Preclinical Pharmacokinetic/Pharmacodynamic Studies and Clinical Trials in the Drug Development Process of EMA-Approved Antibacterial Agents: A Review

Clin Pharmacokinet. 2020 Sep;59(9):1071-1084. doi: 10.1007/s40262-020-00892-0.

Abstract

Development of new antibacterial agents is necessary as drug-resistant bacteria are a threat to global health. In Europe, the European Medicines Agency has been guiding this development process for more than two decades. We investigated preclinical and clinical pre-approval studies to illuminate the current authorization process with emphasis on pharmacokinetic/pharmacodynamic approaches and clinical phases. All centrally authorized systemic antibacterial and antimycobacterial drugs within the European Union were included without any time restriction. Additionally, US Food and Drug Administration-approved antibiotics of the previous 3 years, which were not yet approved by the European Medicines Agency, were included. We focused on preclinical pharmacokinetic/pharmacodynamic studies and phase II and phase III clinical trials. Furthermore, we looked at the recommended dosing regimens and approved indications. In this review, we designed tree diagrams as a new means of illustrating the development process of antibiotics to relate pharmacokinetic/pharmacodynamic phase II and III studies to approved indications. We included 23 (European Medicines Agency, 18; US Food and Drug Administration, 5) antimicrobial agents. Tetracyclines, carbapenems, and cephalosporins were the leading classes. The recommended dosing intervals were significantly shorter in time- vs exposure-dependent drugs (median 8 vs 12, p = 0.006). The majority of approved indications (i.e., acute bacterial skin and soft-tissue infection, community-acquired pneumonia, complicated intra-abdominal infection, complicated urinary tract infection, and complicated skin and soft-tissue infection) used non-inferiority trials. Phase II and III clinical trials investigating community-acquired pneumonia involved the fewest patients. Some promising drugs were marketed in recent years; the individual steps to their authorizations are illuminated. We confirmed the relevance of preclinical pharmacokinetic/pharmacodynamic studies in dosing optimization and decision making in antimicrobial drug development. Non-inferiority clinical trials predominated.

Publication types

  • Review

MeSH terms

  • Anti-Bacterial Agents* / pharmacokinetics
  • Carbapenems / pharmacokinetics
  • Cephalosporins / pharmacokinetics
  • Clinical Trials as Topic
  • Drug Development*
  • Europe
  • Humans
  • United States
  • United States Food and Drug Administration

Substances

  • Anti-Bacterial Agents
  • Carbapenems
  • Cephalosporins