MS/MS analytical method was developed and validated for the simultaneous quantitative analysis of these two peptides. The methodology consisted of a simple protein precipitation step followed by UPLC separation and MRM quantitative analysis using a stable isotope labelled Methionine-Enkephalin as internal standard. The method with a limit of quantitation of 10â¯pg/mL showed good reproducibility with excellent accuracy and precision, and was linear up to 2000â¯pg/mL. An extensive evaluation of the pre-analytical stability of these peptides in human blood was carried out to ensure an adequate sample collection procedure to obtain reliable results in the analysis of clinical samples.
Assuntos
Encefalina Leucina/sangue , Encefalina Metionina/sangue , Cromatografia Líquida de Alta Pressão , Encefalina Leucina/química , Encefalina Metionina/química , Humanos , Espectrometria de Massas , Estrutura MolecularRESUMO
In regulated bioanalysis, the acceptance of results is batch-wise. When during clinical development derived pharmacokinetic or pharmacodynamic results from different studies will be combined or compared, it is recommendable to monitor the long-term reproducibility of bioanalytical assays. Long-term reproducibility can be evaluated by control charts generated from control samples included in each batch. We present a methodology for the implementation, construction and evaluation of control charts next to the regular batch acceptance of bioanalytical results. Decision rules can be set up for a statistical evaluation of the results. Violation of a decision rule may lead to a root-cause investigation and corrective actions to improve assay robustness. Three examples of control charts, for pharmacokinetic and pharmacodynamic analytes are presented.
Assuntos
Algoritmos , Biomarcadores/análise , Meia-Vida , Heparina/sangue , Heparina/metabolismo , Heparina/farmacocinética , Hepcidinas/sangue , Hepcidinas/metabolismo , Hepcidinas/farmacocinética , Humanos , Limite de Detecção , Fator de Crescimento Neural/sangue , Fator de Crescimento Neural/metabolismo , Fator de Crescimento Neural/farmacocinética , Controle de Qualidade , Reprodutibilidade dos TestesRESUMO
To explore the role of ß1 -adrenoceptors (ARs) in the heart rate response to the selective ß3 -adrenoceptor agonist mirabegron, 12 young male volunteers received single oral doses of the nonselective ß1/2 -AR antagonist propranolol (160 mg), the selective ß1 -AR antagonist bisoprolol (10 mg), or placebo on days 1 and 5 of each period in a 3-period crossover study. On day 5, dosing was followed by a supratherapeutic dose of mirabegron (200 mg). Vital signs, impedance cardiography, and plasma renin activity were collected. Mirabegron increased heart rate and systolic blood pressure and reduced stroke volume, whereas cardiac output and diastolic blood pressure were unaffected. Mirabegron-induced changes were attenuated by propranolol and bisoprolol. The data indicate that mirabegron has a positive chronotropic effect at supratherapeutic concentrations, which is at least partly mediated by stimulation of ß1 -AR.
Assuntos
Acetanilidas/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Tiazóis/farmacologia , Acetanilidas/administração & dosagem , Acetanilidas/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Bisoprolol/administração & dosagem , Bisoprolol/farmacologia , Débito Cardíaco/efeitos dos fármacos , Estudos Cross-Over , Humanos , Masculino , Propranolol/administração & dosagem , Propranolol/farmacologia , Renina/sangue , Volume Sistólico/efeitos dos fármacos , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: Mirabeg ron is a selective ß3-adrenoceptor agonist approved for the treatment of overactive bladder (OAB). Four phase 1 studies were conducted in healthy subjects to evaluate the potential for pharmacokinetic interactions between mirabegron and metformin, warfarin, digoxin, or a combination oral contraceptive (COC). METHODS: Thirty-two male subjects received metformin (500 mg twice daily) or mirabegron (160 mg once daily) alone, in combination or with placebo. Twenty-four male and female subjects received single doses of warfarin (25 mg) alone and in combination with mirabegron (100 mg once daily). Twenty-five male and female subjects were administered digoxin (0.25 mg) alone and in combination with mirabegron (100 mg once daily). Thirty female subjects received low-dose COC containing ethinylestradiol (EE)/levonorgestrel (LNG) (30/150 µg once daily) in combination with mirabegron (100 mg once daily) or placebo. Pharmacokinetic parameters were determined by non-compartmental methods. Absence of a Pharmacokinetic interaction was concluded if the 90 % confidence intervals (CI) of geometric least-squares means ratio of area under the curve (AUC) and maximum concentration (C max) were contained within the standard 80-125 % no-effect boundaries. The effect of mirabegron on warfarin International Normalized Ratio (INR) was also assessed. RESULTS: Mirabegron increased digoxin AUC and Cmax by 27 and 29 %, respectively, indicating that mirabegron is a weak inhibitor of P-glycoprotein (P-gp) in vivo. Co-administration of mirabegron did not affect the pharmacokinetics of metformin, warfarin, EE and LNG, or warfarin INR, except for a slight extension of the 90 % CI for the C max ratio for metformin (lower limit 79 %). Metformin decreased mirabegron AUC and C max by 21 %. Most treatment-emergent adverse events were mild, and all resolved by study end. CONCLUSIONS: No dose adjustment of either drug is required when mirabegron is administered concomitantly with metformin, warfarin or COC. Patients receiving mirabegron with digoxin may require additional monitoring of digoxin concentrations with dose adjustments where necessary, due to its narrow therapeutic index.
