Plasma Concentrations Of Rifampicin Research Articles

Variability in plasma rifampicin concentrations and role of SLCO1B1, ABCB1, AADAC2 and CES2 genotypes in Ethiopian patients with tuberculosis

Background Rifampicin, a key drug against tuberculosis (TB), displays wide between-patient pharmacokinetics variability and concentration-dependent antimicrobial effect. We investigated variability in plasma rifampicin concentrations and the role of SLCO1B1, ABCB1, arylacetamide deacetylase (AADAC) and carboxylesterase 2 (CES-2) genotypes in Ethiopian patients with TB. Methods We enrolled adult patients with newly diagnosed TB (n = 119) who had received 2 weeks of rifampicin-based anti-TB therapy. Venous blood samples were obtained at three time points post-dose. Genotypes for SLCO1B1 (c.388A > G, c.521T > C), ABCB1 (c.3435C > T, c.4036A > G), AADACc.841G > A and CES-2 (c.269-965A > G) were determined. Rifampicin plasma concentration was quantified using LC-MS/MS. Predictors of rifampicin C max and AUC0–7 h were analysed. Results The median rifampicin C max and AUC0–7 were 6.76 µg/mL (IQR 5.37–8.48) and 17.05 µg·h/mL (IQR 13.87–22.26), respectively. Only 30.3% of patients achieved the therapeutic efficacy threshold (C max>8 µg/mL). The allele frequency for SLCO1B1*1B (c.388A > G), SLCO1B1*5 (c.521T > C), ABCB1 c.3435C > T, ABCB1c.4036A > G, AADAC c.841G > A and CES-2 c.269-965A > G were 2.2%, 20.2%, 24.4%, 14.6%, 86.1% and 30.6%, respectively. Sex, rifampicin dose and ABCB1c.4036A > G, genotypes were significant predictors of rifampicin C max and AUC0–7. AADACc.841G > A genotypes were significant predictors of rifampicin C max. There was no significant influence of SLCO1B1 (c.388A > G, c.521T > C), ABCB1c.3435C > T and CES-2 c.269-965A > G on rifampicin plasma exposure variability. Conclusions Subtherapeutic rifampicin plasma concentrations occurred in two-thirds of Ethiopian TB patients. Rifampicin exposure varied with sex, dose and genotypes. AADACc.841G/G and ABCB1c.4036A/A genotypes and male patients are at higher risk of lower rifampicin plasma exposure. The impact on TB treatment outcomes and whether high-dose rifampicin is required to improve therapeutic efficacy requires further investigation.

Effect of Metformin on Plasma Exposure of Rifampicin, Isoniazid, and Pyrazinamide in Patients on Treatment for Pulmonary Tuberculosis.

To evaluate the effect of metformin on the plasma levels of rifampicin, isoniazid, and pyrazinamide in patients with drug-sensitive pulmonary tuberculosis being treated with first-line antituberculosis treatment (ATT) and to assess the influence of gene polymorphisms on the metabolic pathway of metformin and plasma levels of antitubercular drugs. Nondiabetic adults aged 18-60 years with pulmonary tuberculosis were randomized to either the standard ATT (ATT group) or ATT plus metformin (METRIF group) groups in a phase IIB clinical trial. An intensive pharmacokinetic study with blood collection at 0 hour (predosing), followed by 1, 2, 4, 6, 8, and 12 hours after dosing was conducted during the first month of treatment in a subset of 60 study participants after a minimum of 14 doses. Plasma concentrations of rifampicin, isoniazid, pyrazinamide, and metformin were measured by high-performance liquid chromatography using validated methods, and pharmacokinetic parameters and OCT1 and MATE1 gene polymorphisms were compared between the groups. Significant increases in the clearance of rifampicin, isoniazid, and pyrazinamide were observed in patients in the METRIF group (n = 29) compared with those in the ATT group (n = 31). The AA genotypes of the single-nucleotide polymorphism of rs2289669 ( MATE1 ) in the METRIF group showed a significantly decreased area under the concentration-time curve to the last observation point and increased clearance of rifampicin. Metformin altered rifampicin and isoniazid plasma concentrations in patients receiving antituberculosis treatment for pulmonary tuberculosis with little effect on sputum conversion at the end of treatment. Studies with larger sample sizes are needed to understand host drug-drug interactions.

