Pharmacokinetics and pharmacodynamics in the development of anti-tuberculosis drugs.

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 anti-infective 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. Re-evaluation 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.