Isoniazid, Rifampin, and Pyrazinamide Plasma Concentrations in Relation to Treatment Response in Indonesian Pulmonary Tuberculosis Patients

Abstract

f Numerous studies have reported low concentrations of antituberculosis drugs in tuberculosis (TB) patients, but few studies have examined whether low drug concentrations affect TB treatment response. We examined steady-state plasma concentrations of isoniazid, rifampin, and pyrazinamide at 2 h after the administration of drugs (C 2 h ) among 181 patients with pulmonary tuberculosis in Indonesia and related these to bacteriological response during treatment. C 2 h values below reference values for either isoniazid, rifampin, or pyrazinamide were found in 91% of patients; 60% had at least two low C 2 h concentrations. The isoniazid C 2 h was noticeably lower in fast versus slow acetylators (0.9 mg/liter versus 2.2 mg/liter, P < 0.001). At the end of treatment, 82% of the patients were cured, whereas 30 patients (17%) had dropped out during the study, and 2 patients (1%) failed treatment. No association was found between C 2 h concentrations and sputum culture results at 8 weeks of treatment. Post hoc analysis showed that patients with low pyrazinamide C 2 h (P ‫؍‬ 0.01) and patients with large extensive lung lesions (P ‫؍‬ 0.01) were at risk of at least one positive culture at week 4, 8, or 24/32. Antituberculosis drug concentrations were often low, but treatment response was nevertheless good. No association was found between drug concentrations and 8 weeks culture conversion, but low pyrazinamide drug concentrations may be associated with a less favorable bacteriological response. The use of higher doses of pyrazinamide may warrant further investigation. G enerally, first-line treatment of drug-susceptible tuberculosis (TB) is highly effective. However, a number of patients do not respond adequately to treatment, develop drug resistance or experience a relapse of TB after completion of treatment. Inadequate exposure to anti-TB drugs may constitute one of the factors underlying suboptimal treatment response (1, 2). Among adults, low plasma concentrations of anti-TB drugs have been found in patients with HIV infection, gastrointestinal tract disorders, high body weight, male gender, or diabetes mellitus (DM) (3-11) and in fast acetylators for isoniazid (12). Low plasma concentrations can also result from interindividual variability in drug absorption, metabolism, or excretion (3, 13). Some studies have reported associations between low concentrations of anti-TB drugs and poor treatment response (1-3, 14), although this was not found in other studies (7,15). In a recent study performed in a preclinical model, pharmacokinetic variability appeared to be more important in the emergence of multidrug-resistant tuberculosis (MDR-TB) than nonadherence (16). Furthermore, a systematic review showed that pharmacokinetic variability to isoniazid in multi-drug TB regimens is significantly associated with therapy failure and acquired drug resistance (17).Nevertheless, the number of studies examining the relation between plasma concentrations of anti-TB drugs and treatment response remains limited and the majority of them inves...

Population Pharmacokinetics of Pyrazinamide in Patients with Tuberculosis

“…In the study by Zhu et al, the average C max and AUC values were 38 g/ml and 373 g · h/ml, respectively, whereas they were 30.8 g/ml and 307 g · h/ml, respectively, in our study, despite the use of similar doses on a milligram-per-kilogram basis (15). Previous clinical studies have shown that a C max of Ͻ35 g/ml or an AUC of Ͻ363 mg · h/ml is associated with treatment failure (10,12,18). However, it is important to note that antimicrobial activity is not linked to the drug concentration alone but is linked to a combination of the drug concentration and the susceptibility of the infecting strain to the antibiotic of interest (the MIC).…”

Suboptimal Exposure to Anti‐TB Drugs in a TBM/HIV+ Population Is Not Related to Antiretroviral Therapy

“…Low systemic exposure levels to RIF have been recently shown to have a direct correlation with mortality rates in TBM patients with high exposure levels (600mg IV) being associated with significantly lower mortality than low exposure levels (450mg orally) 21 . A recent study has investigated, in children with TBM, the CSF exposure to anti-tubercular drugs and found that at a dose of 10mg/kg, rifampicin levels are lower than the minimum inhibitory concentration of susceptible bacteria 32 .…”

“…The data generated suggest that a a 900mg oral dose would be more appropriate in this patient cohort based on the assumptions of the model (Figure 4, B). Increasing RIF dose in fact significantly improves survival rates among TBM patients according to the latest clinical studies where it has been shown that a high dose of 600mg RIF administered intravenously to TBM patients significantly improved the clinical outcome for these patients 21 . Additionally, according to literature data 31 , the systemic exposure that would be anticipated to be achieved in the current cohort with a higher 900mg dose is predictive of CSF exposures that exceed the required TB MIC value of RIF in the CSF.…”

Factors Influencing Tuberculosis Treatment Outcome in Adult Patients Treated with Thrice-Weekly Regimens in India

“…This review failed to draw a firm association between serum drug concentrations and treatment outcome. A study from Indonesia showed that though low RMP, INH, and PZA concentrations occurred in many patients even with the DOT strategy, most patients had a good treatment outcome (30). Narita and colleagues did not find an association between TB recurrence and the serum levels of anti-TB drugs (31).…”