1449. Therapeutic Drug Monitoring of Isoniazid and Rifampicin and Clinical Outcomes in Adults with Tuberculosis.

Abstract Background Directly Observed Treatment Short Course for Tuberculosis (TB) (DOTS) treatment currently produces a cure rate of 80%. Rifampicin (RMP) and isoniazid (INH) are the main bactericides; both show wide inter-individual pharmacokinetics and narrow therapeutic range. Therapeutic drug monitoring (TDM) of antiTB drugs is a strategy to improve the response to treatment. The aim of this work was to optimize and individualize antiTB treatment based on plasma concentrations of RMP and INH, NAT2 genotyping and the Bayesian estimation of PK parameters. Methods A prospective and analytical study including TB patients under DOTS scheme was performed. Venous blood samples were drawn 2 and 4 hours after last dose; INH and RMP were quantified by liquid chromatography coupled to tandem mass spectrometry. Anthropometric and clinical information was retrieved from medical records. Acetylator phenotype was determined based on NAT2 genotyping by real-time PCR. Bayesian estimation of the PK parameters was performed using NONMEM and dosing scheme was proposed to achieve therapeutic concentrations of RIF and INH. Results A total 62 patients were included from 18 to 80 years and 35 to 117 kg of total body weight. The most frequent was pulmonary infection (40%), 25% of patients had type 2 diabetes mellitus and 58.5% were slow acetylators for the NAT2 gene. Lower INH and RMP plasma concentrations were related to adverse clinical outcome, compared to those patients classified with early clinical success [1.9 vs 3.7 mg/L and 16.9 vs 10.0 mg/L (p< 0.05)]. Results indicate the need to adjust anti-TB drugs dose to more than 50% of the patients who show plasma concentrations outside the range for both drugs. Bayesian dosing performed was validated after individualization by quantification and interpretation of INH and RMP plasma concentrations followed by a narrow medical follow up. Conclusion Even with standard anti-TB treatment, great proportion of patients show subtherapeutic concentrations of RMP and INH which is associated with overall therapeutic failure. TDM is a useful tool to individualize antimicrobials dose and improve clinical outcomes at early stages of active TB. Disclosures All Authors: No reported disclosures.

In vitro Dissolution Testing of Rifampicin Powder Formulations For Prediction of Plasma Concentration-Time Profiles After Inhaled Delivery.

The purpose of this study was to evaluate the in vitro lung dissolution of amorphous and crystalline powder formulations of rifampicin in polyethylene oxide (PEO) and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), and to predict the in vivo plasma concentration-time profiles using the in vitro data. The in vitro dissolution and permeation profiles of respirable rifampicin particles were studied using a custom-made dissolution apparatus. Data from the in vitro dissolution test were used to estimate the parameters to be used as the input for the simulation of in vivo plasma concentration-time profiles using STELLA® software. For prediction of in vivo profiles, a one-compartment model either with a first order elimination or with a Michaelis-Menten kinetics-based elimination was used. Compared to the crystalline formulation, the amorphous formulation showed rapid in vitro dissolution suggesting their possible faster in vivo absorption and higher plasma concentrations of rifampicin following lung delivery. However, the simulations suggested that both powder formulations would result in similar plasma-concentration time profiles of rifampicin. Use of an in vitro dissolution test coupled with a simulation model for prediction of plasma-concentration time profiles of an inhaled drug was demonstrated in this work. These models can also be used in the design of inhaled formulations by controlling their release and dissolution properties to achieve desired lung retention or systemic absorption following delivery to the lungs.

Real-life isoniazid and rifampicin plasma concentrations in children: a tool for therapeutic drug monitoring of tuberculosis

BackgroundLow plasma levels of first-line antitubercular drugs can be counted among the main causes of poor response to antitubercular therapy, and therapeutic drug monitoring has been proposed as a method to promote tailored treatments for both child and adult patients. The main aim of the study was to evaluate serum concentrations of isoniazid (INH) and rifampicin (RIF) and to investigate reasons for sub-therapeutic plasma concentrations in order to fix dosages.MethodsChildren with TB were prospectively enrolled from January to August 2019. Two venous blood samples were collected (the first at least 15 days after the beginning of antitubercular treatment, and the second between 1 and 8 weeks later). Plasma concentrations were determined by a validated high-performance liquid chromatography method.ResultsIn all, 45 children were included. Seventy blood samples for INH plasma concentration were collected between 120 and 240 min after drug intake. Adjusting for dose (mg/kg/day) and time of INH administration, when considering three different age groups (≤ 2 years, 2–12 years, > 12 years), a statistically significant lower INH plasma concentration was observed in younger children compared to the older age groups in the multivariate analysis (p < 0.001 and p < 0.001). A total of 68 blood samples were evaluated for RIF concentrations. Both for INH and RIF a statistically significant lower plasma concentration was also observed in adolescents (p < 0.001). Fifteen children (15/45, 33%) presented drug concentrations under the referral therapeutic range.ConclusionsBased on our findings, monitoring patients’ drug plasma concentrations in children under 2 years of age and in adolescents can make treatment more patient-tailored.

