Translational predictions of phase 2a first-in-patient efficacy studies for antituberculosis drugs

Jacqueline P. Ernest, Janice Jia Ni Goh, Natasha Strydom, Qianwen Wang, Rob C. van Wijk, Nan Zhang, Amelia Deitchman, Eric Nuermberger, Rada M. Savic

Research output: Contribution to journalArticlepeer-review


Background: Phase 2a trials in tuberculosis typically use early bactericidal activity (EBA), the decline in sputum CFU over 14 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 19.6 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 and findings: 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 2 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.

Original languageEnglish (US)
Article number2300165
JournalEuropean Respiratory Journal
Issue number2
StatePublished - 2023

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine


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