Ten-year results of an international external quality control programme for measurement of anti-tuberculosis drug concentrations.

OBJECTIVES: Participation in an external (interlaboratory) quality control (QC) programme is an essential part of quality assurance as it provides laboratories with valuable insights into their analytical performance. We describe the 10 year results of an international QC programme for the measurement of anti-tuberculosis (TB) drugs. METHODS: Each year, two rounds were organized in which serum (or plasma) samples, spiked with known concentrations of anti-TB drugs, were provided to participating laboratories for analysis. Reported measurements within 80%-120% of weighed-in concentrations were considered accurate. Mixed model linear regression was performed to assess the effect of the measured drug, concentration level, analytical technique and performing laboratory on the absolute inaccuracy. RESULTS: By 2022, 31 laboratories had participated in the QC programme and 13 anti-TB drugs and metabolites were included. In total 1407 measurements were reported. First-line TB drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) represented 58% of all measurements. Overall, 83.2% of 1407 measurements were accurate, and the median absolute inaccuracy was 7.3% (IQR, 3.3%-15.1%). The absolute inaccuracy was related to the measured anti-TB drug and to the performing laboratory, but not to the concentration level or to the analytical technique used. The median absolute inaccuracies of rifampicin and isoniazid were relatively high (10.2% and 10.9%, respectively). CONCLUSIONS: The 10 year results of this external QC programme illustrate the need for continuous external QC for the measurement of anti-TB drugs for research and patient care purposes, because one in six measurements was inaccurate. Participation in the programme alerts laboratories to previously undetected analytical problems.

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Exposure of anti-infective drugs and the dynamic changes of the gut microbiota during gastrointestinal mucositis in autologous stem cell transplant patients: a pilot study.

Gastrointestinal mucositis could potentially compromise drug absorption due to functional loss of mucosa and other pathophysiological changes in the gastrointestinal microenvironment. Little is known about this effect on commonly used anti-infectives. This study aimed to explore the association between different stages of gastrointestinal mucositis, drug exposure, and gut microbiota. A prospective, observational pilot study was performed in HSCT patients aged ≥ 18 years receiving anti-infectives orally. Left-over blood samples and fecal swabs were collected from routine clinical care until 14 days after HSCT to analyze drug and citrulline concentrations and to determine the composition of the gut microbiota. 21 patients with a median age of 58 (interquartile range 54-64) years were included with 252 citrulline, 155 ciprofloxacin, 139 fluconazole, and 76 acyclovir concentrations and 48 fecal swabs obtained. Severe gastrointestinal mucositis was observed in all patients. Due to limited data correlation analysis was not done for valacyclovir and fluconazole, however we did observe a weak correlation between ciprofloxacin and citrulline concentrations. This could suggest that underexposure of ciprofloxacin can occur during severe mucositis. A follow-up study using frequent sampling rather than the use of left-over would be required to investigate the relationship between gastrointestinal mucositis, drug exposure, and gut microbiome.

Subtherapeutic Exposure of Ganciclovir in Children Despite Appropriate Dosing: A Short Communication.

ABSTRACT: Therapeutic drug monitoring (TDM) results for ganciclovir in 12 different treatment episodes showed large intraindividual and interindividual variabilities in the trough concentration and area under the 24-hour concentration-time curve (AUC24). Despite adequate valganciclovir dosing, subtherapeutic concentrations were found in 30% of the treatment episodes. A decrease in viral load was observed regardless of subtherapeutic exposure. These findings show the need for target concentration evaluation and assessment of the applicability of ganciclovir TDM in children.

Population Pharmacokinetic Modelling and Limited Sampling Strategies for Therapeutic Drug Monitoring of Pyrazinamide in Patients with Tuberculosis.

Pyrazinamide is one of the first-line antituberculosis drugs. The efficacy of pyrazinamide is associated with the ratio of 24-h area under the concentration-time curve (AUC24) to MIC. The objective of this study was to develop and validate a limited sampling strategy (LSS) based on a population pharmacokinetic (popPK) model to predict AUC24. A popPK model was developed using an iterative two-stage Bayesian procedure and was externally validated. Using data from 20 treatment-naive adult tuberculosis (TB) patients, a one compartment model with transit absorption and first-order elimination best described pyrazinamide pharmacokinetics and fed state was the only significant covariate for absorption rate constant (ka). External validation, using data from 26 TB patients, showed that the popPK model predicted AUC24 with a slight underestimation of 2.1%. LSS were calculated using Monte Carlo simulation (n = 10,000). External validation showed LSS with time points 0 h, 2 h, and 6 h performed best with RMSE of 9.90% and bias of 0.06%. Food slowed absorption of pyrazinamide, but did not affect bioavailability, which may be advantageous in case of nausea or vomiting in which food can be used to diminish these effects. In this study, we successfully developed and validated a popPK model and LSS, using 0 h, 2 h, and 6 h postdose samples, that could be used to perform therapeutic drug monitoring (TDM) of pyrazinamide in TB patients.

