Abstract
Poor response to tuberculosis (TB) therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic (PK) parameters can be affected by several factors, such as comorbidities or the interaction of TB drugs with food. This study aimed to determine the PK of isoniazid (INH) in a Peruvian TB population under observed daily and twice-weekly (i.e., biweekly) therapy. Isoniazid levels were analyzed at 2 and 6 h after drug intake using liquid chromatography mass spectrometric methods. A total of 107 recruited patients had available PK data; of these 107 patients, 42.1% received biweekly isoniazid. The mean biweekly dose (12.8 mg/kg of body weight/day) was significantly lower than the nominal dose of 15 mg/kg/day (P < 0.001), and this effect was particularly marked in patients with concurrent diabetes and in males. The median maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 6 h (AUC0–6) were 2.77 mg/liter and 9.71 mg·h/liter, respectively, for daily administration and 8.74 mg/liter and 37.8 mg·h/liter, respectively, for biweekly administration. There were no differences in the Cmax with respect to gender, diabetes mellitus (DM) status, or HIV status. Food was weakly associated with lower levels of isoniazid during the continuation phase. Overall, 34% of patients during the intensive phase and 33.3% during the continuation phase did not reach the Cmax reference value. However, low levels of INH were not associated with poorer clinical outcomes. In our population, INH exposure was affected by weight-adjusted dose and by food, but comorbidities did not indicate any effect on PK. We were unable to demonstrate a clear relationship between the Cmax and treatment outcome in this data set. Twice-weekly weight-adjusted dosing of INH appears to be quite robust with respect to important potentially influential patient factors under program conditions.
Highlights
Poor response to tuberculosis (TB) therapy might be attributable to subtherapeutic levels in drug-compliant patients
Debate continues about the impact of antituberculosis drug pharmacokinetics (PK) on clinical outcomes [11,12,13,14,15]
The mean biweekly dose received on the treatment days was 12.8 mg/kg/day, which was significantly lower than the recommended dose of 15 mg/kg/day (P Ͻ 0.001); and 89% of the patients received doses lower than the nominal dosage
Summary
Poor response to tuberculosis (TB) therapy might be attributable to subtherapeutic levels in drug-compliant patients. Experimental and clinical studies have pointed to the influence of interpatient variability in key PK parameters, such as plasma area under the curve (AUC), on important outcomes, including treatment success and the emergence of resistance [16,17,18,19]. These PK parameters may be affected by several factors, including age, gender, ethnicity, genetics, nutritional status, drug formulation and quality, and drug-drug interactions [20]. The maximum serum drug concentration (Cmax) of INH generally occurs between 1 and 2 h after drug intake, food, high-fat meals, may delay and reduce overall absorption
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