RESUMO
BACKGROUND: Approved systemic treatment options are limited for pediatric patients with moderate to severe plaque psoriasis. OBJECTIVE: To assess the efficacy and safety of apremilast over 16 weeks in pediatric patients with plaque psoriasis. METHODS: SPROUT (NCT03701763) was a phase 3, multicenter, randomized, double-blind, placebo-controlled study of apremilast in patients aged 6-17 years with moderate-to-severe psoriasis (Psoriasis Area and Severity Index [PASI] ≥12, body surface area ≥10%, static Physician Global Assessment [sPGA] ≥3) inadequately controlled by/inappropriate for topical therapy. Patients were stratified by age group and randomized (2:1) to apremilast (20 or 30 mg BID based on weight) or placebo for 16 weeks, followed by apremilast extension to 52 weeks. RESULTS: Of 245 patients randomized (apremilast: 163; placebo: 82), 221 (90%) completed the double-blind phase (apremilast: 149; placebo: 72). Significantly more patients achieved sPGA response and ≥75% reduction in PASI with apremilast than placebo, regardless of baseline age, weight, or disease severity. No new safety signals were observed. LIMITATIONS: Sample size of subgroup analyses. CONCLUSIONS: Improvements in global disease activity and skin involvement were significantly greater in pediatric patients treated with apremilast versus placebo. Adverse events were consistent with the known apremilast safety profile.
Assuntos
Anti-Inflamatórios não Esteroides , Psoríase , Índice de Gravidade de Doença , Talidomida , Humanos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/efeitos adversos , Talidomida/administração & dosagem , Psoríase/tratamento farmacológico , Adolescente , Criança , Método Duplo-Cego , Masculino , Feminino , Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Resultado do Tratamento , Inibidores da Fosfodiesterase 4/efeitos adversos , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/administração & dosagem , Relação Dose-Resposta a DrogaRESUMO
Omecamtiv mecarbil (OM) is a cardiac myosin activator in clinical development for the treatment of heart failure. The effect of food on the pharmacokinetics (PK) of 25, 37.5, and 50 mg strength modified release (MR) tablets and the bioequivalence of two 25 mg tablets versus one 50 mg MR tablet were evaluated in two open-label, randomized, cross-over studies in healthy subjects. Subjects received two 25 mg tablets or one 50 mg OM MR tablet under fed or fasted states in Study 1 (n = 39), and single oral doses of 25 and 37.5 mg OM MR tablets and to assess its relative bioavailability to the 25 mg MR tablet, a 25 mg oral solution under fed or fasted states in Study 2 (n = 34). The area under the concentration-time curve (AUC) and the maximum observed concentration (Cmax ) of 25, 37.5, or 50 mg OM MR tablets were approximately 13%-22% higher and 31%-40% higher, respectively, when taken with food. The two 25 mg and one 50 mg OM MR tablets were bioequivalent (90% confidence intervals) of the geometric mean ratios for Cmax and AUC of OM were within 0.8-1.25 under the fasted or fed state. OM was well tolerated and all treatment-emergent events were mild in severity and resolved by the end of the study. In conclusion, these studies demonstrated that the effect of food on the PK of OM was minimal at all three studied strengths of the MR tablets, and two 25 mg MR tablets may be switched for one 50 mg MR tablet (EudraCT Number: 2019-003683-44).
Assuntos
Ureia/análogos & derivados , Administração Oral , Adulto , Área Sob a Curva , Miosinas Cardíacas , Estudos Cross-Over , Preparações de Ação Retardada , Substituição de Medicamentos , Jejum/metabolismo , Feminino , Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Comprimidos , Equivalência Terapêutica , Ureia/administração & dosagem , Ureia/efeitos adversos , Ureia/sangue , Ureia/farmacocinéticaRESUMO
BACKGROUND: Treatment of patients coinfected with hepatitis C and human immunodeficiency viruses (HCV; HIV) requires careful consideration of potential drug-drug interactions between HCV direct-acting antiviral agents (DAA) and HIV antiretrovirals. Glecaprevir/pibrentasvir is a fixed-dose combination of an NS3/4A protease inhibitor and an NS5A inhibitor approved for the treatment of chronic HCV genotype 1-6 infection, including patients with HIV coinfection. METHODS: A series of phase 1 studies was conducted to evaluate potential interactions of glecaprevir and pibrentasvir with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, abacavir/dolutegravir/lamivudine, raltegravir, rilpivirine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, or efavirenz/emtricitabine/tenofovir disoproxil fumarate. Pharmacokinetics of the antiretrovirals and DAAs were characterized when administered alone and in combination to quantify changes in systemic drug exposure. RESULTS: Glecaprevir area under the curve increased >4-fold in the presence of ritonavir-boosted HIV protease inhibitors, while pibrentasvir concentrations were not significantly affected; elevations in alanine transaminase occurred in combination with atazanavir/ritonavir only. Exposures of glecaprevir and pibrentasvir may be significantly decreased by efavirenz. Coadministration with glecaprevir and pibrentasvir did not result in clinically significant changes in the exposure of any antiretroviral agents. CONCLUSIONS: Atazanavir is contraindicated with glecaprevir/pibrentasvir and use of boosted protease inhibitors or efavirenz is not recommended. No clinically significant interactions were observed with other studied antiretrovirals.
