The importance of clinical pharmacokinetic-pharmacodynamic studies in unraveling the determinants of early and late tuberculosis outcomes

Abstract

Tuberculosis remains a major infectious cause of morbidity and mortality worldwide. Current antibiotic regimens, constructed prior to the development of modern pharmacokinetic-pharmacodynamic (PK-PD) tools, are based on incomplete understanding of exposure-response relationships in drug susceptible and multidrug resistant tuberculosis. Preclinical and population PK data suggest that clinical PK-PD studies may enable therapeutic drug monitoring for some agents and revised dosing for others. Future clinical PK-PD challenges include: incorporation of PK methods to assay free concentrations for all active metabolites; selection of appropriate early outcome measures which reflect therapeutic response; elucidation of genetic contributors to interindividual PK variability; conduct of targeted studies on special populations (including children); and measurement of PK-PD parameters at the site of disease.

Keywords: clinical trials; compartmental pharmacokinetics; multidrug-resistant tuberculosis; pharmacogenetics; pharmacokinetics–pharmacodynamics; therapeutic drug monitoring; tuberculosis.

Figure 1.. Generic study design for clinical PK–PD study in DS-TB.

Procedures to generate PK parameters are shown in green. Procedures to generate PD parameters and study outcome measures are shown in red. PK–PD parameters which may be related to study outcome measures are shown in yellow. Number before drug combinations denotes intended duration of therapy in months. Other abbreviations are as described in the main text. *TB cultures to determine early efficacy measures may be set up in solid or liquid culture. ^‡Treatment failure is normally defined as persistently positive sputum cultures until the end of TB therapy. ^§Relapse is normally defined as cure (negative sputum culture) at the end of TB therapy, but reversion to positive cultures with the same Mtb strain as the baseline isolate during post-treatment follow-up. E: Ethambutol; H: Isoniazid; MIC: Minimum inhibitory concentration; Mtb: Mycobacterium tuberculosis; PTB: Pulmonary tuberculosis; R: Rifampicin; SCC: Sputum culture conversion; Z: Pyrazinamide.

Figure 2.. WHO-approved MDR-TB treatment regimens. MDR-TB regimens combine second-line drugs from the panel on the left.

*Streptomycin may substitute for other injectable agents in specific scenarios. ^‡Thioacetazone must not be used in HIV co-infection. ^§This template should be adapted to the antimicrobial resistance profile of the infecting Mtb isolate. If a regimen containing 5 drugs which are likely to be effective cannot be constructed additional group D1-3 agents should be added. ^¶Most patients will require a second-line injectable agent for 8 months and total treatment for 20 months but there is scope for modification according to patient response. ^#The 9-12 regimen may only be used when resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered unlikely. **Patients who do not adequately respond to therapy (e.g., sputum smear conversion by 4 months) may have the intensive phase of therapy extended.