Effect of Diabetes Mellitus on the Pharmacokinetics and Pharmacodynamics of Tuberculosis Treatment

Abstract

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 (PK) and pharmacodynamics (PD) of anti-TB drugs remains poorly characterized. Newly diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (predose and 0.5, 2, and 6 h postdose) during the intensive and continuation phases of treatment. The effect of DM and HbA1c values on the maximum concentration (C_max) of rifampin, isoniazid, and pyrazinamide and the association between drug concentrations and microbiologic and clinical outcomes were assessed. Of 243 patients, 101 had DM. Univariate analysis showed significant reductions in the C_max of pyrazinamide and isoniazid (but not rifampin) with DM or increasing HbA1c values. After adjusting for age, sex, and weight, DM was associated only with reduced pyrazinamide concentrations (adjusted geometric mean ratio = 0.74, P = 0.03). In adjusted Cox models, female gender (adjusted hazards ratio [aHR] = 1.75, P = 0.001), a lower smear grade with the Xpert assay (aHR = 1.40, P < 0.001), and the pyrazinamide C_max (aHR = 0.99, P = 0.006) were independent predictors of sputum culture conversion to negative. Higher isoniazid or rifampin concentrations were associated with a faster time to culture conversion in patients with DM only. A pyrazinamide C_max above the therapeutic target was associated with higher unfavorable outcomes (treatment failure, relapse, death) (odds ratio = 1.92, P = 0.04). DM and higher HbA1c values increased the risk of not achieving therapeutic targets for pyrazinamide (but not rifampin 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 rifampin.

Keywords: diabetes mellitus; pharmacodynamics; pharmacokinetics; tuberculosis.

FIG 1

Proportion of patients with and without diabetes mellitus who achieved the therapeutic target concentrations of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA).

FIG 2

Maximum concentration (C_max; indicated on the x axis [in micrograms per milliliter]) of pyrazinamide (PZA) (A), isoniazid (INH) (B), and rifampin (RMP) (C) by HbA1c value in the intensive phase.