Assuntos
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Anticoncepcionais Orais Combinados/farmacocinética , Digoxina/farmacocinética , Interações Medicamentosas/fisiologia , Metformina/farmacocinética , Tiazóis/farmacocinética , Varfarina/farmacocinética , Acetanilidas/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Adulto , Área Sob a Curva , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Tiazóis/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológicoRESUMO
OBJECTIVE: Tamsulosin and mirabegron may be used concomitantly in patients with lower urinary tract symptoms. Since alpha1-adrenoceptor antagonists are associated with cardiovascular side effects, potential pharmacokinetic and cardiovascular interactions were evaluated. MATERIALS AND METHODS: This was an open-label, randomized, 2-arm, 2-sequence study in 48 healthy men (24/arm) aged 44 - 72 years. In arm 1, subjects received single-dose tamsulosin hydrochloride modified release capsules (0.4 mg) alone and with steady-state mirabegron oral controlled absorption system tablets (100 mg once daily) in random sequence. In arm 2, subjects received single-dose mirabegron alone and with steady-state tamsulosin. Samples for mirabegron and tamsulosin plasma concentrations were collected. Blood pressure (BP) and pulse rate (PR) were measured and orthostatic stress tests were performed. RESULTS: Mirabegron increased tamsulosin C(max) to 159% (90% confidence interval (CI) 143 - 177%), AUC(∞) to 161% (90% CI 149 - 173%), and t(1/2) to 116%. Tamsulosin reduced mirabegron C(max) to 85% (90% CI 71 - 103%) and AUC(∞) to 84% (90% CI 74 - 95%) without effect on t1/2. Mirabegron and tamsulosin co-treatment caused no statistically significant changes (p > 0.05) in PR or systolic BP versus mono-treatment up to 12 hours post-dose. Mean diastolic BP decreases of -2.1 (95% CI -4.1, -0.1) to -4.2 (-7.5, -0.9) mmHg in arm 1 and -3.0 (-5.7, -0.3) to -4.2 (-7.4, -1.0) mmHg in arm 2 were observed, statistically significant (p < 0.05) at several time points, not accompanied by orthostatic symptoms or increases in positive orthostatic stress tests. Adverse and orthostatic events were balanced across treatments. CONCLUSIONS: The observed pharmacokinetic interactions upon add-on of mirabegron or tamsulosin to existing tamsulosin or mirabegron therapy did not cause clinically relevant changes in cardiovascular safety or safety profiles.