Clinical Relevance of Rifampicin-Moxifloxacin Interaction in Isoniazid-Resistant/Intolerant Tuberculosis Patients.

Moxifloxacin is an attractive drug for the treatment of isoniazid-resistant rifampicin-susceptible tuberculosis (TB) or drug-susceptible TB complicated by isoniazid intolerance. However, co-administration with rifampicin decreases moxifloxacin exposure. It remains unclear whether this drug-drug interaction has clinical implications. This retrospective study in a Dutch TB center investigated how rifampicin affected moxifloxacin exposure in patients with isoniazid-resistant or -intolerant TB. Moxifloxacin exposures were measured between 2015 and 2020 in 31 patients with isoniazid-resistant or -intolerant TB receiving rifampicin, and 20 TB patients receiving moxifloxacin without rifampicin. Moxifloxacin exposure, i.e., area under the concentration-time curve (AUC0-24h), and attainment of AUC0-24h/MIC > 100 were investigated for 400 mg moxifloxacin and 600 mg rifampicin, and increased doses of moxifloxacin (600 mg) or rifampicin (900 mg). Moxifloxacin AUC0-24h and peak concentration with a 400 mg dose were decreased when rifampicin was co-administered compared to moxifloxacin alone (ratio of geometric means 0.61 (90% CI (0.53, 0.70) and 0.81 (90% CI (0.70, 0.94), respectively). Among patients receiving rifampicin, 65% attained an AUC0-24h/MIC > 100 for moxifloxacin compared to 78% of patients receiving moxifloxacin alone; this difference was not significant. Seven out of eight patients receiving an increased dose of 600 mg moxifloxacin reached the target AUC0-24h/MIC > 100. This study showed a clinically significant 39% decrease in moxifloxacin exposure when rifampicin was co-administered. Moxifloxacin dose adjustment may compensate for this drug-drug interaction. Further exploring the impact of higher doses of these drugs in patients with isoniazid resistance or intolerance is paramount.

Standard ganciclovir dosing results in slow decline of cytomegalovirus viral loads.

BACKGROUND: Cytomegalovirus (CMV) can cause severe disease, including rejection in transplant recipients. Ganciclovir and its oral prodrug valganciclovir have been used as first-line therapy for CMV disease in transplant recipients. The exposure targets of ganciclovir are not exactly known, and toxicity and resistance have interfered with ganciclovir therapy. OBJECTIVES: To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ganciclovir in transplant recipients. METHODS: We used patient data from a previous observational study on ganciclovir therapeutic drug monitoring (TDM) in prophylaxis and therapy. The ganciclovir concentrations and CMV viral loads were determined during routine clinical care. The PK/PD population modelling and simulations were done with non-parametric methodology using the Pmetrics program. RESULTS: Eighty-five patients were included in the PK modelling. The final PK model was a two-compartment model with first-order absorption and elimination. A subset of 17 patients on CMV therapy were included in the PD modelling. A median of 4 (range 2-8) viral loads were obtained per patient. A simulation of 10 000 patients showed that an approximately 1 log10 reduction of CMV viral load will be observed after 12.5 days at the current recommended dose. CONCLUSIONS: The developed linked PK/PD population model and subsequent PD simulations showed slow decline of CMV viral load and it appears that dosing of (val)ganciclovir in this study might have been inadequate to achieve fast reduction of viral load. It is clear that further studies are needed to specify the PD effects of ganciclovir by performing systematic measurements of both ganciclovir concentrations and CMV viral loads.

Therapeutic Drug Monitoring of Ganciclovir: Where Are We?

