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 22nd 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.
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