Plasma drug concentrations of 4-drug fixed-dose combination regimen and its efficacy for treatment of pulmonary tuberculosis under National Tuberculosis Elimination Programme: A prospective pilot study

BackgroundThe thrice weekly dosing regimen of DOTS has shown low rifampicin plasma concentrations as an independent risk factor for unfavourable tuberculosis (TB) outcome. With introduction of daily regimen using fixed dose combinations (FDC) under National Tuberculosis Elimination Programme (NTEP) the existence of suboptimal plasma levels of first-line antitubercular drugs and its clinical significance remain poorly understood. MethodWe included a prospective cohort of newly diagnosed pulmonary tuberculosis (PTB) patients receiving 4-FDC daily regimen under NTEP. Plasma concentration at 2 hours (C2h) of each drug was determined after two weeks of treatment using liquid chromatography (LCMS/MS) developed by us. TB card and laboratory reports were reviewed for baseline characteristics and clinical status at 2, 4 and 6 months after the initiation of treatment. At a 1 year follow-up, therapy failure was defined as death or a relapse of tuberculosis. ResultsAmong 40 PTB patients, the C2h post dose plasma concentrations of H, R and E were suboptimal in 25%, 60% and 10% respectively. The C2h of H, R, Z and E were respectively 4.2 ± 2.0, 7.3 ± 2.8, 39.2 ± 8.8 and 3.5 ± 1.2 μg/ml; 60% of the patients had suboptimal plasma concentrations and commonly it was observed with H and R. C2h were lower than expected for at least two drugs i.e. H and R in 25% (10/40) of the patients. Plasma concentration of isoniazid and rifampicin has always been considered important for microbiological response and treatment outcome and low concentrations has been associated with poor treatment response. These patients may require a two year follow up and critical evaluation for prevention of MDR-TB. However, all the TB patients were cured and none of them had recurrence within one year follow up. ConclusionsAll the pulmonary TB patients administering 4-FDC daily regimen under programmatic settings were cured despite the suboptimal levels of isoniaizd and rifampicin. All the patients achieved pyrazinamide plasma levels and probably this could be the reason behind favourable outcome. Further study is required on large sample size with various subset of population to understand the need of therapeutic drug monitoring.

A population approach of rifampicin pharmacogenetics and pharmacokinetics in Mexican patients with tuberculosis

The aim of this study was to develop a population pharmacokinetic model of rifampicin (RMP) in Mexican patients with tuberculosis (TB) to evaluate the influence of anthropometric and clinical covariates, as well as genotypic variants associated with MDR1 and OATP1B1 transporters.A prospective study approved by Research Ethics Committee was performed at Hospital Central in San Luis Potosí, Mexico. TB patients under DOTS scheme and who signed informed consent were consecutively included. Anthropometric and clinical information was retrieved from medical records. Single nucleotide polymorphisms in MDR1 (C3435T) and SLCO1B1 (A388G and T521C) genes were evaluated. RMP plasma concentrations and time data were assessed with NONMEM software.A total of 71 Mexican TB patients from 18 to 72 years old were included for RMP quantification from 0.3 to 12 h after dose; 329 and 97 plasma concentrations were available for model development and validation, respectively. Sequential process includes a typical lag time of 0.25 h prior to absorption start with a Ka of 1.24 h−1 and a zero-order absorption of 0.62 h to characterize the gradual increase in RMP plasma concentrations. Final model includes total body weight in volume of distribution (0.7 L/kg, CV = 26.8%) and a total clearance of 5.96 L/h (CV = 38.5%). Bioavailability was modified according to time under treatment and generic formulation administration.In conclusion, a population pharmacokinetic model was developed to describe the variability in RMP plasma concentrations in Mexican TB patients. Genetic variants evaluated did not showed significant influence on pharmacokinetic parameters. Final model will allow therapeutic drug monitoring at early stages.

