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Fixed-dose combination (FDC) formulations for the treatment of tuberculosis are now being recommended by the World Health Organization and used worldwide for reducing the risk of emerging drug resistance. China also plans that the FDC coverage will be achieved 100% in 2015 in every county in the country. However, the quality of FDCs with respect to variable bioavailability is a major issue. This study was conducted in healthy Chinese subjects to compare the bioavailability of rifampicin, isoniazid, ethambutol, and pyrazinamide from a 4-drug FDC formulation versus that of the separate formulations. The study was designed as randomized, single-dose, 2-treatment, 2-period crossover trial with a washout period of 1 week. Blood samples were collected at 0 (baseline), 10, 20, and 40 minutes and at 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose. Plasma concentrations of the 4 drugs were measured by using a rapid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated by using noncompartmental methods. Bioequivalence was determined if the 90% CIs of the log-transformed test/reference ratios AUC0–24, AUC0–∞, and Cmax were within the predetermined range of 80% to 125%. Tolerability was assessed by using clinical parameters and subject reports. A total of 18 male subjects (mean [SD] age, 36.4 [10.6] years) were enrolled and completed the study. In the case of rifampicin, the 90% CIs for the log-transformed ratios of Cmax, AUC0–24, and AUC0–∞ were 81.8 to 100.9, 89.5 to 100.2, and 87.1 to 98.0, respectively. For ethambutol, these values were 84.7 to 105.7, 93.5 to 105.1, and 92.1 to 105.4. For pyrazinamide, these values were 83.3 to 93.9, 95.8 to 101.4, and 97.0 to 104.1. For isoniazid, the 90% CIs for the log-transformed ratios of AUC0–24, and AUC0∞ were 83.5 to 94.6 and 83.4 to 94.4. However, the point estimates for Cmax (62.2–86.7) were outside the limit for bioequivalence. No adverse events were observed during the study. The findings from this single-dose study in healthy Chinese male volunteers suggest that the combined formulation was bioequivalent to separate formulations of rifampicin, ethambutol, and pyrazinamide at the same dose levels. However, isoniazid was not bioequivalent based on Cmax values. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451.

ObjectiveTo assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM).DesignProspective observational pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis.SettingHasan Sadikin Hospital, Bandung, Indonesia.PatientsIndividuals aged 0–18 years clinically diagnosed with TBM and receiving first-line anti-tuberculosis drug dosages according to revised WHO-recommended treatment guidelines.InterventionsPlasma and cerebrospinal fluid (CSF) concentrations of isoniazid, rifampicin and pyrazinamide were assessed on days 2 and 10 of treatment.Main outcome measuresPlasma exposures during the daily dosing interval (AUC0–24), peak plasma concentrations (C max) and CSF concentrations.ResultsAmong 20 eligible patients, geometric mean AUC0–24 of isoniazid, rifampicin and pyrazinamide was 18.5, 66.9 and 315.5 hour∙mg/L on day 2; and 14.5, 71.8 and 328.4 hour∙mg/L on day 10, respectively. Large interindividual variabilities were observed in AUC0–24 and C max of all drugs. All patients had suboptimal rifampicin AUC0–24 for TBM treatment indication and very low rifampicin CSF concentrations. Four patients developed grade 2–3 drug-induced liver injury (DILI) within the first 4 weeks of treatment, in whom anti-tuberculosis drugs were temporarily stopped, and no DILI recurred after reintroduction of rifampicin and isoniazid. AUC0–24 of isoniazid, rifampicin and pyrazinamide along with C max of isoniazid and pyrazinamide on day 10 were higher in patients who developed DILI than those without DILI (p<0.05).ConclusionHigher rifampicin doses are strongly warranted in treatment of children and adolescents with TBM. The association between higher plasma concentrations of isoniazid, rifampicin and pyrazinamide and the development of DILI needs confirmatory studies.

Background. Based on a hollow-fiber system model of tuberculosis, we hypothesize that microbiologic failure and acquired drug resistance are primarily driven by low drug concentrations that result from pharmacokinetic variability. Methods. Clinical and pharmacokinetic data were prospectively collected from 142 tuberculosis patients in Western Cape, South Africa. Compartmental pharmacokinetic parameters of isoniazid, rifampin, and pyrazinamide were identified for each patient. Patients were then followed for up to 2 years. Classification and regression tree analysis was used to identify and rank clinical predictors of poor long-term outcome such as microbiologic failure or death, or relapse. Results. Drug concentrations and pharmacokinetics varied widely between patients. Poor long-term outcomes were encountered in 35 (25%) patients. The 3 top predictors of poor long-term outcome, by rank of importance, were a pyrazinamide 24-hour area under the concentration-time curve (AUC) ≦363 mg-h/L, rifampin AUC ≦13 mg-h/L, and isoniazid AUC ≦52 mg-h/L. Poor outcomes were encountered in 32/78 patients with the AUC of at least 1 drug below the identified threshold vs 3/64 without (odds ratio = 14.14; 95% confidence interval, 4.08-49.08). Low rifampin and isoniazid peak and AUC concentrations preceded all cases of acquired drug resistance. Conclusions. Low drug AUCs are predictive of clinical outcomes in tuberculosis patients.

