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1.
Clin Pharmacol Ther ; 100(3): 259-67, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27256812

RESUMO

This article reports the clinical investigation of a probe drug cocktail containing substrates of key drug transporters. Single oral doses of 0.25 mg digoxin (P-gp), 5 mg furosemide (OAT1 and OAT3), 500 mg metformin (OCT2, MATE1, and MATE2-K), and 10 mg rosuvastatin (OATP1B1, OATP1B3, and BCRP) were administered separately or as a cocktail in a randomized six-period crossover trial in 24 healthy male volunteers. As a cocktail, relative bioavailabilities of digoxin and metformin and furosemide AUC0-tz were similar to separate dosing. However, when administered as a cocktail the Cmax of furosemide was 19.1% lower and the Cmax and AUC0-tz of rosuvastatin were 38.6% and 43.4% higher, respectively. In addition, the effects of increased doses of metformin or furosemide on the cocktail were investigated in 11 and 12 subjects, respectively. The cocktail explored in this trial has the potential to be used for the in vivo screening of transporter-mediated drug-drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Digoxina/farmacocinética , Furosemida/farmacocinética , Metformina/farmacocinética , Rosuvastatina Cálcica/farmacocinética , 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/metabolismo , Adulto , Área Sob a Curva , Estudos Cross-Over , Digoxina/farmacologia , Interações Medicamentosas , Furosemida/farmacologia , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Taxa de Depuração Metabólica , Metformina/farmacologia , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico , Rosuvastatina Cálcica/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto
2.
Invest New Drugs ; 31(3): 734-41, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23161334

RESUMO

BACKGROUND: A phase I study to assess the maximum tolerated dose (MTD) of a short course of afatinib in combination with docetaxel for the treatment of solid tumors. METHODS: Patients with advanced solid malignancies received docetaxel 75 mg/m(2) intravenously on day 1 and oral afatinib once daily on days 2-4, in 3-week treatment cycles. The afatinib dose was escalated in successive cohorts of 3-6 patients until dose-limiting toxicity (DLT). The MTD cohort was expanded to 13 patients. Pharmacokinetic parameters were assessed. RESULTS: Forty patients were treated. Afatinib doses were escalated to 160 mg/day in combination with 75 mg/m(2) docetaxel. Three patients had drug-related DLTs during cycle 1. The MTD was defined as 90 mg/day afatinib (days 2-4) with docetaxel 75 mg/m(2). The most frequent drug-related adverse events (all grades) were alopecia, diarrhea, stomatitis (all 50 %) and rash (40 %, all grade ≤ 2). Three patients had confirmed responses, two patients had unconfirmed responses and nine patients had durable stable disease >6 cycles. No pharmacokinetic interaction was observed. CONCLUSION: Afatinib 90 mg administered for 3 days after docetaxel 75 mg/m(2) is the MTD for this treatment schedule and the recommended phase II/phase III dose. This combination showed anti-tumor activity in phase I, with a manageable adverse-event profile.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Afatinib , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Docetaxel , Esquema de Medicação , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Dermatopatias/induzido quimicamente , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Taxoides/farmacocinética
3.
Ann Oncol ; 23(8): 2094-2102, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22345119

RESUMO

BACKGROUND: BIBF 1120 is an oral potent inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor, the three key receptor families involved in angiogenesis. This phase I, open-label dose-escalation study investigated BIBF 1120 combined with paclitaxel (Taxol) and carboplatin in first-line patients with advanced (IIIB/IV) non-small-cell lung cancer. PATIENTS AND METHODS: Patients received BIBF 1120 (starting dose 50 mg b.i.d.) on days 2-21 and paclitaxel (200 mg/m2) and carboplatin [area under curve (AUC)=6 mg/ml/min] on day 1 of each 21-day cycle. Primary end points were safety and BIBF 1120 maximum tolerated dose (MTD) in this combination. Pharmacokinetics (PK) profiles were evaluated. RESULTS: Twenty-six patients were treated (BIBF 1120 50-250 mg b.i.d.). BIBF 1120 MTD was 200 mg b.i.d. in combination with paclitaxel and carboplatin. Six dose-limiting toxicity events occurred during treatment cycle 1 (liver enzyme elevations, thrombocytopenia, abdominal pain, and rash). Best responses included 7 confirmed partial responses (26.9%); 10 patients had stable disease. BIBF 1120 200 mg b.i.d. had no clinically relevant influence on the PK of paclitaxel 200 mg/m2 and carboplatin AUC 6 mg/ml/min and vice versa. CONCLUSIONS: BIBF 1120 MTD was 200 mg b.i.d when given with paclitaxel and carboplatin; this combination demonstrated an acceptable safety profile. No relevant changes in PK parameters of the backbone chemotherapeutic agents or BIBF 1120 were observed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/sangue
4.
Ann Oncol ; 22(6): 1374-1381, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21212157

