The Pharmacometric Solution: We Told You So!

Paul G. Ambrose, Pharm.D, FIDSA, Sujata M. Bhavnani, Pharm.D, M.S. and George L. Drusano, M.D., FIDSA

It was 11 October 2007 at a US Food and Drug Administration (US FDA) and Infectious Disease Society of America (IDSA) co-sponsored workshop where we first proposed a pharmacometric solution to some of the most vexing problems in antimicrobial drug development [CID 2008;47:S225-31].  First, we described how pharmacometrics could be used to determine the magnitude of treatment effect, which allows for the estimation of non-inferiority margins using contemporary clinical data [AAC 2012;56:1466-70].  This is important, as the alternative is to use historical data.   In our view, the use of historical data is assuredly unwise because of the disparity between modern medical care and that available at the dawn of antimicrobial chemotherapy. Second we described how continuous, numeric endpoints  holds the promise for the evaluation for evaluating the impact of drug exposure on time to event, thereby reducing the number of patients required to detect between-regimen differences, and defining the optimal length of therapy.

In December of last year, the European Medicines Agency (EMA) released a guideline for the development of antimicrobial drugs, which questioned the usefulness of historical data [EMA guideline 2011] and, importantly, explicitly mentioned the pharmacometric solution.  The EMA guideline said “Historical data are often used to estimate the no-treatment effect but the relevance of these data to current medical practice may be questionable.  Sponsors are encouraged to explore alternative and emerging methods for estimating the no-treatment effect (e.g., using pharmacometric-based approaches)."  We applauded the EMA for taking an important step towards ensuring the development of new antimicrobial agents and urged others to support the pharmacometric-based approach [Lancet ID 2012;12:265-6].  In October 2012, IDSA published recommendations on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections associated with drug-resistant bacteria [CID 2012;55:1031-46].   Therein, IDSA suggested a pharmacometric-based approach to defining the no-treatment effect using contemporary data.

The 22^nd October EMA workshop further highlighted the rising importance of pharmacometric approaches in the development of antimicrobial regimens for the treatment of drug-resistant bacteria.  There we made two presentations.  The first described how the use of in vitro and animal models as well as mathematical models can be used to identify treatment regimens that hold the promise to slow or prevent the amplification of drug-resistant pathogens, while the second described a paradigm where high-quality pharmacometric information obtained from pre-clinical and clinical data sources supported approval and balanced unmet medical need and data quantity.

The in vitro models provide insight into the relationship between drug concentration and cell kill as well as resistant subpopulation response to drug pressure. The animal models allow the impact of drug penetration to the infection space to be elucidated and also allow some insight into the impact of the immune system, which is completely missing from the in vitro system. The mathematical modeling ties this information together to allow delineation of exposure profiles that are linked to specific endpoints (2 Log kill, resistance suppression, etc). Human pharmacokinetic information, including penetration into specialized spaces such as ELF allow the final bridging between pre-clinical data and the clinic. This also allows the generation of optimal approaches to study patients in the clinic so that exposure-response relationships may be developed.

Given the rising tide of resistance to our existing antimicrobial armamentarium, a risk-benefit approach for the assessment of the effectiveness of is appropriate.  Simply put, it is unacceptable to have an absence of active antimicrobial agents for the management of infections associated with drug-resistant pathogens.  The EMA is listening and acting.  The FDA is clearly listening.