10 Jun 21
By Dave Griffin
Both the FDA and EMA consider robust PK/PD data to be central to antibacterial drug development programmes [1, 2]. Whilst guidance documents are available, the exact scope of data needed is not clearly defined  which can result in a company’s PK/PD data package being considered inadequate or can be problematic during the regulatory review process. In this article, we briefly discuss the goals of PK/PD assessment in the development of antimicrobial agents and look at some real-life, but anonymised, examples where the PK/PD package generated fell short of the regulator’s expectations and the consequences this had for the antimicrobial agent.
Pharmacokinetics/Pharmacodynamics (PK/PD) is a quantitative approach to predict clinical efficacy based on both PK and PD data . PK relates the administered dose of the agent with the concentrations seen in the body over time whilst PD is concerned with the magnitude and time course of the observed pharmacological effect. Antimicrobial agents differ from other drugs in that their PD effect is exerted on microbial pathogens rather than (ideally) any direct effect on human cells and tissues .
The discipline of PK/PD has been developing for several decades now and the evidence demonstrating that clinical outcomes can be predicted by non-clinical infection models is extensive . Characterising the PK/PD relationship of new antimicrobial agents during development is important as this can contribute valuable information to the selection of a dose that will ensure clinical efficacy but is least likely to cause adverse effects or the emergence of resistant organisms . Solid PK/PD data is even more critical when the new agent is being developed to treat drug-resistant bacterial species as demonstrating clinical efficacy is challenging due to the relative rarity of patients infected with target bacterial species .
Over the past 10 years, both the FDA and EMA have issued guidance enabling streamlined development programmes of agents for the treatment of infections with limited therapeutic options [1, 2, 8]. Both agencies expect the PK/PD data package to support and complement the clinical trial data and to justify the selected dose when granting an application for marketing authorisation [5, 7]. In addition, PK/PD data are critical for setting appropriate clinical breakpoints  which are published by the Clinical and Laboratory Standards Institute (CLSI) and the US Committee on Antimicrobial Susceptibility Testing (USCAST) in the US and by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in Europe.
Best practices for assessing PK/PD during the development of antibacterial agents were identified in 2017, at a workshop organised by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) . To be robust, the non-clinical PK/PD package should (a) quantify the PK/PD targets for efficacy in ideally two experimental systems, including in vitro and in vivo infection models, (b) be based on bacterial isolates which have a range of susceptibilities (MICs) and resistance mechanisms expected clinically, (c) be derived from a sample size sufficient to assess the variability in the magnitude of the targets, and (d) be externally consistent and reproducible, i.e., ideally based on data generated by two or more groups of investigators [3, 6].
The recommendations from the NIAID/NIH workshop are extremely useful to companies developing new antimicrobials, but they are the opinions of the workshop participants and do not constitute regulatory guidance. Whilst regulatory agency guidance documents are available, they do not clearly define the exact scope of data needed . Consequently, some companies have generated PK/PD data packages that have been considered inadequate or problematic by the regulators during the review process. Sometimes this does not cause any major problem but in other cases has required considerable effort to alleviate the regulators’ concerns, from re-analyses of data and provision of a convincing position piece to the need to conduct additional studies which can delay approval. The following illustrates some of the problems that tranScrip has come across which either resulted in or may have resulted in a PK/PD package that fell short of the regulator’s expectations:
In summary, PK/PD assessments are critical in the development of antimicrobial agents. Whilst guidelines are available, there is a lack of well-defined requirements, which can result in a PK/PD package that is sub-optimal. Submission of such a package for regulatory review could result in the need for considerable effort to be made to resolve queries during the regulatory review process, including additional studies to be conducted with a subsequent delay in approval. As a worst case, poor PK/PD assessment could lead to the selection of an ineffective clinical dose.
tranScrip has considerable experience in developing antimicrobial agents and assessing PK/PD packages.
If you would like assistance with ensuring that your PK/PD package is optimal, please contact us on 0118 963 7846 or email us firstname.lastname@example.org.
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