Assuntos
Antirretrovirais/farmacologia , Benzimidazóis/farmacologia , Coinfecção/tratamento farmacológico , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Pirrolidinas/farmacologia , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Adulto , Antirretrovirais/farmacocinética , Antirretrovirais/uso terapêutico , Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Contraindicações de Medicamentos , Combinação de Medicamentos , Feminino , Hepatite C Crônica/complicações , Humanos , Masculino , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Quinoxalinas/farmacocinética , Quinoxalinas/uso terapêutico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents. METHODS: We analyzed data from 2369 patients infected with HCV genotypes 1-6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8-16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents. RESULTS: Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI. CONCLUSIONS: In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection-even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I).
Assuntos
Antivirais/administração & dosagem , Antivirais/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Quinoxalinas/administração & dosagem , Quinoxalinas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resposta Viral Sustentada , Resultado do Tratamento , Adulto JovemRESUMO
Glecaprevir (nonstructural protein 3/4A protease inhibitor) and pibrentasvir (nonstructural protein 5A inhibitor) (G/P), a coformulated once-daily, all oral, ribavirin (RBV)-free, direct-acting antiviral regimen, was evaluated for safety and efficacy in hepatitis C virus genotype 2 (GT2)-infected Japanese patients, including those with compensated cirrhosis. CERTAIN-2 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in treatment-naive and interferon ± RBV treatment-experienced Japanese patients without cirrhosis but with GT2 infection. Patients were randomized 2:1 to receive 8 weeks of G/P (arm A) or 12 weeks of sofosbuvir (400 mg once daily) + RBV (600-1000 mg weight-based, twice daily) (arm B). The primary endpoint was noninferiority of G/P compared to sofosbuvir + RBV by assessing sustained virologic response at posttreatment week 12 (SVR12) among patients in the intent-to-treat population. SVR12 was also assessed in treatment-naive and interferon ± RBV treatment-experienced patients with GT2 infection and compensated cirrhosis who received G/P for 12 weeks in the CERTAIN-1 study. A total of 136 patients were enrolled in CERTAIN-2. SVR12 was achieved by 88/90 (97.8%) patients in arm A and 43/46 (93.5%) patients in arm B. No patient in arm A experienced virologic failure, while 2 did in arm B. The primary endpoint was achieved. In CERTAIN-1, 100% (18/18) of GT2-infected patients with compensated cirrhosis achieved SVR12. Treatment-emergent serious adverse events were experienced by 2 patients without cirrhosis in each arm and no patient with cirrhosis. Conclusion: The results demonstrate high efficacy and favorable tolerability of G/P in GT2-infected Japanese patients. (Hepatology 2018;67:505-513).
Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Ácidos Aminoisobutíricos , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Ciclopropanos , Quimioterapia Combinada , Feminino , Genótipo , Hepatite C Crônica/virologia , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas/efeitos adversos , Quinoxalinas/farmacocinética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Resposta Viral SustentadaRESUMO
This phase I thorough QTc, double-blind, randomized, placebo- and positive-controlled, parallel group, multiple-dose study evaluated avacopan's effect on cardiac repolarization using concentration-QTc (C-QTc) as the primary analysis. Avacopan 30 mg b.i.d. (therapeutic dose) was administered orally on days 1 through 7 followed by avacopan 100 mg b.i.d. (supratherapeutic dose) on days 8 through 14 in 29 healthy participants. Moxifloxacin 400 mg and placebo were administered on days 1 and 15 in a nested crossover design for assay sensitivity in separate cohorts to 28 participants. Time-matched plasma concentrations and up to 10 replicate ECGs were obtained on prespecified days at baseline and postdose on days 1, 7, 14, and 15. The mean change from baseline on QTcF for avacopan (-5.5 to 3.5 ms) was similar to placebo (-6.9 to 1.4 ms) across days 1, 7, and 14. The mean effect on ΔΔQTcF (90% CI) was estimated as 1.5 ms (-0.17 to 3.09) and 0.8 ms (-2.41 to 4.05) for 30 and 100 mg avacopan b.i.d. treatments, respectively. Based on the C-QTc analysis, avacopan's effect on ΔΔQTcF >10 ms can be excluded within the observed plasma concentration range of up to ~1220 and ~335 ng/mL for avacopan and active major metabolite, M1, respectively. The estimated population slopes showed a shallow relationship, which was not statistically significant. There was no clinically meaningful effect of avacopan on heart rate or cardiac conduction (PR and QRS intervals). Avacopan appeared to be generally well tolerated in this study population.
Assuntos
Estudos Cross-Over , Relação Dose-Resposta a Droga , Eletrocardiografia , Voluntários Saudáveis , Frequência Cardíaca , Humanos , Masculino , Adulto , Feminino , Método Duplo-Cego , Adulto Jovem , Frequência Cardíaca/efeitos dos fármacos , Pessoa de Meia-Idade , Moxifloxacina/administração & dosagem , Moxifloxacina/efeitos adversos , Moxifloxacina/farmacocinética , AdolescenteRESUMO
Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R). AMG 133 (maridebart cafraglutide) is a bispecific molecule engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. In a phase 1, randomized, double-blind, placebo-controlled clinical study in participants with obesity ( NCT04478708 ), AMG 133 had an acceptable safety and tolerability profile along with pronounced dose-dependent weight loss. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133.
Assuntos
Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Redução de Peso , Animais , Humanos , Masculino , Camundongos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Peptídeos/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidoresRESUMO
This study quantitatively assessed transport mechanisms that limit the brain distribution of sunitinib and investigated adjuvant strategies to improve its brain delivery for the treatment of glioblastoma multiforme (GBM). Sunitinib has not shown significant activity in GBM clinical trials, despite positive results seen in preclinical xenograft studies. We performed in vivo studies in transgenic Friend leukemia virus strain B mice: wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) genotypes were examined. The brain-to-plasma area under the curve ratio after an oral dose (20 mg/kg) was similar to the steady-state tissue distribution coefficient, indicating linear distribution kinetics in mice over this concentration range. Furthermore, the distribution of sunitinib to the brain increased after administration of selective P-glycoprotein (P-gp) or breast cancer resistance protein (Bcrp) pharmacological inhibitors and a dual inhibitor, elacridar, comparable to that of the corresponding transgenic genotype. The brain-to-plasma ratio after coadministration of elacridar in wild-type mice was ≈ 12 compared with ≈ 17.3 in Mdr1a/b(-/-)Bcrp1(-/-) mice. Overall, these findings indicate that there is a cooperation at the blood-brain barrier (BBB) in restricting the brain penetration of sunitinib, and brain delivery can be enhanced by administration of a dual inhibitor. These data indicate that the presence of cooperative efflux transporters, P-gp and Bcrp, in an intact BBB can protect invasive glioma cells from chemotherapy. Thus, one may consider the use of transporter inhibition as a powerful adjuvant in the design of future clinical trials for the targeted delivery of sunitinib in GBM.