RESUMO

BACKGROUND: To assess the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). METHODS: Patients with locally advanced or metastatic relapsed NSCLC in whom first- or second-line platinum-based chemotherapy failed were randomly allocated to daily 250 mg BIBF 1120 b.i.d. or 150 mg BIBF 1120 b.i.d. Primary end points were progression-free survival (PFS) and objective tumour response (RECIST). Incidence and severity of adverse events (AEs) were reported. RESULTS: Seventy-three patients received BIBF 1120. Median PFS was 6.9 weeks, with no significant difference between treatment arms. Median overall survival (OS) was 21.9 weeks. Eastern Cooperative Oncology Group (ECOG) 0-1 patients (n = 56) had a median PFS of 11.6 weeks and a median OS of 37.7 weeks. Tumour stabilisation was achieved in 46% of patients (ECOG 0-1 patients: 59%), with one confirmed partial response (250 mg b.i.d.). Most commonly reported drug-related AEs were nausea (57.5%), diarrhoea (47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) and reversible alanine transaminase (13.7%) and aspartate aminotransferase elevations (9.6%). BIBF 1120 displayed dose-linear pharmacokinetic characteristics. CONCLUSION: Continuous treatment with BIBF 1120 was well tolerated, with no difference in efficacy between treatment arms. PFS and objective response with single-agent treatment in advanced disease warrants further exploration.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/patologia , Método Duplo-Cego , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Recidiva , Resultado do Tratamento
5.
Ann Oncol ; 21(2): 370-375, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19889612

RESUMO

BACKGROUND: The purpose of the phase I dose-escalation study was to evaluate the maximum tolerated dose (MTD) of BIBF 1120, an oral triple angiokinase inhibitor of vascular endothelial growth factor, platelet derived growth factor and fibroblast growth factor receptors, combined with paclitaxel and carboplatin. PATIENTS AND METHODS: Patients with advanced gynecological malignancies received BIBF 1120 twice-daily (b.i.d.) continuously at 100, 150, 200 or 250 mg, combined with paclitaxel (175 mg/m(2)) and carboplatin (area under the curve 5 min.mg/ml) every 3 weeks. The MTD, safety, pharmacokinetics (PK) and clinical activity were evaluated. RESULTS: Twenty-two patients were treated. Three experienced dose-limiting toxic effects in the first treatment cycle: 1 of 13 at 200 mg b.i.d. BIBF 1120 [diarrhea, common terminology criteria for adverse events (CTCAE) grade 3]; two of two at 250 mg b.i.d. BIBF 1120 (elevated alanine aminotransferase and aspartate aminotransferase, CTCAE grade 3/4). The MTD was defined as 200 mg b.i.d. Principal adverse events were gastrointestinal disorders. No clinically relevant drug-drug interaction was observed after 20 days treatment with 200 mg b.i.d. BIBF 1120 on the PK of paclitaxel or carboplatin and vice versa. CONCLUSIONS: The MTD of BIBF 1120 in a 20-day continuous dosing regimen with standard-dose paclitaxel and carboplatin was 200 mg b.i.d. This combination had an acceptable safety profile and no clinically relevant drug-drug interactions. Further evaluation of this combination is warranted in this indication.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Neoplasias dos Genitais Femininos/tratamento farmacológico , Indóis/administração & dosagem , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Paclitaxel/administração & dosagem , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/efeitos adversos , Carboplatina/farmacocinética , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Neoplasias dos Genitais Femininos/metabolismo , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/metabolismo , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Resultado do Tratamento
6.
Br J Cancer ; 98(1): 80-5, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18026190

RESUMO

To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.


Assuntos
Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Quinazolinas/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Adolescente , Adulto , Afatinib , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Pele/citologia , Pele/efeitos dos fármacos , Pele/metabolismo , Fatores de Tempo , Distribuição Tecidual , Resultado do Tratamento
7.
Clin Exp Immunol ; 136(1): 21-9, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15030510

RESUMO

The lymphotoxin-beta receptor (LTbetaR) pathway is critical for maintenance of organized lymphoid structures and is involved in the development of colitis. To investigate the mechanisms by which LTbetaR activation contributes to the pathology of chronic inflammation we used a soluble LTbetaR-Ig fusion protein as a competitive inhibitor of LTbetaR activation in the mouse model of chronic colitis induced by oral administration of dextran sulphate sodium. Strong expression of LTbeta which constitutes part of the LTalpha(1)beta(2) ligand complex was detected in colonic tissue of mice with chronic colitis. Treatment with LTbetaR-Ig significantly attenuated the development and histological manifestations of the chronic inflammation and reduced the production of inflammatory cytokines such as TNF, IL-1beta, and IL-6. Moreover, LTbetaR-Ig treatment significantly down-regulated mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression, leading to reduced leucocyte rolling and sticking in postcapillary and collecting venules and reduced extravasation into the intestinal mucosa as quantified by in vivo fluorescence microscopy. Thus, LTbetaR pathway inhibition ameliorates DSS-induced experimental chronic colitis in mice by MAdCAM-1 down-regulation entailing reduced lymphocyte margination and extravasation into the inflamed mucosa. Therefore, a combined treatment with reagents blocking T cell-mediated perpetuation of chronic inflammation such as LTbetaR-Ig together with direct anti-inflammatory reagents such as TNF inhibitors could constitute a promising treatment strategy for chronic colitis.


Assuntos
Colite Ulcerativa/prevenção & controle , Imunoglobulinas/metabolismo , Mucoproteínas/metabolismo , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Animais , Moléculas de Adesão Celular , Doença Crônica , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Feminino , Mucosa Intestinal/irrigação sanguínea , Mucosa Intestinal/metabolismo , Leucócitos/fisiologia , Ligantes , Receptor beta de Linfotoxina , Camundongos , Camundongos Endogâmicos BALB C , Microcirculação , Receptores do Fator de Necrose Tumoral/fisiologia
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