Can diabetes mellitus modify the plasma concentrations of rifampicin in patients under treatment for tuberculosis?

Rifampicin is a key component of treatment for tuberculosis and its efficacy is determined by the blood levels attained after therapeutic doses. However, there is a high variability of rifampicin blood levels that is related to both the patient and the formulation used. To date, the effect of diabetes mellitus on the plasma levels of rifampicin was low exploited, which could be relevant either by the significant increase of the comorbidity worldwide as by the probable influence of diabetes on the rifampicin exposure. The study aims to evaluate whether diabetes mellitus contribute to the variation of the maximum concentration of rifampicin in patients with tuberculosis treated with a daily dose of 10mg/kg. Rifampicin and glycated hemoglobin were measured by high-performance liquid chromatography, and blood glucose by spectrophotometry. A total of 62 male patients were included in the study, and 26 presented diabetes mellitus. Rifampicin plasma levels in 2-h plasma samples collected at day 61 ranged from 3μg/mL to 14.2μg/mL. Drugs levels were similar between diabetic and non-diabetic patients and were not correlated with blood glucose and glycated hemoglobin. Moreover, a high percentage of patients in both groups presented low levels of rifampicin.

Individualised dosing algorithm and personalised treatment of high-dose rifampicin for tuberculosis.

To propose new exposure targets for Bayesian dose optimisation suited for high-dose rifampicin and to apply them using measured plasma concentrations coupled with a Bayesian forecasting algorithm allowing predictions of future doses, considering rifampicin's auto-induction, saturable pharmacokinetics and high interoccasion variability. Rifampicin exposure targets for Bayesian dose optimisation were defined based on literature data on safety and anti-mycobacterial activity in relation to rifampicin's pharmacokinetics i.e. highest plasma concentration up to 24hours and area under the plasma concentration-time curve up to 24hours (AUC0-24h ). Targets were suggested with and without considering minimum inhibitory concentration (MIC) information. Individual optimal doses were predicted for patients treated with rifampicin (10mg/kg) using the targets with Bayesian forecasting together with sparse measurements of rifampicin plasma concentrations and baseline rifampicin MIC. The suggested exposure target for Bayesian dose optimisation was a steady state AUC0-24h of 181-214h×mg/L. The observed MICs ranged from 0.016-0.125mg/L (mode: 0.064mg/L). The predicted optimal dose in patients using the suggested target ranged from 1200-3000mg (20-50mg/kg) with a mode of 1800mg (30mg/kg, n=24). The predicted optimal doses when taking MIC into account were highly dependent on the known technical variability of measured individual MIC and the dose was substantially lower compared to when using the AUC0-24h -only target. A new up-to-date exposure target for Bayesian dose optimisation suited for high-dose rifampicin was derived. Using measured plasma concentrations coupled with Bayesian forecasting allowed prediction of the future dose whilst accounting for the auto-induction, saturable pharmacokinetics and high between-occasion variability of rifampicin.

Concentrations of rifampicin in pre-dose samples in patients with pulmonary tuberculosis

Rifampicin is used in both phases of treatment for tuberculosis. In chronic use, the short half-life and the self-induction of metabolism can decrease the levels of the drug below the minimal inhibitory concentration. The aim of the study was to investigate whether plasma concentrations of rifampicin are sustained above 0.5μg/mL in patients with tuberculosis using 600mg/day. Rifampicin was measured in plasma by high-performance liquid chromatography and a sputum smear microscopy was performed in all days of the study. A total of 44 male patients completed the study. On days 31, 61 and 91, the mean plasma concentrations of rifampicin were 0.6 (0.5)μg/mL, 0.55 (0.5)μg/mL and 0.46 (0.4)μg/mL. There was a high variation of rifampicin levels leading to a high percentage of samples with concentrations below 0.5μg/mL. There was no significant association between the frequency of samples with drug levels below 0.5μg/mL with the conversion of the sputum microscopy. These data suggest that pre-doses samples offer limited information on the exposure of M. tuberculosis to rifampicin.

Effect of Rifampicin on the Distribution of [11C]Erlotinib to the Liver, a Translational PET Study in Humans and in Mice.