Assuntos
Antineoplásicos/farmacocinética , Encéfalo/metabolismo , Indóis/farmacocinética , Pirróis/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/metabolismo , Área Sob a Curva , Barreira Hematoencefálica/metabolismo , Cromatografia Líquida de Alta Pressão , Interpretação Estatística de Dados , Meia-Vida , Indóis/metabolismo , Camundongos , Camundongos Knockout , Pirróis/metabolismo , Sunitinibe , Espectrometria de Massas em TandemRESUMO
Sunitinib malate is a multi-targeted tyrosine-kinase inhibitor, currently in clinical trials for glioma. Previously developed methods for preclinical studies in species such as mice have either employed high-performance liquid chromatography (HPLC) or did not describe a detailed analytical method, which could be employed by other preclinical laboratories. In this paper, we have developed and validated a simple, sensitive high-performance liquid chromatography tandem mass-spectrometric method (LC-MS/MS) for the determination of sunitinib concentration in mouse plasma and brain tissue homogenate using dasatinib-free base as the internal standard. A single step liquid-liquid extraction method was used for both the matrices. Since sunitinib exhibits light-induced E/Z isomerism, all sample preparation was done in light-protected conditions. Separation was performed on a ZORBAX Eclipse XDB C18 column 4.6 × 50 mm, 1.8 µm. The mobile phase consisted of 20 mM ammonium formate (with 0.1 % formic acid): acetonitrile (70:30, v/v) pumped isocratically at a flow rate of 0.25 mL min-1 with a total run-time of 13 min. The retention times of sunitinib and dasatinib were 7.8 and 5.5 min, respectively. The calibration curve was linear over the range from 1.95 to 500 ng mL-1 in both plasma and brain tissue homogenate with 1.95 ng mL-1 as the lower limit of quantification (LLOQ) for both the matrices. Inter- and intra-day accuracy and precision was <15 % for low QC, med QC and high QC and <20 % for LLOQ. The method was applied to a pharmacokinetic study in FVB wild-type mice to determine the plasma and brain concentrations after a single oral sunitinib malate dose of 20 mg kg-1.
RESUMO
Glecaprevir (GLE)/pibrentasvir (PIB) is an all-oral, interferon- and ribavirin-free, pan-genotypic fixed-dose combination regimen approved for the treatment of all major genotypes of hepatitis C virus (HCV) infection in many countries worldwide. To support clinical development in China, an open-label, single-center phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of GLE/PIB in healthy Chinese adults in Mainland China. Eighteen participants received 3 tablets of coformulated GLE/PIB 100/40 mg once daily (QD) for 7 days. Following GLE/PIB 300 mg/120 mg administration, GLE and PIB reached maximum concentration in 4-5 hours with a terminal elimination half-life of 5.9 and 25 hours, respectively. Both GLE and PIB reached steady state by day 5, with no-to-minimal accumulation (≤17% higher). GLE/PIB exposures in healthy Chinese participants were similar to historical observations across phase 1 studies in healthy Western participants. GLE/PIB was safe and well-tolerated, with most adverse events being mild. These pharmacokinetics and safety data, together with existing global efficacy and safety data in healthy and HCV-infected Western participants, support the use of GLE/PIB 300 mg/120 mg QD in adult Chinese patients with chronic HCV infection.
Assuntos
Antivirais , Hepatite C , Adulto , Humanos , População do Leste Asiático , Hepacivirus/genética , Hepatite C/tratamento farmacológico , ComprimidosRESUMO
Glioblastoma multiforme, because of its invasive nature, can be considered a disease of the entire brain. Despite recent advances in surgery, radiotherapy and chemotherapy, current treatment regimens have only a marginal impact on patient survival. A crucial challenge is to deliver drugs effectively to invasive glioma cells residing in a sanctuary within the central nervous system. The blood-brain barrier (BBB) restricts the delivery of many small and large molecules into the brain. Drug delivery to the brain is further restricted by active efflux transporters present at the BBB. Current clinical assessment of drug delivery and hence efficacy is based on the measured drug levels in the bulk tumour mass that is usually removed by surgery. Mounting evidence suggests that the inevitable relapse and lethality of glioblastoma multiforme is due to a failure to effectively treat invasive glioma cells. These invasive cells hide in areas of the brain that are shielded by an intact BBB, where they continue to grow and give rise to the recurrent tumour. Effective delivery of chemotherapeutics to the invasive glioma cells is therefore critical, and long-term efficacy will depend on the ability of a molecularly targeted agent to penetrate an intact and functional BBB throughout the entire brain. This review highlights the various aspects of the BBB, and also the brain-tumour-cell barrier (a barrier due to expression of efflux transporters in tumour cells), that together can significantly influence drug response. It then discusses the challenge of glioma as a disease of the whole brain, which lends emphasis to the need to deliver drugs effectively across the BBB to reach both the central tumour and the invasive glioma cells.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Terapia de Alvo Molecular , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Transporte Biológico , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/metabolismo , Glioblastoma/patologia , HumanosRESUMO
BACKGROUND AND OBJECTIVE: Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure with reduced ejection fraction. The objective of this study was to evaluate the potential for OM to affect the pharmacokinetics of metformin. METHODS: This was an open-label, fixed-sequence study in 14 healthy subjects. On Day 1, subjects received an 850 mg oral dose of metformin. From Days 4 to 9, subjects received twice-daily 25 mg oral doses of OM tablets. On Day 10, subjects received an 850 mg oral dose of metformin and a single 25 mg tablet of OM. Blood and urine samples were collected up to 36 h post-dose following administration of metformin on Days 1 and 10 to characterize concentrations of metformin in plasma and urine. RESULTS: The ratios of the geometric least square means of metformin coadministered with OM compared to metformin alone were 98.7%, 99.3%, and 110.2% for AUCinf, AUClast, and Cmax, respectively. The mean renal clearance of metformin was similar following metformin administered alone (34.2 L/h) compared to metformin coadministered with OM (32.9 L/h). All adverse events were mild in severity and resolved prior to the end of the study. No serious adverse events or treatment-emergent adverse events led to discontinuation from the study. CONCLUSIONS: There was no clinically relevant effect of OM on the pharmacokinetics of metformin in healthy subjects.