Assuntos
Acetanilidas/farmacologia , Sulfonamidas/farmacologia , Tiazóis/farmacologia , Agentes Urológicos/farmacologia , Acetanilidas/administração & dosagem , Acetanilidas/efeitos adversos , Adulto , Idoso , Área Sob a Curva , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Interações Medicamentosas , Teste de Esforço , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Tansulosina , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Agentes Urológicos/administração & dosagem , Agentes Urológicos/efeitos adversosRESUMO
Mirabegron is a potent and selective ß3-adrenoceptor agonist developed for the treatment of overactive bladder. In vitro studies demonstrated that mirabegron partly acts as a (quasi-) irreversible, metabolism-dependent inhibitor of CYP2D6. The effect of steady-state mirabegron on single doses of the sensitive CYP2D6 substrates metoprolol (100 mg) and desipramine (50 mg) was assessed in two open-label, one-sequence crossover studies in healthy subjects (CYP2D6 extensive metabolizers). Mirabegron 160 mg/day increased metoprolol maximum plasma concentration (C max) 1.90-fold (90 % confidence interval [CI] 1.54; 2.33) and total exposure (AUC0-∞) 3.29-fold (90 % CI 2.70; 4.00) in 12 males (study 1). Mean metoprolol half-life increased from 2.96 to 4.11 h. α-Hydroxymetoprolol C max and AUC to last measurable concentration decreased 2.6-fold and 2.2-fold, respectively. In study 2, mirabegron 100 mg/day increased desipramine C max 1.79-fold (90 % CI 1.69; 1.90) and AUC0-∞ 3.41-fold (90 % CI 3.07; 3.80) in 14 males and 14 females. Mean desipramine half-life increased from 19.5 to 35.8 h. C max of 2-hydroxydesipramine decreased ~twofold, while AUC increased ~1.3-fold. Desipramine was administered again 2 weeks after the last mirabegron dose. Desipramine C max and AUC0-∞ were still ~1.13-fold increased; the 90 % CIs fell within the 0.80-1.25 interval. All treatments were well tolerated. In conclusion, mirabegron is a moderate CYP2D6 inhibitor (ratio and 90 % CI <5.0).
Assuntos
Acetanilidas/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Inibidores do Citocromo P-450 CYP2D6 , Desipramina/farmacocinética , Inibidores Enzimáticos/administração & dosagem , Metoprolol/farmacocinética , Tiazóis/administração & dosagem , Bexiga Urinária Hiperativa/tratamento farmacológico , Acetanilidas/efeitos adversos , Adolescente , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Adulto , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Desipramina/administração & dosagem , Desipramina/efeitos adversos , Desipramina/sangue , Interações Medicamentosas , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Metoprolol/administração & dosagem , Metoprolol/efeitos adversos , Metoprolol/sangue , Pessoa de Meia-Idade , Tiazóis/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Mirabegron is a ß3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6. OBJECTIVE: To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism. METHODS: Two open-label, randomized, one-sequence crossover drug-drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype. RESULTS: Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C(max)) and area under the curve extrapolated to infinity (AUC∞) to 145 % (90 % confidence interval [CI] 123-172 %] and 181 % (90 % CI 163-201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUC∞ to 65 % (90 % CI 50-86 %) and 56 % (90 % CI 49-65 %), respectively, without an effect on terminal elimination half-life (t(½)). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t ½ from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t ½, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval τ of 24 h (AUCτ) were 30-47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C(max) was 14 % and AUC∞ 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t ½. All treatments were well tolerated. CONCLUSIONS: Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.
Assuntos
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Tiazóis/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Estudos Cross-Over , Interações Medicamentosas , Feminino , Meia-Vida , Humanos , Cetoconazol/farmacologia , Masculino , Pessoa de Meia-Idade , Rifampina/farmacologia , Adulto JovemRESUMO
Mirabegron, a selective ß3 -adrenoceptor agonist, is approved for the treatment of overactive bladder (OAB). Solifenacin is a muscarinic receptor antagonist widely used in the treatment of OAB. This open-label, 1-sequence, 2-arm study investigated whether any pharmacokinetic interaction exists between mirabegron and solifenacin. In arm 1, 21 healthy men and women received 10 mg solifenacin succinate alone and in combination with mirabegron 100 mg qd. In arm 2, 20 healthy men and women received 100 mg mirabegron alone and in combination with solifenacin succinate 10 mg qd. Plasma samples were collected and tolerability was assessed. Following coadministration of mirabegron and solifenacin in arm 1, solifenacin geometric mean ratios (90% confidence interval [CI]) for Cmax and AUCinf were 1.23 (1.15, 1.31) and 1.26 (1.17, 1.35), respectively, compared with solifenacin alone, with a 1.07-fold increase in mean t1/2 . In arm 2, mirabegron ratios (90% CI) for Cmax and AUCinf were 0.99 (0.78, 1.26) and 1.15 (1.01, 1.30), respectively, for the combination relative to mirabegron alone, with an increase in mean tmax of approximately 1 hour. Mirabegron or solifenacin alone or in combination was generally well tolerated.