Organic anion-transporting polypeptides (OATPs) mediate the uptake of various drugs from blood into the liver in the basolateral membrane of hepatocytes. Positron emission tomography (PET) is a potentially powerful tool to assess the activity of hepatic OATPs in vivo, but its utility critically depends on the availability of transporter-selective probe substrates. We have shown before that among the three OATPs expressed in hepatocytes (OATP1B1, OATP1B3, and OATP2B1), [11C]erlotinib is selectively transported by OATP2B1. In contrast to OATP1B1 and OATP1B3, OATP2B1 has not been thoroughly explored yet, and no specific probe substrates are currently available. To assess if the prototypical OATP inhibitor rifampicin can inhibit liver uptake of [11C]erlotinib in vivo, we performed [11C]erlotinib PET scans in six healthy volunteers without and with intravenous pretreatment with rifampicin (600 mg). In addition, FVB mice underwent [11C]erlotinib PET scans without and with concurrent intravenous infusion of high-dose rifampicin (100 mg/kg). Rifampicin caused a moderate reduction in the liver distribution of [11C]erlotinib in humans, while a more pronounced effect of rifampicin was observed in mice, in which rifampicin plasma concentrations were higher than in humans. In vitro uptake experiments in an OATP2B1-overexpressing cell line indicated that rifampicin inhibited OATP2B1 transport of [11C]erlotinib in a concentration-dependent manner with a half-maximum inhibitory concentration of 72.0 ± 1.4 μM. Our results suggest that rifampicin-inhibitable uptake transporter(s) contributed to the liver distribution of [11C]erlotinib in humans and mice and that [11C]erlotinib PET in combination with rifampicin may be used to measure the activity of this/these uptake transporter(s) in vivo. Furthermore, our data suggest that a standard clinical dose of rifampicin may exert in vivo a moderate inhibitory effect on hepatic OATP2B1.

Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting.

Therapeutic drug monitoring (TDM) could improve current TB treatment, but few studies have reported pharmacokinetic data together with MICs. To investigate plasma concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol along with MICs. Drug concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol were analysed pre-dose and 2, 4 and 6 h after drug intake at week 2 in 31 TB patients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (Chigh) were determined, as well as estimates of Chigh/MIC and area under the concentration-time curve (AUC0-6)/MIC including the corresponding ratios based on calculated free-drug concentrations. This trial was registered at www.clinicaltrials.gov (NCT02042261). After 2 weeks of treatment, the median Chigh values for rifampicin, isoniazid, pyrazinamide and ethambutol were 10.0, 5.3, 41.1 and 3.3 mg/L respectively. Lower than recommended drug concentrations were detected in 42% of the patients for rifampicin (<8 mg/L), 19% for isoniazid (<3 mg/L), 27% for pyrazinamide (<35 mg/L) and 16% for ethambutol (<2 mg/L). The median Chigh/MIC values for rifampicin, isoniazid, pyrazinamide and ethambutol were 164, 128, 1.3 and 2.5, respectively, whereas the AUC0-6/MIC was 636 (range 156-2759) for rifampicin and 351 (range 72-895) for isoniazid. We report low levels of first-line TB drugs in 16%-42% of patients, in particular for rifampicin. There was a wide distribution of the ratios between drug exposures and MICs. The future use of MIC determinations in TDM is dependent on the development of a reference method and clinically validated pharmacokinetic/pharmacodynamic targets.

Exposure of Nursed Infants to Maternal Treatment with Ethambutol and Rifampicin.

Mycobacterial diseases remain a significant cause of morbidity and mortality worldwide. Rifampicin and ethambutol are among the drugs recommended by WHO as first-line treatment. In this work, we addressed the question whether doses of the two anti-tuberculosis agents ethambutol and rifampicin transferred to a nursed infant could be of health concerns when the mother is under treatment. We used the approach of pharmacokinetic modelling using a structural model with two interconnected organisms: the first one being the organism of the nursing mother and the second one being the organism of the nursed child. Physiological data were taken from the literature. The models were parameterised by data from the literature concerning clearance, absorption and plasma/milk ratio. Distribution into the tissues was calculated by an algorithm. The predictive power of the model was tested by comparing the predicted plasma concentrations in the mothers with measured data from the literature. Comparison with measured data after direct infant treatment was performed for the rifampicin plasma concentrations predicted in the nursed infant. Both comparisons confirmed the appropriateness of the modelling results. The transfer of 0.08 mg/kg bw/day ethambutol via breast milk to the nursed infant, the dose we have estimated, when the mother received a therapeutic dose of 24.5 mg/kg bw, can be judged as being without health concern. Likewise, for rifampicin, the transferred dose of 0.4 mg/kg bw to the nursed infant resulting from a therapeutic dose of 10.9 mg/kg bw to the mother does not raise health concerns.