Assuntos
Metformina/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ureia/análogos & derivados , Administração Oral , Adulto , Área Sob a Curva , Diarreia/etiologia , Interações Medicamentosas/fisiologia , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Análise dos Mínimos Quadrados , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Metformina/química , Pessoa de Meia-Idade , Curva ROC , Especificidade por Substrato , Comprimidos/química , Ureia/administração & dosagem , Ureia/efeitos adversos , Ureia/químicaRESUMO
Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under investigation for the treatment of heart failure with reduced ejection fraction. OM is primarily eliminated via metabolism mediated by multiple cytochrome P450 enzymes. This phase 1 single-dose, multicenter, open-label, nonrandomized study evaluated the pharmacokinetics (PK) of OM and major metabolites M3 and M4, safety, and tolerability following oral administration of a single dose of 25-mg MR tablet in subjects with mild (n = 6) or moderate (n = 6) hepatic impairment (according to Child-Pugh classification) versus subjects with normal hepatic function (n = 6). Relative to subjects with normal hepatic function, for subjects with mild or moderate hepatic impairment, OM AUCinf was 103.2% (90%CI, 58.0%-183.6%) and 94.8% (90%CI, 54.7%-164.1%), respectively, and OM Cmax was 126.8% (90%CI, 85.7%-187.7%) and 117.3% (90%CI, 80.7%-170.5%), respectively. Exposures to M3 were similar across groups, whereas slightly lower exposures were observed for M4 with worsening hepatic function. The OM, M3, and M4 tmax and t1/2 values were similar between groups. There were no serious adverse events (AEs) or treatment-related treatment-emergent AEs. Overall, OM, M3, and M4 PK were not meaningfully affected by mild or moderate hepatic impairment, suggesting the same dosing strategy can be used in subjects with mild or moderate hepatic impairment.
Assuntos
Ureia , Administração Oral , Área Sob a Curva , Humanos , Comprimidos , Ureia/efeitos adversos , Ureia/análogos & derivadosRESUMO
BACKGROUND AND OBJECTIVE: Omecamtiv mecarbil is a novel selective cardiac myosin activator (myotrope) under investigation for the treatment of heart failure with reduced ejection fraction. The objective of this clinical study was to estimate the effect of varying degrees of renal impairment on the pharmacokinetics of omecamtiv mecarbil single dose (50 mg) under fasted conditions. METHODS: This phase I, open-label, non-randomized, parallel-group study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of omecamtiv mecarbil 50 mg in individuals with normal renal function or mild, moderate, and severe renal impairment, including end-stage renal disease requiring dialysis. Geometric least-squares mean ratios of maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) and 90% confidence intervals were derived for comparisons of renal impairment vs normal renal function. Participants were monitored for adverse events. RESULTS: Thirty-one participants received treatment and completed the study. Geometric mean exposures were similar for participants with renal impairment (AUC∞ range, 2550-3220 h*ng/mL; Cmax range, 78.9-107 ng/mL) and participants with normal renal function (AUC∞, 2790 h*ng/mL; Cmax, 92.6 ng/mL), with geometric least-squares mean ratios of 85.2-125.9. Exposure was similar on dialysis vs non-dialysis days in participants with end-stage renal disease (AUC0-24, 1650 vs 1700 h*ng/mL; Cmax, 100.0 vs 107.0 ng/mL). Four participants (12.9%) reported four treatment-emergent adverse events. No deaths, treatment-emergent adverse events leading to discontinuation, or serious adverse events occurred. CONCLUSIONS: Omecamtiv mecarbil pharmacokinetics were not meaningfully affected by renal function or hemodialysis, suggesting the same dosing strategy can be used in individuals with normal renal function or renal impairment. Oral administration of omecamtiv mecarbil was not associated with major tolerability findings. This study supports omecamtiv mecarbil for the treatment of heart failure in individuals with or without renal impairment.