BACKGROUND: Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of Cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such as myelosuppression, which often leads to therapy cessation. Underdosing, as an attempt to prevent side effects, can lead to drug resistance and therapy failure. Therapeutic drug monitoring (TDM) has been used to overcome these problems. The purpose of this narrative review was to give an overview of ganciclovir TDM, available assays, population pharmacokinetic models, and discuss the current knowledge gaps. METHODS: For this narrative review, a nonsystematic literature search was performed on the PubMed database in April 2021. The following search terms were used: ganciclovir, valganciclovir, pharmacokinetics, pharmacodynamics, population pharmacokinetics, therapeutic drug monitoring, bioassay, liquid chromatography coupled with tandem mass spectrometry, liquid chromatography, chromatography, spectrophotometry, and toxicity. In addition, the reference lists of the included articles were screened. RESULTS: The most common bioanalysis method identified was liquid chromatography coupled with tandem mass spectrometry. There are different models presenting ganciclovir IC50; however, establishing a pharmacokinetic/pharmacodynamic target for ganciclovir based on preclinical data is difficult because there are no studies combining dynamic drug exposure in relation to inhibition of viral replication. The data on ganciclovir TDM show large interindividual variability, indicating that TDM may play a role in modifying the dose to reduce toxicity and prevent treatment failure related to low concentrations. The main hurdle for implementing TDM is the lack of robust data to define a therapeutic window. CONCLUSIONS: Although the pharmacokinetics (PK) involved is relatively well-described, both the pharmacodynamics (PD) and pharmacokinetic/pharmacodynamic relationship are not. This is because the studies conducted to date have mainly focused on estimating ganciclovir exposure, and owing to the limited therapeutic options for CMV infections, future studies on ganciclovir are warranted.

Therapeutic Drug Monitoring of Anti-infective Drugs: Implementation Strategies for 3 Different Scenarios.

BACKGROUND: Therapeutic drug monitoring (TDM) supports personalized treatment. For successful implementation, TDM must have a turnaround time suited to the clinical needs of patients and their health care settings. Here, the authors share their views of how a TDM strategy can be tailored to specific settings and patient groups. METHODS: The authors selected distinct scenarios for TDM: high-risk, complex, and/or critically ill patient population; outpatients; and settings with limited laboratory resources. In addition to the TDM scenario approach, they explored potential issues with the legal framework governing dose escalation. RESULTS: The most important issues identified in the different scenarios are that critically ill patients require rapid turnaround time, outpatients require an easy sampling procedure for the sample matrix and sample collection times, settings with limited laboratory resources necessitate setting-specific analytic techniques, and all scenarios warrant a legal framework to capture the use of escalated dosages, ideally with the use of trackable dosing software. CONCLUSIONS: To benefit patients, TDM strategies need to be tailored to the intended population. Strategies can be adapted for rapid turnaround time for critically ill patients, convenient sampling for outpatients, and feasibility for those in settings with limited laboratory resources.

Ganciclovir therapeutic drug monitoring in transplant recipients.

BACKGROUND: The use of (val)ganciclovir is complicated by toxicity, slow response to treatment and acquired resistance. OBJECTIVES: To evaluate a routine therapeutic drug monitoring (TDM) programme for ganciclovir in a transplant patient population. METHODS: An observational study was performed in transplant recipients from June 2018 to February 2020. Dose adjustments were advised by the TDM pharmacist as part of clinical care. For prophylaxis, a trough concentration (Cmin) of 1-2 mg/L and an AUC24h of >50 mg·h/L were aimed for. For treatment, a Cmin of 2-4 mg/L and an AUC24h of 80-120 mg·h/L were aimed for. RESULTS: Ninety-five solid organ and stem cell transplant patients were enrolled. Overall, 450 serum concentrations were measured; with a median of 3 (IQR = 2-6) per patient. The median Cmin and AUC24h in the treatment and prophylaxis groups were 2.0 mg/L and 90 mg·h/L and 0.9 mg/L and 67 mg·h/L, respectively. Significant intra- and inter-patient patient variability was observed. The majority of patients with an estimated glomerular filtration rate of more than 120 mL/min/1.73 m2 and patients on continuous veno-venous haemofiltration showed underexposure. The highest Cmin and AUC24h values were associated with the increase in liver function markers and decline in WBC count as compared with baseline. CONCLUSIONS: This study revealed that a standard weight and kidney function-based dosing regimen resulted in highly variable ganciclovir Cmin and under- and over-exposure were observed in patients on dialysis and in patients with increased renal function. Clearly there is a need to explore the impact of concentration-guided dose adjustments in a prospective study.

