The effect of diabetes mellitus on the pharmacokinetics and pharmacodynamics of tuberculosis treatment

Background

Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c (HbA1c) values on the pharmacokinetics and pharmacodynamics of anti-TB drugs remains poorly-characterized.

Methods

Newly-diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (pre-dose, 0.5, 2, 6 hours post-dose) during intensive and continuation phases of treatment. The effect of DM and HbA1c on the maximum concentration (Cmax) of rifampin, isoniazid, and pyrazinamide and the association between drug concentrations and microbiologic and clinical outcomes were assessed.

Results

Of 243 patients, 101 had DM. Univariate analysis showed significant reductions in Cmax of pyrazinamide and isoniazid (but not rifampicin) with DM or increasing HbA1c. After adjusting for age, sex, and weight, DM was associated only with reduced pyrazinamide concentrations [adjusted GMR: 0.74, p=.032]. In adjusted Cox models, female gender (aHR=1.75, p=0.001), lower Xpert smear grade (aHR=1.40, p<0.001) and pyrazinamide Cmax (aHR=0.99, p=0.006) were independent predictors of sputum culture conversion to negative. Higher isoniazid or rifampicin concentrations were associated with faster time to culture conversion in patients with DM only. Pyrazinamide Cmax above the therapeutic target was associated with higher unfavorable outcomes (treatment failure, relapse, death) [OR: 1.92, p=.041].

Conclusion

DM and higher HbA1c increased the risk of not achieving therapeutic targets for pyrazinamide (but not rifampicin or isoniazid). Higher pyrazinamide concentrations, though, were associated with worse microbiologic and clinical outcomes. DM status also appeared to influence PK-PD relationships for isoniazid and rifampicin.