Assuntos
Insuficiência Cardíaca , Ureia , Administração Oral , Área Sob a Curva , Miosinas Cardíacas/metabolismo , Miosinas Cardíacas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Ureia/análogos & derivados , Ureia/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVE: Risankizumab, a humanized monoclonal interleukin-23 antagonist antibody, has efficacy for treatment of plaque psoriasis, generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP). These analyses characterized the relationships between risankizumab exposures and key efficacy and safety variables in Japanese patients with moderate-to-severe plaque psoriasis, GPP, or EP following treatment with 75 or 150 mg subcutaneous doses at weeks 0, 4, and every 12 weeks thereafter. METHODS: Risankizumab average plasma concentrations (Cavg) were correlated with probabilities of achieving efficacy end points (PASI 75, PASI 90, PASI 100, and sPGA 0/1) using data from Japanese patients (N = 225) and non-Japanese patients (N = 1678) with moderate-to-severe plaque psoriasis enrolled in global trials, or a Japan Phase 2/3 trial. RESULTS: The exposure-efficacy relationships in Japanese patients were consistent with relationships for patients in global Phase 3 trials. At Week 16, a plateau of efficacy was demonstrated for 150 mg subcutaneous dose providing estimated PASI 90 and sPGA 0/1 response probabilities of 77%, and 88%, respectively. The exposures for 75 mg dose appeared to be suboptimal for PASI 100 response and other efficacy responses in heavier patients. Exposure-safety analyses (N = 242) indicated no apparent relationship between risankizumab Cavg and key safety variables, including any adverse event, serious adverse event, infection and infestation, and serious infection during treatment, consistent with observations in the global trials. CONCLUSIONS: Overall, risankizumab 150 mg maximized efficacy, including PASI 100 response, in Japanese patients with psoriasis with no apparent relationship between exposure and evaluated safety variables. CLINICAL TRIAL REGISTRATION: NCT03000075, NCT03022045, NCT02672852, NCT02684357, NCT02684370, NCT02694523, NCT02054481.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Psoríase , Anticorpos Monoclonais/farmacocinética , Relação Dose-Resposta a Droga , Humanos , Japão , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
PURPOSE: Fixed-dose combination glecaprevir (GLE) 300 mg + pibrentasvir (PIB) 120 mg is an orally administered once daily antiviral regimen approved for the treatment of hepatitis C virus (HCV) infection. The objective of this study was to evaluate the potential for cardiac repolarization following GLE + PIB administration in healthy adults. METHODS: This placebo- and active-controlled, randomized, single-dose, 4-period, 4-sequence crossover study enrolled 48 healthy subjects. The doses of GLE 400 mg + PIB 120 mg were selected to provide exposures comparable to those with the doses that are therapeutic in the HCV-infected population, GLE 300 mg + PIB 120 mg. The doses of GLE 600 mg + PIB 240 mg were selected to provide supratherapeutic exposures without exceeding the exposures of the GLE + PIB maximal tolerated doses. Moxifloxacin 400 mg (active control/open label) was used for confirming the sensitivity of the ECG assay in detecting QTc prolongation. Time-matched plasma concentrations and triplicate ECGs were obtained on treatment days -1 and 1. The primary end point was time-matched, placebo-corrected, baseline-adjusted Fridericia-corrected QT interval (ΔΔQTcF). Pharmacokinetic-pharmacodynamic analyses characterized the relationship between GLE and PIB plasma concentrations and ΔΔQTcF using a linear regression model and linear mixed-effects model. Findings from categorical analyses of ECG-interval data were also summarized. Tolerability was evaluated through adverse-events monitoring, physical examination including vital sign measurements, ECGs, and laboratory tests. FINDINGS: A total of 48 subjects (22 women [46%], 26 men [54%]), were enrolled in the study, and 47 subjects completed all 4 periods. None of the subjects had a change from baseline in QTcF interval of >30 msec or an absolute QTcF interval of >450 msec. Peak ΔΔQTcF values observed at 5 h postdose (Tmax) were 2.9 msec (upper 95% confidence limit, 4.9 msec) with the therapeutic dose and 3.1 msec (upper 95% confidence limit, 5.1 msec) with the supratherapeutic dose, with both upper 95% confidence limits well below the 10-msec threshold. Assay sensitivity was confirmed by peak ΔΔQTcF in the positive control (12.8 ms at 2 h postdose). No statistically significant GLE or PIB concentration-dependent effects on ΔΔQTcF were observed. Headache and skin irritation from ECG electrodes were the most commonly reported AEs. No clinically significant vital sign measurements, ECG findings, or laboratory measurements were observed. There were no patterns of T- and U-wave morphologic abnormalities. IMPLICATIONS: The fixed-dose combination regimen of GLE/PIB does not prolong the QTc interval. ClinicalTrials.gov identifier.