RESUMO
BACKGROUND AND OBJECTIVES: Mirabegron, a selective ß3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is eliminated by renal and metabolic routes. The potential influence of renal or hepatic impairment on the pharmacokinetics of mirabegron was evaluated. METHODS: Two separate open-label, single-dose, parallel-group studies were conducted. Male and female subjects (n = 8 per group) were categorized according to their baseline renal function (mild, moderate, severe or no impairment as determined by estimated glomerular filtration rate [eGFR] using the abbreviated modification of diet in renal disease formula) or hepatic function (mild, moderate or no impairment as determined by the Child-Pugh classification). All subjects received a single oral 100 mg dose of mirabegron. Non-compartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data of mirabegron and metabolites. RESULTS: Compared with healthy subjects who were similar overall in terms of age, sex and body mass index (BMI), the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(∞)) for mirabegron was 31, 66 and 118 % higher in subjects with mild, moderate and severe renal impairment, respectively. Peak plasma concentrations (C(max)) increased 6, 23 and 92 %, respectively, in subjects with mild, moderate and severe renal impairment. Renal clearance but not apparent total body clearance of mirabegron correlated well with renal function. Compared with healthy subjects matched for age, sex and BMI, mirabegron AUC(∞) values were 19 and 65 % higher in subjects with mild and moderate hepatic impairment, respectively. Mirabegron C(max) was 9 and 175 % higher, respectively, compared with matched healthy subjects. No clear relationship was evident between pharmacokinetic parameters and Child-Pugh scores. Protein binding was approximately 71 % in healthy subjects and was not altered to a clinically significant extent in subjects with renal or hepatic impairment. No consistent changes in mirabegron elimination half-life were observed in subjects with renal or hepatic impairment. There was high pharmacokinetic variability and significant overlap in exposures between subjects with renal or hepatic impairment and healthy subjects. CONCLUSION: Mirabegron AUC(∞) and C(max) increased 118 and 92 %, respectively, in subjects with severe renal impairment, and 65 and 175 %, respectively, in subjects with moderate hepatic impairment. Pharmacokinetic changes observed in subjects with mild or moderate renal impairment or mild hepatic impairment are of small magnitude and likely to be without clinical importance.
Assuntos
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Nefropatias/metabolismo , Rim/metabolismo , Hepatopatias/metabolismo , Fígado/metabolismo , Tiazóis/farmacocinética , Acetanilidas/administração & dosagem , Acetanilidas/efeitos adversos , Acetanilidas/sangue , Acetanilidas/urina , Administração Oral , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 3/sangue , Agonistas de Receptores Adrenérgicos beta 3/urina , Adulto , Idoso , Área Sob a Curva , Feminino , Taxa de Filtração Glomerular , Meia-Vida , Humanos , Rim/fisiopatologia , Nefropatias/diagnóstico , Nefropatias/fisiopatologia , Fígado/fisiopatologia , Hepatopatias/diagnóstico , Hepatopatias/fisiopatologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Índice de Gravidade de Doença , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Tiazóis/sangue , Tiazóis/urinaRESUMO
BACKGROUND: Mirabegron (YM178) is a ß(3)-adrenoceptor agonist for the treatment of overactive bladder (OAB). As part of the clinical development program for mirabegron, 2 human volunteer studies were performed to derive detailed data on the multiple-dose pharmacokinetic (PK) properties of mirabegron. OBJECTIVE: Two randomized Phase I studies were conducted to evaluate the PK properties of mirabegron, including metabolic profile and effects of age and sex, following multiple oral doses in healthy subjects. METHODS: In study 1, mirabegron oral controlled absorption system (OCAS) tablets were administered once daily to healthy young subjects (18-55 years) at doses of 50, 100, 200, and 300 mg and in elderly subjects (65-80 years) at 50 and 200 mg in a double-blind placebo-controlled, parallel-group design. In study 2, mirabegron OCAS was administered once daily to healthy young (18-45 years) and older (≥55 years) subjects at doses of 25, 50, and 100 mg in an