Plasma levels of Rifampicin and Pyrazinamide with pre and post meal administration in tuberculosis patients

ContextVarious factors affect plasma concentrations of antitubercular drugs in different populations so dosing schedule should be adjusted after therapeutic drug monitoring. AimsTo study variability in plasma concentrations of Rifampicin and Pyrazinamide with pre and post-meal administration of drugs in tuberculosis patients. Methods and material52 patients of pulmonary tuberculosis, divided in to two groups, pre and post-meal through systemic randomization. After taking pre-dose sample, drugs were administered according to the group. Samples were withdrawn at 2, 4, 6, and 10h after drug administration. Analysis of samples was done using HPLC. ResultsMean±1SD of Cmax of Rifampicin was 7.75±2.82μg/ml, mean±1SD of AUC0–10 was 42.17±17.25μgh/ml, adjusted Tmax was 4.25h. In pre-meal samples, the corresponding values were 7.75±2.88μg/ml, 42.83±18.47μgh/ml, 3.76h and in post-meal samples 8.03±2.30μg/ml, 41.56±16.46μgh/ml and 4.75h.Mean±1SD of Cmax levels of Pyrazinamide was 54.49±21.86μg/ml, mean±1SD of AUC0–10 was 337.94±124.28μgh/ml and adjusted Tmax was 3.49h. In pre-meal samples the corresponding values were 52.00±19.13μg/ml, 329.96±112.11μgh/ml, 3.23h, and in post-meal samples 57.43±23.61μg/ml, 345.58±136.99μgh/ml, 3.54h. ConclusionThere is huge variability in the plasma levels of Rifampicin and Pyrazinamide in population of this sub-himalayan region.

Food significantly reduces plasma concentrations of first-line anti-tuberculosis drugs.

Background & objectives:Concomitant feeding and anti-tuberculosis (TB) drug administration are likely to reduce nausea and enhance compliance to treatment. However, food could lower plasma drug concentrations. This study was undertaken to examine the effect of food on two-hour plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA), and pharmacokinetics of these drugs in adult TB patients.Methods:Newly diagnosed adult TB patients were recruited from the Revised National Tuberculosis Control Programme (RNTCP) treatment centres in Chennai Corporation, Chennai, India. Two-hour post-dosing plasma concentrations were determined in 25 patients, and a semi-intensive pharmacokinetic study was undertaken in six patients. RMP, INH and PZA concentrations were determined by high-performance liquid chromatography.Results:The geometric mean two-hour concentrations with food and under fasting conditions were 2.2 and 5.5 μg/ml for RMP (P<0.001), 3.9 and 11.3 μg/ml for INH (P<0.001), and 18.0 and 28.2 μg/ml for PZA (P<0.001), respectively. Drug administration with food caused the plasma concentration to decrease by 50, 45 and 34 per cent for RMP, INH and PZA, respectively. Significant decreases in peak concentrations and exposures of drugs and delay in time to attain peak concentrations of drugs when taken with food were also observed.Interpretation & conclusions:Our findings showed that food lowered anti-TB drug concentrations significantly and delayed absorption. Patients may be explained the beneficial effects of taking anti-TB drugs in a fasting state and advised to do so. There is a need for more research on optimization of dosing to maximize efficacy and safety of currently used drugs.

Rifampicin and isoniazid plasma concentrations in relation to adverse reactions in tuberculosis patients: a retrospective analysis.