Assuntos
Ácidos Aminoisobutíricos/administração & dosagem , Benzimidazóis/administração & dosagem , Ciclopropanos/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Coração/efeitos dos fármacos , Lactamas Macrocíclicas/administração & dosagem , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Ácidos Aminoisobutíricos/sangue , Ácidos Aminoisobutíricos/farmacocinética , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Estudos Cross-Over , Ciclopropanos/sangue , Ciclopropanos/farmacocinética , Método Duplo-Cego , Combinação de Medicamentos , Eletrocardiografia/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Coração/fisiologia , Humanos , Lactamas Macrocíclicas/sangue , Lactamas Macrocíclicas/farmacocinética , Leucina/administração & dosagem , Leucina/sangue , Leucina/farmacocinética , Síndrome do QT Longo , Masculino , Pessoa de Meia-Idade , Prolina/administração & dosagem , Prolina/sangue , Prolina/farmacocinética , Pirrolidinas , Quinoxalinas/sangue , Quinoxalinas/farmacocinética , Método Simples-Cego , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , Adulto JovemRESUMO
Glecaprevir (GLE)/pibrentasvir (PIB) 300 mg/120 mg once daily (Mavyret/Maviret) is an all-oral, pangenotypic, interferon- and ribavirin-free combination regimen approved for the treatment of chronic hepatitis C virus (HCV) infection. The objective of the current analyses was to characterize the pharmacokinetics (PK) of GLE/PIB in HCV-infected Japanese patients. Data from 332 subjects enrolled in 2 Japan phase 3 trials, CERTAIN-1 and CERTAIN-2, were used in the analyses. Pharmacokinetics of GLE/PIB were characterized using a nonlinear mixed-effects modeling. The analyses evaluated the impact of covariates (concomitant medications and demographic and clinical covariates such as renal impairment, effect of cirrhotic status) on GLE/PIB PK. GLE and PIB PK were described by 1- and 2-compartment models, respectively. Presence of cirrhosis, age, and body weight were identified as significant covariates on GLE/PIB PK. A trend toward higher GLE and PIB exposures in older patients and higher PIB exposures in heavier patients was observed; however, these increases were not considered clinically meaningful. GLE and PIB exposures were higher in HCV-infected subjects with cirrhosis (Child-Pugh A; GLE area under the plasma concentration-time curve was 160% higher, and PIB area under the plasma concentration-time curve was 21% higher) compared to subjects without cirrhosis. Renal function (including subjects with end-stage renal disease with dialysis) had no impact on GLE or PIB exposures. The GLE/PIB dose was well tolerated in the Japanese population, and no dose adjustment is needed for the evaluated intrinsic and extrinsic factors.