Introduction Tuberculosis (TB) remains one of the world’s deadliest communicable diseases. Although cure rates of the standard four-drug (rifampicin, isoniazid, pyrazinamide, ethambutol) treatment schedule can be as high as 95–98 % under clinical trial conditions, success rates may be much lower in less well resourced countries. Unsuccessful treatment with these first-line anti-TB drugs may lead to the development of multidrug resistant and extensively drug resistant TB. The intrinsic interindividual variability in the pharmacokinetics (PK) of the first-line anti-TB drugs is further exacerbated by co-morbidities such as HIV infection and diabetes. Methods Therapeutic drug monitoring has been proposed in an attempt to optimize treatment outcome and reduce the development of drug resistance. Several studies have shown that maximum plasma concentrations ( C max ), especially of rifampicin and isoniazid, are well below the proposed target C max concentrations in a substantial fraction of patients being treated with the standard four-drug treatment schedule, even though treatment’s success rate in these studies was typically at least 85 %. Discussion The proposed target C max concentrations are based on the concentrations of these agents achieved in healthy volunteers and patients receiving the standard doses. Estimation of C max based on one or two sampling times may not have the necessary accuracy since absorption rate, especially for rifampicin, may be highly variable. In addition, minimum inhibitory concentration (MIC) variability should be taken into account to set clinically meaningful susceptibility breakpoints. Clearly, there is a need to better define the key target PK and pharmacodynamic (PD) parameters for therapeutic drug monitoring (TDM) of the first-line anti-TB drugs to be efficacious, C max (or area under the curve (AUC)) and C max /MIC (or AUC/MIC). Conclusion Although TDM of first-line anti-TB drugs has been successfully used in a limited number of specialized centers to improve treatment outcome in slow responders, a better characterization of the target PK and/or PK/PD parameters is in our opinion necessary to make it cost-effective.

Background. There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion. Methods. One hundred patients with pulmonary tuberculosis (65% human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7–8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5–6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC (%TMIC). Results. Twenty-six percent of patients had Cmax of rifampicin <8 mg/L, pyrazinamide <35 mg/L, and isoniazid <3 mg/L. No relationship was found between PK exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversation. If isoniazid Cmax was <4.6 mg/L and rifampicin Cmax/MIC <28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax>4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversions. Conclusions. PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.

Background The 24-h area under the concentration–time curve (AUC 24 )/minimal inhibitory concentration ratio is the best predictive pharmacokinetic/pharmacodynamic (PK/PD) parameter of the efficacy of first-line anti-tuberculosis (TB) drugs. An optimal sampling strategy (OSS) is useful for accurately estimating AUC 24 ; however, OSS has not been developed in the fed state or in the early phase of treatment for first-line anti-TB drugs. Methods An OSS for the prediction of AUC 24 of isoniazid, rifampicin, ethambutol and pyrazinamide was developed for TB patients starting treatment. A prospective, randomized, crossover trial was performed during the first 3 days of treatment in which first-line anti-TB drugs were administered either intravenously or in fasting or fed conditions. The PK data were used to develop OSS with best subset selection multiple linear regression. The OSS was internally validated using a jackknife analysis and externally validated with other patients from different ethnicities and in a steady state of treatment. Results OSS using time points of 2, 4 and 8 h post-dose performed best. Bias was < 5% and imprecision was < 15% for all drugs except ethambutol in the fed condition. External validation showed that OSS 2-4-8 cannot be used for rifampicin in steady state conditions. Conclusion OSS at 2, 4 and 8 h post-dose enabled an accurate and precise prediction of AUC 24 values of first-line anti-TB drugs in this population. Trial Registration ClinicalTrials.gov (NCT02121314).

