{"doi":"10.1183/13993003.00165-2023","title":"Translational predictions of phase 2a first-in-patient efficacy studies for antituberculosis drugs","abstract":"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.","journal":"European Respiratory Journal","year":2023,"id":339841,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1073821,"name":"Janice Jia Ni Goh","orcid":"0009-0005-0203-5949","position":1,"is_corresponding":false},{"id":341203,"name":"Natasha Strydom","orcid":"0000-0002-0929-0783","position":2,"is_corresponding":false},{"id":689632,"name":"Qianwen Wang","orcid":"0000-0003-3553-1162","position":3,"is_corresponding":false},{"id":1073822,"name":"Rob C. van Wijk","orcid":"0000-0001-7247-1360","position":4,"is_corresponding":false},{"id":341202,"name":"Nan Zhang","orcid":"0000-0001-5031-9480","position":5,"is_corresponding":false},{"id":393111,"name":"Amelia N. Deitchman","orcid":"0000-0002-4722-463X","position":6,"is_corresponding":false},{"id":291391,"name":"Eric L. Nuermberger","orcid":"0000-0003-1440-9889","position":7,"is_corresponding":false},{"id":343028,"name":"Rada Savic","orcid":null,"position":8,"is_corresponding":false},{"id":355785,"name":"Jacqueline P. Ernest","orcid":"0000-0002-7664-7287","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T01:10:49.535464Z","pmid":"37321622","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}