RESUMO
Cell therapies offer the promise of treating and altering the course of diseases which cannot be addressed adequately by existing pharmaceuticals. Cell therapies are a diverse group across cell types and therapeutic indications and have been an active area of research for many years but are now strongly emerging through translation and towards successful commercial development and patient access. In this article, we present a description of a classification of cell therapies on the basis of their underlying technologies rather than the more commonly used classification by cell type because the regulatory path and manufacturing solutions are often similar within a technology area due to the nature of the methods used. We analyse the progress of new cell therapies towards clinical translation, examine how they are addressing the clinical, regulatory, manufacturing and reimbursement requirements, describe some of the remaining challenges and provide perspectives on how the field may progress for the future.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos/classificação , Animais , Biotecnologia/tendências , Linhagem Celular Transformada , Terapia Baseada em Transplante de Células e Tecidos/economia , Terapia Baseada em Transplante de Células e Tecidos/tendências , Técnicas de Reprogramação Celular , Vetores Genéticos , Humanos , Edição de RNA , Engenharia Tecidual , Pesquisa Translacional Biomédica/tendênciasRESUMO
There is considerable ongoing investment in the research and development of selective progesterone receptor (PR) modulators for the treatment of gynecological conditions such as endometriosis. Here, we provide the first report on the clinical evaluation of a nonsteroidal progesterone receptor antagonist 4-[3-cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873) in healthy female subjects. In in vitro assays, PF-02413873 behaved as a selective and fully competitive PR antagonist, blocking progesterone binding and PR nuclear translocation. The pharmacological mode of action of PF-02413873 seems to differ from the founding member of the class of steroidal PR antagonists, 11ß-4-dimethylaminophenyl-17ß-hydroxy-17α-propinyl-4,9-estradiene-3-one (RU-486; mifepristone). Exposure-effect data from studies in the cynomolgus macaque, however, demonstrated that PF-02413873 reduced endometrial functionalis thickness to a comparable degree to RU-486 and this effect was accompanied by a decrease in proliferation rate (as measured by bromodeoxyuridine incorporation) for both RU-486 and high-dose PF-02413873. These data were used to underwrite a clinical assessment of PF-02413873 in a randomized, double-blinded, third-party open, placebo-controlled, dose-escalation study in healthy female volunteers with dosing for 14 days. PF-02413873 blocked the follicular phase increase in endometrial thickness, the midcycle lutenizing hormone surge, and elevation in estradiol in a dose-dependent fashion compared with placebo. This is the first report of translational efficacy data with a nonsteroidal PR antagonist in cynomolgus macaque and human subjects.
Assuntos
Endométrio/efeitos dos fármacos , Estrogênios não Esteroides/farmacologia , Fase Folicular/efeitos dos fármacos , Pirazóis/farmacologia , Receptores de Progesterona/antagonistas & inibidores , Sulfonas/farmacologia , Adulto , Animais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Endometriose/tratamento farmacológico , Estradiol/sangue , Feminino , Antagonistas de Hormônios/farmacologia , Humanos , Hormônio Luteinizante/sangue , Macaca , Mifepristona/farmacologia , Terapia de Alvo Molecular , Pesquisa Translacional Biomédica , Adulto JovemRESUMO
The recently discovered selective nonsteroidal progesterone receptor (PR) antagonist 4-[3-cyclopropyl-1-(methylsulfonylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile (PF-02413873) was characterized in metabolism studies in vitro, in preclinical pharmacokinetics in rat and dog, and in an initial pharmacokinetic study in human volunteers. Clearance (CL) of PF-02413873 was found to be high in rat (84 ml · min(-1) · kg(-1)) and low in dog (3.8 ml · min(-1) · kg(-1)), consistent with metabolic stability determined in liver microsomes and hepatocytes in these species. In human, CL was low in relation to hepatic blood flow, consistent with metabolic stability in human in vitro systems, where identified metabolites suggested predominant cytochrome P450 (P450)-catalyzed oxidative metabolism. Prediction of CL using intrinsic CL determined in human liver microsomes (HLM), recombinant human P450 enzymes, and single species scaling (SSS) from pharmacokinetic studies showed that dog SSS and HLM scaling provided the closest estimates of CL of PF-02413873 in human. These CL estimates were combined with a physiologically based pharmacokinetic (PBPK) model to predict pharmacokinetic profiles after oral suspension administration of PF-02413873 in fasted and fed states in human. Predicted plasma concentration versus time profiles were found to be similar to those observed in human over the PF-02413873 dose range 50 to 500 mg and captured the enhanced exposure in fed subjects. This case study of a novel nonsteroidal PR antagonist underlines the utility of PBPK modeling techniques in guiding prediction confidence and design of early clinical trials of novel chemical agents.
Assuntos
Pirazóis/farmacocinética , Receptores de Progesterona/antagonistas & inibidores , Sulfonas/farmacocinética , Animais , Biotransformação , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Cães , Relação Dose-Resposta a Droga , Método Duplo-Cego , Avaliação Pré-Clínica de Medicamentos , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Injeções Intravenosas , Secreções Intestinais/química , Masculino , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Estrutura Molecular , Valor Preditivo dos Testes , Estudos Prospectivos , Ligação Proteica , Pirazóis/sangue , Pirazóis/química , Ratos , Ratos Sprague-Dawley , Solubilidade , Especificidade da Espécie , Sulfonas/sangue , Sulfonas/química , Espectrometria de Massas em TandemRESUMO
Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.