RESUMO
Lambert-Eaton myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4-diaminopyridine (3,4-DAP) free base is an investigational orphan drug used to treat LEM-related weakness. We performed a population pharmacokinetic/pharmacodynamic (PK/PD) analysis using 3,4-DAP and metabolite concentrations collected from a phase II study in patients with LEM. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1,270 PK samples (49 patients) and 1,091 3TUG data points (32 randomized patients) were included in the PK/PD analysis. A two-compartment and one-compartment model for parent and metabolite, respectively, described the PK data well. Body weight and serum creatinine partially explained the variability in clearance for the final PK model. A fractional inhibitory maximum effect (Emax ) model characterized the exposure-response relationship well. The PK/PD model was applied to identify a suggested dosing approach for 3,4-DAP free base.
Assuntos
4-Aminopiridina/análogos & derivados , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Modelos Biológicos , Debilidade Muscular/tratamento farmacológico , Bloqueadores dos Canais de Potássio , 4-Aminopiridina/sangue , 4-Aminopiridina/farmacocinética , 4-Aminopiridina/farmacologia , 4-Aminopiridina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Amifampridina , Arilamina N-Acetiltransferase/genética , Feminino , Humanos , Síndrome Miastênica de Lambert-Eaton/sangue , Síndrome Miastênica de Lambert-Eaton/fisiopatologia , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/sangue , Debilidade Muscular/genética , Debilidade Muscular/fisiopatologia , Polimorfismo de Nucleotídeo Único , Bloqueadores dos Canais de Potássio/sangue , Bloqueadores dos Canais de Potássio/farmacocinética , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220 nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition.
Assuntos
4-Aminopiridina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quinase 1 do Ponto de Checagem/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirazinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , 4-Aminopiridina/farmacocinética , 4-Aminopiridina/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proteína Quinase CDC2 , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Quinase do Ponto de Checagem 2/antagonistas & inibidores , Quinases Ciclina-Dependentes/antagonistas & inibidores , Dano ao DNA/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Células HT29 , Humanos , Irinotecano , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos Transgênicos , Pirazinas/farmacocinética , GencitabinaRESUMO
A new strategy to build caged-compounds is presented. The approach is based on heterolytic photocleavage of a metal-ligand bond in a coordination compound. A ruthenium polypyridine complex, containing the neurocompound 4-amino pyridine (4AP) is used as the core of the phototrigger. The biomolecule is released by irradiation with visible light (>480 nm). The liberated 4AP promotes the activation of a leech neuron by means of blocking its K+ channels. The syntesis, characterization, and the inherent advantages of this method are discussed.