Assuntos
Ácidos Aminoisobutíricos/farmacocinética , Antivirais/farmacocinética , Benzimidazóis/farmacocinética , Ciclopropanos/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Lactamas Macrocíclicas/farmacocinética , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Administração Oral , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Ácidos Aminoisobutíricos/administração & dosagem , Ácidos Aminoisobutíricos/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Área Sob a Curva , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Disponibilidade Biológica , Peso Corporal , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Esquema de Medicação , Combinação de Medicamentos , Feminino , Hepatite C Crônica/sangue , Humanos , Japão , Lactamas Macrocíclicas/administração & dosagem , Lactamas Macrocíclicas/efeitos adversos , Leucina/administração & dosagem , Leucina/efeitos adversos , Leucina/farmacocinética , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Prolina/administração & dosagem , Prolina/efeitos adversos , Prolina/farmacocinética , Pirrolidinas , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Adulto JovemRESUMO
Risankizumab, a humanized monoclonal antibody that targets interleukin-23 p19 subunit, was developed for the treatment of psoriasis. This work characterizes risankizumab pharmacokinetics in Japanese and Chinese healthy subjects compared with white healthy subjects and in Japanese patients with moderate to severe plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis. A phase 1, single-dose study evaluated risankizumab pharmacokinetics and safety/tolerability in healthy white (18 and 300 mg subcutaneous [SC]), Japanese (18, 90, and 300 mg SC and 200, 600, and 1200 mg intravenous [IV]), and Chinese (18, 90, and 300 mg SC) subjects; pharmacokinetic data were analyzed using noncompartmental methods. Risankizumab pharmacokinetic data from phase 2/3 studies in Japanese patients with plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis following multiple SC doses of 75 mg or 150 mg were analyzed using a population pharmacokinetic approach along with data from the phase 1 and global phase 1 to 3 studies. Risankizumab plasma exposures (peak plasma concentration and area under the concentration-time curve) were approximately dose-proportional across 18- to 300-mg SC or 200- to 1200-mg IV doses. Risankizumab terminal elimination half-life (harmonic mean 27-34 days) was comparable across doses and ethnicities. Risankizumab exposures were approximately 20% to 30% higher in Japanese and Chinese healthy subjects compared with white healthy subjects or in Japanese patients compared with non-Japanese patients. After accounting for body-weight differences, risankizumab exposures were comparable across ethnicities. Overall, there was no ethnic impact on risankizumab pharmacokinetics, and the small difference in exposure due to body weight has no clinical relevance.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Psoríase/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Injeções Subcutâneas/métodos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , População Branca , Adulto JovemRESUMO
Glecaprevir (GLE) and pibrentasvir (PIB) are direct-acting antivirals coformulated as a combination tablet for once-daily treatment of chronic hepatitis C virus infection. The objective of this study was to evaluate the effect of different methods of tablet manipulations-cutting in half, grinding into powder, or crushing-on the bioavailability of GLE and PIB relative to whole film-coated bilayer tablets. This was a phase 1, single-dose, open-label, randomized, 5-period, nonfasting crossover study in 25 healthy adult male and female subjects. Intensive pharmacokinetic measurements were carried out up to 48 h after dosing on day 1 of each period. Safety and tolerability was assessed throughout the study. Compared with the reference whole tablets, cutting into half had minimal impact on GLE and PIB exposures (≤15% difference), whereas grinding or crushing the tablets resulted in lower exposures (27% to 61%) for GLE and higher exposures (21% to 83%) for PIB. These results provide guidance on appropriate administration of GLE/PIB in patients who have difficulty swallowing whole tablets.
Assuntos
Antivirais/sangue , Benzimidazóis/sangue , Quinoxalinas/sangue , Sulfonamidas/sangue , Adulto , Ácidos Aminoisobutíricos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Área Sob a Curva , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Disponibilidade Biológica , Estudos Cross-Over , Ciclopropanos , Feminino , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , ComprimidosRESUMO
BACKGROUND: Once-daily, orally administered, co-formulated glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor) (G/P) demonstrated pangenotypic activity and high sustained virologic response (SVR) rates in studies outside Japan. Here we report safety and efficacy in a subset of Japanese patients with chronic HCV infection who received G/P 300/120 mg in a phase 3, open-label, multicenter study (CERTAIN-1). METHODS: This analysis focuses on three difficult-to-treat subgroups: HCV GT1/2-infected patients who failed to achieve SVR after treatment with a direct acting antiviral (DAA)-containing regimen; GT1/2-infected patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2); and GT3-infected patients. Patients in the renal impairment and GT3 cohorts were treatment-naive or interferon treatment-experienced. Noncirrhotic GT1/2-infected, DAA-naïve patients in the renal impairment cohort received G/P for 8 weeks; all other patients were treated for 12 weeks. Primary outcome was SVR (HCV RNA < 15 IU/mL) 12 weeks post-treatment (SVR12). RESULTS: The study enrolled 33 GT1/2-infected patients who failed previous DAA treatment (four with cirrhosis); 12 GT1/2-infected patients with severe renal impairment (two with cirrhosis); and 12 GT3-infected patients (two with cirrhosis). SVR12 was achieved by 31/33 (93.9%), 12/12 (100%), and 10/12 (83.3%) patients, respectively. One serious adverse event (fluid overload, not related to G/P) occurred in a patient on chronic intermittent hemodialysis. CONCLUSIONS: G/P achieved high SVR12 rates and was well tolerated in three difficult-to-treat patient subgroups with limited treatment options in Japan (DAA-experienced patients, patients with severe renal impairment, and GT3-infected patients). These results support the potential suitability of this regimen for these special populations in Japan.