Purpose The aim of the study was to compare plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) between tuberculosis (TB) patients with and without diabetes mellitus (DM). Methods Two-hour post-dosing concentrations of RMP, INH and PZA were determined in adult TB patients that were studied with ( n  = 452) and without DM ( n  = 1460), treated with a thrice-weekly regimen in India. Drug concentrations were estimated by HPLC. Results The median (IQR) INH [6.6 (3.9–10.0) and 7.8 (4.6–11.3)] and PZA [31.0 (22.3–38.0) and 34.1 (24.6–42.7)] microgram per milliliter concentrations were significantly lower in diabetic than non-diabetic TB patients ( p  < 0.001 for both drugs). Blood glucose was negatively correlated with plasma INH ( r  = −0.09, p  < 0.001) and PZA ( r  = −0.092, p  < 0.001). Multiple linear regression analysis showed RMP, INH and PZA concentrations were influenced by age and drug doses, INH and PZA by DM, RMP by alcohol use and PZA by gender and category of ATT. DM reduced INH and PZA concentrations by 0.8 and 3.0 μg/ml, respectively. Conclusions TB patients with DM had lower INH and PZA concentrations. Negative correlation between blood glucose and drug concentrations suggests delayed absorption/faster elimination of INH and PZA in the presence of elevated glucose.

ABSTRACT Adverse reactions to antituberculosis drugs can lead to treatment abandonment, prolonging the burden of the disease. The role of sex in pyrazinamide exposure and uric acid metabolism raises questions about its influence on the rates of arthralgia and hyperuricemia in patients with tuberculosis. Given the limited evidence in the literature regarding sex-related differences in adverse reaction rates, this study compares serum levels of pyrazinamide and uric acid, as well as the rates of hyperuricemia and arthralgia, between male and female patients with pulmonary tuberculosis. Uric acid levels were measured using the spectrophotometric uricase method, and serum pyrazinamide levels were determined by high-performance liquid chromatography. A total of 88 patients were enrolled in the study. The mean weight, pyrazinamide dosage, and median uric acid levels were similar between sexes. However, the proportion of males with hyperuricemia was higher than that of females. Pyrazinamide maximum concentrations ranged from 10 to 98 µg/mL and were higher in females than in males. The overall rate of arthralgia was 25%, occurring primarily in male patients with hyperuricemia. Serum pyrazinamide levels were higher in patients with arthralgia compared to those without it. No significant correlations were found between drug levels and uric acid in either sex. In conclusion, sex influences pyrazinamide exposure and arthralgia and hyperuricemia rates. Close monitoring of uric acid levels may help improve adherence to tuberculosis therapy.

ObjectivesTo evaluate pharmacokinetics of first-line antitubercular drugs, isoniazid (INH) and pyrazinamide (PZA), with revised WHO dosages and to assess its adequacy in relation to age and nutritional status.DesignObservational study.SettingThis study was conducted at Sarojini Naidu Medical College, Agra, and National Institute for Research in Tuberculosis, Chennai.Patients40 subjects diagnosed with tuberculosis were registered in the study and started on daily first-line antitubercular regimen based on the revised WHO guidelines.InterventionsBlood samples were collected at 0, 2, 4, 6 and 8 hours from these subjects after 15 days of treatment for drug estimations.Main outcome measureThe measurement of drug concentrations (maximum peak concentration (Cmax) and area under the time –concentration curve (AUC0–8 hours)) for INH and PZA. Appropriate statistical methods were used to evaluate the impact of age and nutritional status on pharmacokinetic variables.ResultsFor INH, the difference in drug exposures in children <3 years (Cmax 3.18 µg/mL and AUC0–8 hours15.76 µg/mL hour) and children >3 years (Cmax3.05 µg/mL and AUC0–8 hours 14.37 µg/mL hour) was not significant (P=0.94, P=0.81, respectively). The drug levels in children with low body mass index (BMI) (Cmax3.08 µg/mL; AUC0–8 hours14.81 µg/mL hour) were also comparable with their normal counterparts (Cmax3.09 µg/mL, P=0.99; AUC0–8 hours 14.69 µg/mL hour, P=0.82). PZA drug exposures obtained in children less than 3 years (Cmax29.22 µg/mL, AUC0–8 hours 155.45 µg/mL hour) were significantly lower compared with drug levels in children above 3 years (Cmax 37.12 µg/mL, P=0.03; AUC 202.63 µg/mL hour, P value=0.01). Children with low BMI had significantly lower drug concentrations (Cmax 31.90 µg/mL, AUC0–8 hours167.64 µg/mL hour) when compared with normal counterparts (Cmax 37.60 µg/mL, P=0.02; AUC0–8 hours 208.77 µg/mL hour, P=0.01).ConclusionsThe revised WHO drug dosages were found to be adequate for INH with respect to age and nutritional status, whereas PZA showed significantly lower drug levels in children <3 years and in malnourished children.