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

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.

The Minimum Inhibitory Concentration of Antibiotics: Methods, Interpretation, Clinical Relevance

“…The presence of resistance mechanisms to various antibiotics is also subject to phenotypic and genotypic evaluation. Among very important steps is the analysis of pharmacokinetic/dynamic parameters (the fate of drugs in the body and their activity against bacteria) in preclinical and clinical trials [ 34 , 38 ]. Literature reports also need to be analyzed and clinical breakpoints for MIC need to be finally set but in such a manner so that they do not separate MIC values for wild type strains [ 34 ].…”

Pivotal Role of Translation in Anti‐Infective Development

“…A clear advantage in the development of antibiotics is the possibility to study the PK/pharmacodynamic (PD) relationship of the infecting pathogen experimentally in in vitro and in vivo systems 7–9 . In vitro time‐kill and in vivo murine infection model data are commonly included in the submission to support the suggested dosing strategy 10 and such nonclinical PK/PD data are requested by regulatory authorities 5,11 . In so‐called “static” time‐kill studies, bacteria are exposed to constant antibiotic concentrations in tubes over, for example, 24–48 hours, whereas in “dynamic” time‐kill studies the concentration varies over time, typically mimicking the PK profile expected in patients.…”

The Role of PK/PD Analysis in the Development and Evaluation of Antimicrobials

“…For the time-dependent pattern, the antibacterial effect is best described by the percentage of time the free drug concentration remains above the MIC throughout the dosing interval (f T >MIC ). Finally, the best PK/PD ratio for concentration-dependent with time-dependence antibiotics, is f AUC 24 /MIC [5,9,12,13]. The PK/PD indices have also been related to suppression of emergence of resistance [14].…”

“…Preclinical models require robust indicators for antibacterial activity in humans, and therefore, their results are very useful to optimize dose regimens for efficacy and prevention of resistance [5]. The EMA guidelines on the use of the PK and PD in the development of antimicrobial medicinal products [17] recommends testing about 4-5 organisms of the major target species or organism groups.…”

“…The optimization of the use of antimicrobial agents is one of the five strategic objectives set out to achieve this goal [4]. This objective is especially relevant considering that in the last 10 years, no new group of antibiotics has been marketed in Europe [5].…”