Optimization of dosing strategies and companion drugs prior to Phase III
trials is currently a critical obstacle in the development of new
anti-tuberculosis drugs. Pharmacokinetic-pharmacodynamic (PK-PD) methods
have assumed an important role in improving the efficiency of this
process across the pharmaceutical industry and in other areas of
antiinfective therapy. Information gained using PK-PD methods from the
earliest in vitro assessments right up to the end of Phase II
development can underpin proof-of-concept and ensure that agents are
fully pharmacologically optimized. Despite our limited understanding of
the biology of bacillary elimination in vivo, such an approach has
already provided key insights into these mechanisms and helped to
identify the role of different drugs in therapy and assess their
potential for progression to pivotal trials. While isoniazid appears
historically to have been effectively exploited, human studies suggest
that it does not play a key role in the sterilizing phase of treatment.
Reevaluation of the PK-PD of rifamycins by contrast suggests that there
may be considerable scope for improving their activity by intensifying
current dosing strategies. Various PK-PD analyses of the fluoroquinolone
series demonstrate remarkable agreement concerning the ranking of their
sterilizing activity, results which appear to be confirmed in recent
human phase II studies. The pharmacological characteristics of
completely new classes of drugs now entering clinical development
suggest that experience with existing drugs, particularly EBA studies,
should not prejudice evaluation of their pharmacodynamic activity which
may differ qualitatively from that of many current agents. In
conclusion, PK-PD analysis has a vital role to play in the rational
development of new anti-tuberculosis drugs and combination regimens.
This is one of a series of articles commissioned and edited by the TB
Alliance and published in a special issue of Tuberculosis, entitled
'Key issues in TB drug research and development'.
Tuberculosis (2008) 88, Supplement 1, S65-S74 [doi:10.1016/S1472-9792(08)70037-4]
Pharmacokinetics and pharmacodynamics in the development of anti-tuberculosis drugs.