Marieke G. G. Sturkenboom

Therapeutic Drug Monitoring of Posaconazole: an Update

Posaconazole is a second-generation triazole agent with a potent and broad antifungal activity. In addition to the oral suspension, a delayed-release tablet and intravenous formulation with improved pharmacokinetic properties have been introduced recently. Due to the large interindividual and intraindividual variation in bioavailability and drug-drug interactions, therapeutic drug monitoring (TDM) is advised to ensure adequate exposure and improve clinical response for posaconazole. Here, we highlight and discuss the most recent findings on pharmacokinetics and pharmacodynamics of posaconazole in the setting of prophylaxis and treatment of fungal infections and refer to the challenges associated with TDM of posaconazole.

Incorporating therapeutic drug monitoring into the World Health Organization hierarchy of tuberculosis diagnostics

Tuberculosis (TB), once considered as a disease of the past generally afflicting poor people, still claims 1.5 million lives annually [1]. Although 86% of patients with drug susceptible TB are cured with established first-line drugs, treatment is often longer than 6 months due to slow response, compliance problems or adverse drug reactions. In addition, emergence of drug-resistant Mycobacterium tuberculosis strains with an unacceptably low treatment success rate of 50% and TB–HIV co-infection have challenged the goals of global TB control and elimination [1]. Incorporating therapeutic drug monitoring into the WHO hierarchy of tuberculosis diagnostics http://ow.ly/YcRMw

End TB with precision treatment

We read with interest the recent Perspective paper by Lönnroth et al. [1] describing a framework for tuberculosis (TB) elimination. In our opinion, monitoring drug exposure by measuring blood concentrations over time (therapeutic drug monitoring (TDM)) may be helpful in contributing to TB elimination in low- and medium-burden setting. TB precision treatment, including optimised drug exposure in relation to drug susceptibility testing, may help end TB http://ow.ly/Utu2u

An interlaboratory quality control programme for the measurement of tuberculosis drugs

Tuberculosis (TB) remains a major global health problem. Inadequate exposure to TB drugs constitutes one of the main factors underlying suboptimal treatment response and development of resistance, as evidenced by results from: the in vitro hollow fibre model [1]; clinical studies on relationships between drug concentrations and response [2–5]; a pharmacogenetic trial [6]; and a recent meta-analysis [7]. Quality control in TB drug measurement is essential for the development of new drugs and for patient care http://ow.ly/KxWNc

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

ABSTRACT 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 r2 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.

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

ABSTRACT Bedaquiline, a diarylquinoline for the treatment of multidrug-resistant tuberculosis (TB), relies on exposure-dependent killing. As data on drug exposure in specific populations are scarce, pharmacokinetic studies may be of interest. No simple and robust validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been reported to date. Therefore, a new method using a quadrupole mass spectrometer was developed for analysis of bedaquiline and N-monodesmethyl bedaquiline (M2) in human serum, using deuterated bedaquiline as the internal standard. The calibration curve was linear over a range of 0.05 (lower limit of quantification [LLOQ]) to 6.00 mg/liter for both bedaquiline and M2, with correlation coefficient values of 0.997 and 0.999, respectively. The calculated accuracy ranged from 1.9% to 13.6% for bedaquiline and 2.9% to 8.5% for M2. Within-run precision ranged from 3.0% to 7.2% for bedaquiline and 3.1% to 5.2% for M2, and between-run precision ranged from 0.0% to 4.3% for bedaquiline and 0.0% to 4.6% for M2. Evaluation of serum concentrations in a patient receiving bedaquiline showed high levels at the end of treatment, reflecting accumulation of the drug. More observational pharmacokinetic data are needed to relate altered drug concentrations to clinical outcome or adverse drug effects. A simple LC-MS/MS method to quantify bedaquiline and M2 levels in human serum using a deuterated internal standard has been validated. This method can be used in clinical studies and daily practice.

Quantification of amikacin and kanamycin in serum using a simple and validated LC-MS/MS method

BACKGROUND Amikacin and kanamycin are frequently used in the treatment of multidrug-resistant TB. The current commercially available immunoassay is unable to analyze kanamycin and trough levels of amikacin. The objective was therefore to develop a LC-MS/MS method for the quantification of amikacin and kanamycin in human serum. MATERIALS & METHODS Using apramycin as internal standard, selectivity, accuracy, precision, recovery, matrix effects and stability were evaluated. RESULTS The presented LC-MS/MS method meets the recommendations of the US FDA with a low LLOQ of 250 ng/ml for amikacin and 100 ng/ml for kanamycin. No statistical significant difference was found between the LC-MS/MS method and the immunoassay of amikacin (Architect(®) assay, p = 0.501). CONCLUSION The low LLOQ of amikacin and the ability to analyze kanamycin makes the LC-MS/MS method the preferred method for analyzing these aminoglycosides.

Adequate Design of Pharmacokinetic-Pharmacodynamic Studies Will Help Optimize Tuberculosis Treatment for the Future

Marieke G. G. Sturkenboom, Onno W. Akkerman, Mathieu S. Bolhuis, Wiel C. M. de Lange, Tjip S. van der Werf, Jan-Willem C. Alffenaar University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands

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.

Emerging drugs and alternative possibilities in the treatment of tuberculosis

ABSTRACT Introduction: Tuberculosis (TB) remains a global health problem. Drug resistance, treatment duration, complexity, and adverse drug reactions associated with anti-TB regimens are associated with treatment failure, prolonged infectiousness and relapse. With the current set of anti-TB drugs the goal to end TB has not been met. New drugs and new treatment regimens are needed to eradicate TB. Areas covered: Literature was explored to select publications on drugs currently in phase II and phase III trials. These include new chemical entities, immunotherapy, established drugs in new treatment regimens and vaccines for the prophylaxis of TB. Expert opinion: Well designed trials, with detailed pharmacokinetic/pharmacodynamic analysis, in which information on drug exposure and drug susceptibility of the entire anti-TB regimen is included, in combination with long-term follow-up will provide relevant data to optimize TB treatment. The new multi arm multistage trial design could be used to test new combinations of compounds, immunotherapy and therapeutic vaccines. This new approach will both reduce the number of patients exposed to inferior treatment and the financial burden. Moreover, it will speed up drug evaluation. Considering the investments involved in development of new drugs it is worthwhile to thoroughly investigate existing, non-TB drugs in new regimens.