Limited Sampling Strategies Using Linear Regression and the Bayesian Approach for Therapeutic Drug Monitoring of Moxifloxacin in Tuberculosis Patients.

Therapeutic drug monitoring (TDM) of moxifloxacin is recommended to improve the response to tuberculosis treatment and reduce acquired drug resistance. Limited sampling strategies (LSSs) are able to reduce the burden of TDM by using a small number of appropriately timed samples to estimate the parameter of interest, the area under the concentration-time curve. This study aimed to develop LSSs for moxifloxacin alone (MFX) and together with rifampin (MFX+RIF) in tuberculosis (TB) patients. Population pharmacokinetic (popPK) models were developed for MFX (n = 77) and MFX+RIF (n = 24). In addition, LSSs using Bayesian approach and multiple linear regression were developed. Jackknife analysis was used for internal validation of the popPK models and multiple linear regression LSSs. Clinically feasible LSSs (one to three samples, 6-h timespan postdose, and 1-h interval) were tested. Moxifloxacin exposure was slightly underestimated in the one-compartment models of MFX (mean -5.1%, standard error [SE] 0.8%) and MFX+RIF (mean -10%, SE 2.5%). The Bayesian LSSs for MFX and MFX+RIF (both 0 and 6 h) slightly underestimated drug exposure (MFX mean -4.8%, SE 1.3%; MFX+RIF mean -5.5%, SE 3.1%). The multiple linear regression LSS for MFX (0 and 4 h) and MFX+RIF (1 and 6 h), showed mean overestimations of 0.2% (SE 1.3%) and 0.9% (SE 2.1%), respectively. LSSs were successfully developed using the Bayesian approach (MFX and MFX+RIF; 0 and 6 h) and multiple linear regression (MFX, 0 and 4 h; MFX+RIF, 1 and 6 h). These LSSs can be implemented in clinical practice to facilitate TDM of moxifloxacin in TB patients.

Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment.

Linezolid has been successfully used for treatment of multidrug-resistant tuberculosis (MDR-TB). However, dose- and duration-related toxicity limit its use. Here, our aim was to search relevant pharmacokinetics (PK)/pharmacodynamics (PD) literature to identify the effective PK/PD index and to define the optimal daily dose and dosing frequency of linezolid in MDR-TB regimens. The systematic search resulted in 8 studies that met inclusion criteria. A significant PK variability was observed. Efficacy of linezolid seems to be driven by area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC). Literature is inconclusive about the preferred administration of a daily dose of 600 mg. To prevent development of drug resistance, an AUC/MIC ratio of 100 in the presence of a companion drug at relevant exposure is required. A daily dose of 600 mg seems appropriate to balance between efficacy and toxicity. Being a drug with a very narrow therapeutic window, linezolid treatment may benefit from a more personalized approach, that is, measuring actual MIC values and therapeutic drug monitoring.

Amikacin Dosing for MDR Tuberculosis: A Systematic Review to Establish or Revise the Current Recommended Dose for Tuberculosis Treatment.

Background: Amikacin has been used for over 40 years in multidrug resistant tuberculosis (MDR-TB), but there is still debate on the right dose. The aim of this review was to search relevant pharmacokinetic (PK) and pharmacodynamic (PD) literature for the optimal dose and dosing frequency of amikacin in MDR-TB regimens trying to optimize efficacy while minimizing toxicity. Methods: A systematic review on the value of amikacin as second-line drug in the treatment of MDR-TB was performed. Results: Five articles were identified with data on PK, hollow-fiber system model for TB and or early bactericidal activity of amikacin. Despite the long period in which amikacin has been available for the treatment of MDR-TB, very little PK data is available. This highlights the need for more research. Conclusions: Maximum concentration (Cmax) of amikacin related to MIC proved to be the most important PK/PD index for efficacy. The target Cmax/MIC ratio should be 10 at site of infection. Cumulative area under the concentration-time curve (AUC) corresponding with cumulative days of treatment was associated with an increased risk of toxicity.

d-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal.