open-label crossover design. Blood samples were collected up to 72 hours (study 1) and 168 hours (study 2) after the last dose. Urine samples were collected up to 24 hours after the last dose. Plasma and urine concentrations of mirabegron and its metabolites (study 2 only) were analyzed by LC-MS/MS. PK parameters were determined using noncompartmental methods. Tolerability assessments included physical examinations, supine blood pressure and pulse rate, orthostatic stress testing (study 1), resting 12-lead ECGs, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse-events (AE) monitoring using investigators' questionnaires and subjects' spontaneous reports. RESULTS: Thirty-two young male (mean age, 30.3 years; mean weight, 77.1 kg), 32 young female (27.6 years; 64.6 kg), 16 elderly male (69.8 years; 79.3 kg), and 16 elderly female (68.1 years; 67.4 kg) subjects were enrolled in study 1. Eighteen young male (mean age, 28.6 years; mean weight, 68.9 kg), 18 young female (28.7 years; 58.8 kg), 21 older male (63.4 years; 72.6 kg), and 18 older female (65.1 years; 62.3 kg) subjects were enrolled in study 2. Most of the subjects were white (91% in study 1 and 88% in study 2). Mirabegron plasma concentrations peaked at â¼3 to 5 hours and declined multiexponentially with a t of â¼32 hours in study 1 and 60 hours in study 2. Steady state was achieved within 7 days of once daily administration, with an accumulation ratio of â¼2. Mirabegron and its metabolites demonstrated a greater-than-dose-proportional increase in C(max) and AUC(0-τ) after multiple-dose administration. Two major circulating metabolites were observed, representing 17% and 10% of total drug-related AUC(0-τ). Excretion of unchanged mirabegron in urine over the 24-hour dosing interval (Ae(0-τ)%) increased from approximately 7% at 25 mg to 18% at 300 mg once daily in young subjects. Renal clearance (CL(R)) of mirabegron was independent of dose and averaged â¼13 L/h. Mirabegron C(max) and AUC(0-τ) were similar in older and young subjects. Women exhibited â¼40% higher mirabegron C(max) and AUC(0-τ) than men; weight-corrected values were â¼20% higher in women. Mirabegron was generally well tolerated up to 300 mg once daily. No clear trends for increased incidence of AEs occurred with higher doses of mirabegron. The AE with the highest incidence was headache. CONCLUSION: Oral mirabegron exhibited a greater-than-dose-proportional increase in exposure. Sex but not age significantly affected mirabegron exposure. ClinicalTrials.gov identifier: NCT01478503 (Study 1) and NCT01285596 (Study 2).
Assuntos
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Modelos Biológicos , Tiazóis/farmacocinética , Acetanilidas/administração & dosagem , Acetanilidas/efeitos adversos , Administração Oral , Adolescente , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Cromatografia Líquida , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento de Medicamentos , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Espectrometria de Massas em Tandem , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: Mirabegron is a potent and selective ß3-adrenoceptor agonist in development for treatment of overactive bladder. METHODS: Mirabegron pharmacokinetics after single intravenous (i.v.) and oral doses, absolute bioavailability (F), dose proportionality, sex differences and tolerability were assessed in 2 single-dose, open-label, randomized, parallel-group, cross-over studies in healthy men (exploratory Study 1, n = 12) and men and women (Study 2, n = 91). RESULTS: After oral dosing (25 - 150 mg), peak plasma concentrations were attained after ~ 4 h. Mean half-life was around 40 h for both routes of administration. Volume of distribution at steady state was 1,670 l and total clearance was around 57 l/h for i.v. dosing. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but exposure increased more than proportionally after oral dosing due to increased F (29% for 25 mg to 45% at 150 mg). About 20% of the (absorbed) dose was excreted unchanged into urine. Area under the curve (AUC) was 27% and 64% higher in females than males after i.v. and oral dosing respectively; differences were mostly attributed to body weight, and for oral dosing, also to F. CONCLUSIONS: Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but increased more than proportionally after oral dosing (25 - 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral.
