Translational predictions of phase 2a first-in-patient efficacy studies for antituberculosis drugs.
Eur Respir J
; 62(2)2023 08.
Article
em En
| MEDLINE
| ID: mdl-37321622
ABSTRACT
BACKGROUND:
Phase 2a trials in tuberculosis typically use early bactericidal activity (EBA), the decline in sputum CFU over 14â days, as the primary end-point for testing the efficacy of drugs as monotherapy. However, the cost of phase 2a trials can range from USD 7 million to USD 19.6â million on average, while >30% of drugs fail to progress to phase 3. Better utilising pre-clinical data to predict and prioritise the most likely drugs to succeed will thus help to accelerate drug development and reduce costs. We aim to predict clinical EBA using pre-clinical in vivo pharmacokinetic (PK)-pharmacodynamic (PD) data and a model-based translational pharmacology approach. METHODS ANDFINDINGS:
First, mouse PK, PD and clinical PK models were compiled. Second, mouse PK-PD models were built to derive an exposure-response relationship. Third, translational prediction of clinical EBA studies was performed using mouse PK-PD relationships and informed by clinical PK models and species-specific protein binding. Presence or absence of clinical efficacy was accurately predicted from the mouse model. Predicted daily decreases of CFU in the first 2â days of treatment and between day 2 and day 14 were consistent with clinical observations.CONCLUSION:
This platform provides an innovative solution to inform or even replace phase 2a EBA trials, to bridge the gap between mouse efficacy studies and phase 2b and phase 3 trials, and to substantially accelerate drug development.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tuberculose
/
Antituberculosos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article