Background: d-cycloserine is used to treat multidrug-resistant tuberculosis. Its efficacy, contribution in combination therapy, and best clinical dose are unclear, also data on the d-cycloserine minimum inhibitory concentration (MIC) distributions is scant. Methods: We performed a systematic search to identify pharmacokinetic and pharmacodynamic studies performed with d-cycloserine. We then performed a combined exposure-effect and dose fractionation study of d-cycloserine in the hollow fiber system model of tuberculosis (HFS-TB). In parallel, we identified d-cycloserine MICs in 415 clinical Mycobacterium tuberculosis (Mtb) isolates from patients. We utilized these results, including intracavitary concentrations, to identify the clinical dose that would be able to achieve or exceed target exposures in 10000 patients using Monte Carlo experiments (MCEs). Results: There were no published d-cycloserine pharmacokinetics/pharmacodynamics studies identified. Therefore, we performed new HFS-TB experiments. Cyloserine killed 6.3 log10 colony-forming units (CFU)/mL extracellular bacilli over 28 days. Efficacy was driven by the percentage of time concentration persisted above MIC (%TMIC), with 1.0 log10 CFU/mL kill achieved by %TMIC = 30% (target exposure). The tentative epidemiological cutoff value with the Sensititre MYCOTB assay was 64 mg/L. In MCEs, 750 mg twice daily achieved target exposure in lung cavities of 92% of patients whereas 500 mg twice daily achieved target exposure in 85% of patients with meningitis. The proposed MCE-derived clinical susceptibility breakpoint at the proposed doses was 64 mg/L. Conclusions: Cycloserine is cidal against Mtb. The susceptibility breakpoint is 64 mg/L. However, the doses likely to achieve the cidality in patients are high, and could be neurotoxic.

Population Pharmacokinetic Model and Limited Sampling Strategies for Personalized Dosing of Levofloxacin in Tuberculosis Patients.

Levofloxacin is an antituberculosis drug with substantial interindividual pharmacokinetic variability; therapeutic drug monitoring (TDM) could therefore be helpful to improve treatment results. TDM would be more feasible with limited sampling strategies (LSSs), a method to estimate the area under the concentration curve for the 24-h dosing interval (AUC0-24) by using a limited number of samples. This study aimed to develop a population pharmacokinetic (popPK) model of levofloxacin in tuberculosis patients, along with LSSs using a Bayesian and multiple linear regression approach. The popPK model and Bayesian LSS were developed using data from 30 patients and externally validated with 20 patients. The LSS based on multiple linear regression was internally validated using jackknife analysis. Only clinically suitable LSSs (maximum time span, 8 h; minimum interval, 1 h; 1 to 3 samples) were tested. Performance criteria were root-mean-square error (RMSE) of <15%, mean prediction error (MPE) of <5%, and r2 value of >0.95. A one-compartment model with lag time best described the data while only slightly underestimating the AUC0-24 (mean, -7.9%; standard error [SE], 1.7%). The Bayesian LSS using 0- and 5-h postdose samples (RMSE, 8.8%; MPE, 0.42%; r2 = 0.957) adequately estimated the AUC0-24, with a mean underestimation of -4.4% (SE, 2.7%). The multiple linear regression LSS using 0- and 4-h postdose samples (RMSE, 7.0%; MPE, 5.5%; r2 = 0.977) was internally validated, with a mean underestimation of -0.46% (SE, 2.0%). In this study, we successfully developed a popPK model and two LSSs that could be implemented in clinical practice to assist TDM of levofloxacin. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.).

An enhanced regimen as post-exposure chemoprophylaxis for leprosy: PEP+.

The ongoing transmission of Mycobacterium (M.) leprae reflected in a very slow decline in leprosy incidence, forces us to be innovative and conduct cutting-edge research. Single dose rifampicin (SDR) as post-exposure prophylaxis (PEP) for contacts of leprosy patients, reduces their risk to develop leprosy by 60%. This is a promising new preventive measure that can be integrated into routine leprosy control programmes, as is being demonstrated in the Leprosy Post-Exposure Programme that is currently ongoing in eight countries.The limited (60%) effectiveness of SDR is likely due to the fact that some contacts have a preclinical infection beyond the early stages for which SDR is not sufficient to prevent the development of clinical signs and symptoms of leprosy. An enhanced regimen, more potent against a higher load of leprosy bacteria, would increase the effectiveness of this preventive measure significantly.The Netherlands Leprosy Relief (NLR) is developing a multi-country study aiming to show that breaking the chain of transmission of M. leprae is possible, evidenced by a dramatic reduction in incidence. In this study the assessment of the effectiveness of an enhanced prophylactic regimen for leprosy is an important component. To define the so called PEP++ regimen for this intervention study, NLR convened an Expert Meeting that was attended by clinical leprologists, public health experts, pharmacologists, dermatologists and microbiologists.The Expert Meeting advised on combinations of available drugs, with known efficacy against leprosy, as well as on the duration of the intake, aiming at a risk reduction of 80-90%. To come to a conclusion the Expert Meeting considered the bactericidal, sterilising and bacteriostatic activity of the potential drugs. The criteria used to determine an optimal enhanced regimen were: effectiveness, safety, acceptability, availability, affordability, feasibility and not inducing drug resistance.The Expert Meeting concluded that the enhanced regimen for the PEP++ study should comprise three standard doses of rifampicin 600 mg (weight adjusted when given to children) plus moxifloxacin 400 mg given at four-weekly intervals. For children and for adults with contraindications for moxifloxacin, moxifloxacin should be replaced by clarithromycin 300 mg (weight adjusted).