Assuntos
Acetanilidas/administração & dosagem , Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Bexiga Urinária Hiperativa/tratamento farmacológico , Acetanilidas/sangue , Administração Oral , Adolescente , Agonistas de Receptores Adrenérgicos beta 3/sangue , Adulto , Área Sob a Curva , Disponibilidade Biológica , Biotransformação , Peso Corporal , Estudos Cross-Over , Feminino , Humanos , Infusões Intravenosas , Modelos Lineares , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Países Baixos , Fatores Sexuais , Tiazóis/sangue , Washington , Adulto JovemRESUMO
Mirabegron is being developed for the treatment of overactive bladder. To support the development of mirabegron, including pharmacokinetic studies, liquid chromatography/tandem mass spectrometry methods for mirabegron and eight metabolites (M5, M8, M11-M16) were developed and validated for heparinized human plasma containing sodium fluoride. Four separate bioanalytical methods were developed for the analysis of: (1) mirabegron; (2) M5 and M16; (3) M8; and (4) M11-M15. Either solid-phase extraction or liquid-liquid extraction was used to extract the analytes of interest from matrix constituents. For mirabegron, an Inertsil C8-3 analytical column was used and detection was performed using a triple-quad mass spectrometer equipped with an atmospheric pressure chemical ionization interface. For the metabolite assays, chromatographic separation was performed through a Phenomenex Synergi Fusion-RP C18 analytical column and detection was performed using a triple-quad mass spectrometer equipped with a Heated Electrospray Ionization interface. The validation results demonstrated that the developed liquid chromatography/tandem mass spectrometry methods were precise, accurate, and selective for the determination of mirabegron and its metabolites in human plasma. All methods were successfully applied in evaluating the pharmacokinetic parameters of mirabegron and metabolites in human plasma.
Assuntos
Acetanilidas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Tiazóis/sangue , Acetanilidas/química , Acetanilidas/farmacocinética , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
The mass balance and metabolite profiles of 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)[U-(14)C]phenyl]acetamide ([(14)C]mirabegron, YM178), a ß(3)-adrenoceptor agonist for the treatment of overactive bladder, were characterized in four young, healthy, fasted male subjects after a single oral dose of [(14)C]mirabegron (160 mg, 1.85 MBq) in a solution. [(14)C]Mirabegron was rapidly absorbed with a plasma t(max) for mirabegron and total radioactivity of 1.0 and 2.3 h postdose, respectively. Unchanged mirabegron was the most abundant component of radioactivity, accounting for approximately 22% of circulating radioactivity in plasma. Mean recovery in urine and feces amounted to 55 and 34%, respectively. No radioactivity was detected in expired air. The main component of radioactivity in urine was unchanged mirabegron, which accounted for 45% of the excreted radioactivity. A total of 10 metabolites were found in urine. On the basis of the metabolites found in urine, major primary metabolic reactions of mirabegron were estimated to be amide hydrolysis (M5, M16, and M17), accounting for 48% of the identified metabolites in urine, followed by glucuronidation (M11, M12, M13, and M14) and N-dealkylation or oxidation of the secondary amine (M8, M9, and M15), accounting for 34 and 18% of the identified metabolites, respectively. In feces, the radioactivity was recovered almost entirely as the unchanged form. Eight of the metabolites characterized in urine were also observed in plasma. These findings indicate that mirabegron, administered as a solution, is rapidly absorbed after oral administration, circulates in plasma as the unchanged form and metabolites, and is recovered in urine and feces mainly as the unchanged form.
Assuntos
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Receptores Adrenérgicos beta 3/metabolismo , Tiazóis/farmacocinética , Absorção , Acetanilidas/administração & dosagem , Acetanilidas/sangue , Acetanilidas/metabolismo , Acetanilidas/urina , Administração Oral , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/sangue , Agonistas de Receptores Adrenérgicos beta 3/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/urina , Adulto , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Fezes/química , Humanos , Masculino , Espectrometria de Massas , Taxa de Depuração Metabólica , Estrutura Molecular , Tiazóis/administração & dosagem , Tiazóis/sangue , Tiazóis/metabolismo , Tiazóis/urina , Adulto JovemRESUMO
Antioxidants prevent oxidative stress that possibly causes neuronal loss in Alzheimer's disease (AD). We examined whether high plasma levels of the antioxidant vitamins A and E were associated with lower prevalence of AD or cognitive decline (CD). We performed a cross-sectional study within the Rotterdam Study. In an univariate model, higher levels of vitamins A and E were significantly associated with lower prevalence of AD. However, when additional adjustments were made for important confounders, such as age, gender and total cholesterol, the relation substantially weakened -- odds ratios per standard deviation increase were 0.87 (95% CI 0.64-1.19) for vitamin A and 0.94 (95% CI 0.60-1.48) for vitamin E. Antioxidants were not related to CD in non-demented subjects. Our findings suggest no association between plasma levels of vitamin A and E and AD or CD.