Pharmacokinetics of thrice-weekly rifampicin, isoniazid and pyrazinamide in adult tuberculosis patients in India

Kumar, Ashish; Thiruvengadam, Kannan; Chandrasekaran, Venkatesh; Sudha, Vasudevan; Vijayakumar, A; Ramesh, K; Jayabal, Lavanya; Swaminathan, Soumya; Ramachandran, Geetha

doi:10.5588/ijtld.16.0048

Cited by 31 publications

(43 citation statements)

References 16 publications

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“…In contrast to adults, data on isoniazid elimination clearance in children are scarce. The median simulated AUC 0–8 obtained in this study was 25.53 [interquartile range (IQR) 18.22–31.76], which is much lower compared to the median AUC 0–8 of 41.1 (IQR 33.0–59.9) obtained in an adult population in a study from India . One of the limitations of the present study is that the acetylator status of the children is not known.…”

Section: Discussioncontrasting

confidence: 79%

Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India

Aruldhas

Hoglund

Ranjalkar

et al. 2019

Brit J Clinical Pharma

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Aims Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens. Methods Data were collected from 41 children, aged 2–16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed‐effects model. Results Isoniazid pharmacokinetics were described by a one‐compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one‐compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed‐dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed‐dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg–1, was found to provide adequate drug exposure in most children. Conclusions The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose–effect relationship of higher doses of rifampicin.

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Section: Discussioncontrasting

confidence: 79%

Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India

Aruldhas

Hoglund

Ranjalkar

et al. 2019

Brit J Clinical Pharma

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“…This effect was not mitigated after adjusting for other factors. These results are in keeping with the results from other studies that reported lower pyrazinamide and isoniazid C max concentrations in DM patients in the intensive phase, even after adjusting for possible confounders (23,25).…”

Section: Discussionsupporting

confidence: 92%

“…A few studies have evaluated the effect of DM on the pharmacokinetics (PK) of antituberculosis drugs, and the results have been mixed, with some reporting lower anti-TB drug concentrations in people with DM (17)(18)(19)(20) and others showing no effect of DM on first-line drug exposures (21)(22)(23). In the context of a large prospective cohort study involving patients with and without DM in India, we evaluated the effects of DM (and the HbA1c value) on first-line anti-TB drug pharmacokinetics.…”

mentioning

confidence: 99%

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

Alfarisi

Mave

Gaikwad

et al. 2018

Antimicrob Agents Chemother

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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 ( ) 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 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, = 0.03). In adjusted Cox models, female gender (adjusted hazards ratio [aHR] = 1.75, = 0.001), a lower smear grade with the Xpert assay (aHR = 1.40, < 0.001), and the pyrazinamide (aHR = 0.99, = 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 above the therapeutic target was associated with higher unfavorable outcomes (treatment failure, relapse, death) (odds ratio = 1.92, = 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.

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“…Since this study was undertaken in programmatic settings, we chose to estimate the drug concentrations at 2 h postdosing, which is predictive of the pharmacokinetic parameters obtained from intensive sampling (12). We have shown that the RMP, INH, and PZA concentrations at 2 h postdosing correlate with the peak concentrations and are often used as a surrogate for peak concentrations, though this sample does not account for slow drug absorption (13).…”

Section: Discussionmentioning

confidence: 99%

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

Ramachandran

Kupparam

Chandrasekaran

et al. 2017

Antimicrob Agents Chemother

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The Indian Revised National Tuberculosis (TB) Control Programme uses thrice-weekly treatment with standard drug dosages. The role of plasma drug levels and other factors in determining TB treatment outcomes is not well understood. We aimed to determine the factors influencing the concentrations of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) at 2 h postdosing in adult TB patients and to study the factors impacting TB treatment outcome. We recruited 1,912 adult TB patients (newly treated and retreated patients) with pulmonary/extrapulmonary TB receiving antitubercular treatment (ATT) in the RNTCP in Chennai, India. At steady state, the concentrations of RMP, INH, and PZA were determined at 2 h postdosing after supervised drug administration. A total of 1,648 patients had a favorable outcome, while 264 (14%) had an unfavorable outcome. A total of 91%, 16%, and 17% of the patients had suboptimal concentrations of RMP (Ͻ8 g/ml), INH (Ͻ3 g/ml), and PZA (Ͻ20 g/ml), respectively. Factors associated with treatment outcome were low RMP concentrations (adjusted odds ratio [aOR], 0.94; 95% confidence interval [CI], 0.89 to 0.99; P ϭ 0.036), category II ATT (aOR, 2.39; 95% CI, 1.56 to 3.65; P Ͻ 0.001), low body weight (aOR, 0.96; 95% CI, 0.94 to 0.98; P Ͻ 0.001), alcohol use (aOR, 2.17; 95% CI, 1.42 to 3.31; P Ͻ 0.001), male gender (aOR, 1.92; 95% CI, 1.02 to 3.62; P ϭ 0.043), and baseline INH resistance (aOR, 5.74; 95% CI, 3.12 to 10.59; P Ͻ 0.001), which significantly increased the likelihood of an unfavorable outcome in multivariate logistic regression analysis. Further studies are needed to optimize anti-TB drug dosages and improve cure rates. Drug susceptibility testing at the baseline and attention to undernutrition and alcohol dependence are other important interventions.

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Pharmacokinetics of thrice-weekly rifampicin, isoniazid and pyrazinamide in adult tuberculosis patients in India

Abstract: Several risk factors for drug concentration variations were identified. Two-hour post-dosing drug concentrations mimicked Cmax. A high proportion of TB patients had RMP Cmax below the expected range, which is a matter of concern.

Cited by 31 publications

References 16 publications

Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India

Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India

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

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

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