RESUMO
INTRODUCTION: The aim of the study was to clarify the dose response for inhibition of catechol-O-methyltransferase (COMT) by opicapone, a third generation COMT inhibitor, after acute and repeated administration to the cynomolgus monkey with pharmacokinetic evaluation at the higher dose. METHODS: Three cynomolgus monkeys were used in the study. In the first experiment, COMT inhibition was evaluated over 24â¯h after the first and at 24â¯h after the last of 14 daily oral administrations of vehicle, 1, 10 and 100â¯mg/kg opicapone using a crossover design. In the second experiment, the effect of the maximally effective dose, 100â¯mg/kg, was retested under the same conditions with additional monitoring of plasma opicapone levels to explore the relationship between pharmacokinetics and pharmacodynamics. RESULTS: Opicapone dose-dependently inhibited COMT activity, significantly so at 10 and 100â¯mg/kg. Maximal inhibition was 13.1%, 76.4% and 93.2% at 1, 10 and 100â¯mg/kg respectively, and COMT remained significantly inhibited at 24â¯h after 10 and 100â¯mg/kg (42.6% and 60.2% respectively). Following repeated administration of opicapone residual COMT inhibition at 24â¯h was 15-25% greater at all doses. In contrast to its pharmacodynamic effect, opicapone was rapidly absorbed and eliminated, with no accumulation in plasma following repeated administration. CONCLUSION: Opicapone showed sustained and dose-dependent COMT inhibition despite being rapidly eliminated from plasma and with no evidence for accumulation in plasma after 14 days administration. Opicapone fills the unmet need for a compound with sustained COMT inhibition which will improve levodopa bioavailability in patients with Parkinson's disease.
Assuntos
Inibidores de Catecol O-Metiltransferase/administração & dosagem , Inibidores de Catecol O-Metiltransferase/farmacocinética , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Catecol O-Metiltransferase/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Eritrócitos/efeitos dos fármacos , Eritrócitos/enzimologia , Feminino , Macaca fascicularis , Distribuição Aleatória , Fatores de TempoRESUMO
ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this modeling study were to (1) develop exposure-response (E-R) models to relate ONO-5334 exposure to bone mineral density (BMD), (2) predict BMD responses to various doses of ONO-5334 for both immediate release tablet (IRT) and sustained release tablet (SRT) formulations where only BMD response after administration of IRT had been studied to date, (3) inform selection of appropriate formulation/dose using simulation for future clinical trials. A population pharmacokinetic (PK) model was developed to simultaneously analyze data for both IRT and SRT. The exposure metrics at steady state were estimated by post hoc Bayesian prediction using the final population PK model. E-R models were developed using dose-ranging data with only IRT from postmenopausal females with osteoporosis. Based on the developed model, lumbar spine and total hip BMD after administration of ONO-5334 SRT as well as IRT were simulated. The simulation results showed that ONO-5334 SRT should provide comparable BMD responses at a lower dose relative to IRT (a finding consistent with the results from a previous population PK-PD modeling study with bone resorption markers).
Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Catepsina K/antagonistas & inibidores , Modelos Biológicos , Osteoporose Pós-Menopausa/tratamento farmacológico , Tiazolidinas/administração & dosagem , Idoso , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Simulação por Computador , Relação Dose-Resposta a Droga , Feminino , Humanos , Pessoa de Meia-Idade , Tiazolidinas/uso terapêuticoRESUMO
ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50 ) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT.
Assuntos
Catepsina K/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacocinética , Pós-Menopausa/metabolismo , Tiazolidinas/farmacocinética , Idoso , Algoritmos , Área Sob a Curva , Povo Asiático , Peso Corporal/fisiologia , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Inibidores de Cisteína Proteinase/administração & dosagem , Relação Dose-Resposta a Droga , Europa (Continente) , Feminino , Humanos , Japão , Pessoa de Meia-Idade , Modelos Estatísticos , Espectrometria de Massas em Tandem , Tiazolidinas/administração & dosagem , População BrancaRESUMO
"Sandwich-type" noncompetitive (immunometric) assays allow for high-sensitivity high-throughput macromolecule sensing and determination but cannot be used on small molecules (haptens). Here, we isolated single-chain Fv fragments from a phage-display library, which bound to complexes of particular haptens (vitamin D and A derivatives) with immobilized beta-cyclodextrin or beta-maltosyl residues, and formed ternary complexes. These scFvs enabled novel "semisandwich-type" immunometric assays of haptens with nanomole-range sensitivities.