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1.
Clin Pharmacol Drug Dev ; 8(5): 647-656, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30748125

RESUMO

Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg lesinurad. Food did not alter the plasma AUC of lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of lesinurad by approximately 20% despite reducing the Cmax of lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6 hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter lesinurad PK and PD. High doses of antacids reduced lesinurad AUC up to 40% and reduced the lesinurad uric acid-lowering effect.


Assuntos
Hidróxido de Alumínio/farmacologia , Antiácidos/farmacologia , Carbonato de Cálcio/farmacologia , Interações Alimento-Droga , Supressores da Gota , Hidróxido de Magnésio/farmacologia , Tioglicolatos , Triazóis , Ácido Úrico/sangue , Adolescente , Adulto , Estudos Cross-Over , Gorduras na Dieta/administração & dosagem , Combinação de Medicamentos , Supressores da Gota/sangue , Supressores da Gota/farmacocinética , Supressores da Gota/farmacologia , Supressores da Gota/urina , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Tioglicolatos/sangue , Tioglicolatos/farmacocinética , Tioglicolatos/farmacologia , Tioglicolatos/urina , Triazóis/sangue , Triazóis/farmacocinética , Triazóis/farmacologia , Triazóis/urina , Adulto Jovem
2.
Clin Cancer Res ; 22(10): 2368-76, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26644411

RESUMO

PURPOSE: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation. RESULTS: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ∼16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year. CONCLUSIONS: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368-76. ©2015 AACR.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Difenilamina/análogos & derivados , Neoplasias/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/uso terapêutico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Terapia Combinada/métodos , Difenilamina/efeitos adversos , Difenilamina/sangue , Difenilamina/farmacocinética , Difenilamina/uso terapêutico , Feminino , Meia-Vida , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/metabolismo , Niacinamida/efeitos adversos , Niacinamida/sangue , Niacinamida/farmacocinética , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/sangue , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe , Sulfonamidas/efeitos adversos , Sulfonamidas/sangue
3.
Clin Cancer Res ; 19(5): 1232-43, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23434733

RESUMO

PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. EXPERIMENTAL DESIGN: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. RESULTS: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ~12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate-stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. CONCLUSION: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types.


Assuntos
Difenilamina/análogos & derivados , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Difenilamina/farmacocinética , Difenilamina/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Estadiamento de Neoplasias , Neoplasias/patologia , Prognóstico , Inibidores de Proteínas Quinases/farmacocinética , Sulfonamidas/farmacocinética , Distribuição Tecidual , Adulto Jovem
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