High concentrations of antituberculosis (anti-TB) drugs can be associated with many adverse drug reactions (ADRs). The objective of this study was to examine the plasma concentrations of rifampicin (RMP) and isoniazid (INH) in patients with and without ADRs. Concentration monitoring data of patients treated with anti-TB drugs were retrospectively analyzed from 2009 to 2011. RMP and INH plasma concentrations were measured 2 and 3 h after drug administration respectively using high-performance liquid chromatography. A total of 54 out of 120 patients have experienced ADRs to anti-TB drugs. The median concentrations [interquartile range (IQR)] obtained in patients with and without ADRs were 6.7 mg/l (3.7-9.9) and 5.6 mg/l (2.9-8.6) (p = 0.56) for RMP and 4.3 mg/l (2.3-5.3) and 3.1 mg/l (1.7-4.8) (p = 0.04) for INH, respectively. Related median doses (IQR) were 8.7 mg/kg (8.0-10.0) and 8.6 mg/kg (6.5-9.9) (p = 0.42) for RMP and 4.8 mg/kg (4.3-5.0) and 4.0 mg/kg (2.8-5) (p < 0.01) for INH, respectively. Concentrations above the expected range in patients with and without ADRs were not reached for RMP, but were 76% and 65% for INH, respectively. Correlation between concentrations and doses has not been established for RMP or INH. In addition, high INH concentrations showed no association with sex, age, liver injury or renal or diabetes. High INH concentrations were common in patients with and without ADRs whereas RMP concentrations were low or within the normal range in most patients. Further studies are required to assess the association between high INH concentrations and the occurrence of ADRs.

A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children.

Low rifampicin plasma concentrations can lead to treatment failure and increased risk of developing drug resistant tuberculosis. The objectives of this study were to characterize the population pharmacokinetics (popPK) of rifampicin in Malawian children and adults with tuberculosis, simulate exposures under revised WHO dosing guidelines that aim to reduce the risk of low exposures of rifampicin and examine predicted exposures using weight- and age-based dosing bands under new dosing recommendations. Patients were recruited at least two weeks after initiation of the intensive phase of treatment and received RIF in FDC of anti-TB drugs. A total of 5-6 rich and 1-2 sparse samples were collected. nonmem (v7.2) was used to build a population-PK model. A 165 TB patients, 115 adults and 50 children, aged 7 months to 65 years and weighing 4.8 to 87 kg, were included in the one compartment model with first order absorption best described the data. The mean population estimate for CL/F was 23.9 (lh(-1) 70kg(-1) ) with inter-individual variability of 46.6%. Exposure was unaffected by HIV status. Relative bioavailability in children was estimated at 49% lower compared to adults (100% relative bioavailability). Simulations showed significantly lower rifampicin exposure in children vs. adults. In children average AUC was 13.5mgl(-1) h, which was nearly half that was observed in adults (26.3mgl(-1) h). Using age as a surrogate for weight in dosing bands gave similar results compared with the weight bands. Increasing dose to approximately 15mg kg(-1) , increased AUC in children to an average of 22mgl(-1) h. bringing expected exposures in children closer to those predicted for adults. The popPK model developed can be used to optimize rifampicin exposures through dosing simulations. WHO dosing recommendations may not be achieved using currently licensed fixed dose combination formulations of TB therapy.

A Modified and Cost-Effective HPLC Method for Determination of Plasma Concentrations of Rifampicin in Pulmonary TB Patients

Objective: To evaluate the pharmacokinetics of standard doses of rifampicin (RMP) in fixed dose combination in pulmonarytuberculosis patients by a modified high performance liquid chromatography (HPLC) methodMaterials and Methods: This descriptive study was conducted after approval from Ethical Committee, Army Medical CollegeRawalpindi and was funded in part by National University of Sciences and Technology (NUST), Islamabad. Twenty adultpatients with newly diagnosed pulmonary TB consented to participate in the study. RMP plasma concentrations were assayedby a simple and sensitive HPLC method in the initial phase of pulmonary tuberculosis treatment. The method was modifiedto use naproxen as an internal standard and validated according to International Conference on Hormonization (ICH) guidelines.Results: The calibration curve of rifampicin was linear within the range of 0.781–50 μg/ml. Both intra-day and inter-dayvariability and accuracy demonstrated good reproducibility at all quality control levels. The developed method was found tobe simple, precise and accurate for estimation of rifampicin in plasma. The pharmacokinetic parameters of RMP showed markedinter-individual differences and sub-therapeutic levels.Conclusion: Evaluation of pharmacokinetics of standard doses of rifampicin in fixed dose combination in pulmonary tuberculosispatients by a modified high performance liquid chromatography (HPLC) method is precise, accurate and cost-effective. It maybe used for monitoring plasma RMP levels in TB patients who are slow to respond or are non-responders and have less availabilityof resources.Keywords: Tuberculosis,