Impact of food on the pharmacokinetics of first-line anti-TB drugs in treatment-naive TB patients: a randomized cross-over trial.

OBJECTIVES: Concomitant food intake influences pharmacokinetics of first-line anti-TB drugs in healthy volunteers. However, in treatment-naive TB patients who are starting with drug treatment, data on the influence of food intake on the pharmacokinetics are absent. This study aimed to quantify the influence of food on the pharmacokinetics of isoniazid, rifampicin, ethambutol and pyrazinamide in TB patients starting anti-TB treatment. METHODS: A prospective randomized cross-over pharmacokinetic study was conducted in treatment-naive adults with drug-susceptible TB. They received isoniazid, rifampicin and ethambutol intravenously and oral pyrazinamide on day 1, followed by oral administration of these drugs under fasted and fed conditions on two consecutive days. Primary outcome was the bioavailability while fasting and with concomitant food intake. This study was registered with clinicaltrials.gov identifier NCT02121314. RESULTS: Twenty subjects completed the study protocol. Absolute bioavailability in the fasted state and the fed state was 93% and 78% for isoniazid, 87% and 71% for rifampicin and 87% and 82% for ethambutol. Food decreased absolute bioavailability of isoniazid and rifampicin by 15% and 16%, respectively. Pyrazinamide AUC0-24 was comparable for the fasted state (481 mg·h/L) and the fed state (468 mg·h/L). Food lowered the maximum concentrations of isoniazid, rifampicin and pyrazinamide by 42%, 22% and 10%, respectively. Time to maximum concentration was delayed for isoniazid, rifampicin and pyrazinamide. The pharmacokinetics of ethambutol were unaffected by food. CONCLUSIONS: Food decreased absolute bioavailability and maximum concentration of isoniazid and rifampicin, but not of ethambutol or pyrazinamide, in treatment-naive TB patients. In patients prone to low drug exposure, this may further compromise treatment efficacy and increase the risk of acquired drug resistance.

Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis.

Rifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0-24 values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n = 1,000). The geometric mean AUC0-24 value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with an r(2) value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of -0.4%. This study showed that the rifampin AUC0-24 in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.

Derivation and Clinical Utility of Safety Targets for Linezolid-Related Adverse Events in Drug-Resistant Tuberculosis Treatment.

Long-term usage of linezolid can result in adverse events such as peripheral neuropathy, anemia and thrombocytopenia. Therapeutic drug monitoring data from 75 drug-resistant tuberculosis patients treated with linezolid were analyzed using a time-to-event (TTE) approach for peripheral neuropathy and anemia and indirect response modelling for thrombocytopenia. Different time-varying linezolid pharmacokinetic exposure indices (AUC0-24h,ss, Cav, Cmax and Cmin) and patient characteristics were investigated as risk factors. A treatment duration shorter than 3 months was considered dropout and was modelled using a TTE approach. An exposure-response relationship between linezolid Cmin and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC0-24h. The final TTE dropout model indicated an association between linezolid Cmin and dropout. New safety targets for each adverse event were proposed which can be used for individualized linezolid dosing. According to the model predictions at 6 months of treatment, a Cmin of 0.11 mg/L and 1.4 mg/L should not be exceeded to keep the cumulative probability to develop anemia and peripheral neuropathy below 20%. The AUC0-24h should be below 111 h·mg/L or 270 h·mg/L to prevent thrombocytopenia and severe thrombocytopenia, respectively. A clinical utility assessment showed that the currently recommended dose of 600 mg once daily is safer compared to a 300 mg BID dosing strategy considering all four safety endpoints.