The Comparison of Conventional and Novel Fixed Dose Combination of Rifampicin and Isoniazid to Improve Bioavailability of Rifampicin for Treatment of Tuberculosis

Background: Fixed-dose combinations (FDCs) of anti-tubercular drugs have been recommended as a step towards ensuring better treatment and compliance of patients receiving anti-tubercular therapy (ATT). Methods: The study was an open-label and randomized controlled trial. Patients were randomized to receive daily treatment with the conventional FDC dosage formulation or the novel FDC formulation of rifampicin and isoniazid as a part of 4 drug ATT regimen. The outcome measures were sputum conversion rates, radiological response and clinical response. Results: Of the 105 patients who were randomized 55 received the conventional FDC formulation while 50 received the novel FDC formulation. Of the 105 participants, 51 (48.6%) had PTB with the rest having extrapulmonary tuberculosis (EPTB). Of the 87 patients could be assessed at the end of 6 months treatment,10/42 (23.8%) of the patients in group A and 13/45 (28.9%) of the patients in group B had some evidence of disease activity at the end of 6 months of treatment on the CT scan or in the Chest X-Ray. A total of 6 (5.8%) patients, three in each group (5.6% in group A and 6.4% in Group B) experienced treatment failure. Of these 3 were classified as treatment failure due to radiological deterioration and 3 due to persistent culture positivity. There was no significant difference in the microbiological, clinical or radiological response rates between the two groups. There was no significant difference in the plasma concentrations of rifampicin and isoniazid at various time points between the two groups. Conclusion: In conclusion, we found no difference in the clinical efficacy of rifampicin and isoniazid drug levels of the novel FDC formulation as compared to the conventional FDC formulation. Further studies are required with larger sample size to study the usefulness of novel FDC formulation.

Simultaneous determination of rifampicin, clarithromycin and their metabolites in dried blood spots using LC–MS/MS

Rifampicin (RIF) and clarithromycin (CLR) are common drugs for the treatment of infections like Mycobacterium tuberculosis and Mycobacterium ulcerans. Treatment for these diseases are long-term and the individual pharmacokinetic variation, drug-drug interactions or non-adherence may introduce sub-therapeutic exposure or toxicity. The application of therapeutic drug monitoring (TDM) can be used to ensure efficacy and avoid toxicity. With the use of dried blood spot (DBS), TDM may be feasible in rural areas. During DBS method development, unexpected interactions or matrix effects may be encountered due to endogenous components in the blood. Another complication compared to plasma analysis is that RIF can form chelate complexes with ferric ions or can bind with hemes, which are potentially present in the extracts of dried blood spots. The investigation focused on the interaction between RIF and the endogenous components of the DBS. The use of ethylenediaminetetraacetic acid (EDTA) and deferoxamine (DFX) as chelator agents to improve recoveries and matrix effects were investigated. A rapid analytical method was developed and validated to quantify RIF and CLR and their active metabolites desacetyl rifampicin (DAc-RIF) and 14-hydroxyclarythromcin (14OH-CLR) in DBS samples. A clinical application study was performed in tuberculosis patients by comparing DBS concentrations with plasma concentrations. The interaction between RIF and the DBS matrix was avoided using the complexing agents EDTA and DFX, which improved recoveries and matrix effects. The developed sample procedure resulted in a simple and fast method for the simultaneous quantification of RIF, CLR and their metabolites in DBS samples. High stability was observed as all four substances were stable at ambient temperature for 2 months. Deming regression analysis of the clinical application study showed no significant differences for RIF, DAc-RIF, CLR and 14OH-CLR between patient plasma and DBS analysis. The slopes of the correlation lines between DBS and plasma concentrations of RIF, DAc-RIF, CLR and 14OH-CLR were 0.90, 0.99, 0.80 and 1.09 respectively. High correlations between plasma and DBS concentrations were observed for RIF (R(2)=0.9076), CLR (R(2)=0.9752) and 14OH-CLR (R(2)=0.9421). Lower correlation was found for DAc-RIF (R(2) of 0.6856). The validated method is applicable for TDM of RIF, CLR and their active metabolites. The stability of the DBS at high temperatures can facilitate the TDM and pharmacokinetic studies of RIF and CLR even in resource limited areas. The role of EDTA and DFX as complexing agents in the extraction was well investigated and may provide a solution for potential applications to other DBS analytical methods.