169 research outputs found
Fundament and Prerequisites for the Application of an Antifungal TDM Service
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155326.pdf (Publisher’s version ) (Open Access)Therapeutic drug monitoring (TDM) involves the measurement of plasma or serum drug concentration to adapt dosages to achieve predefined target concentrations that are associated with optimal clinical response while minimizing the chance of encountering toxicity. Many papers in the field of antifungal drugs have focused on the evidence that supports the use of TDM thereby emphasizing the breakpoints or target concentrations in general literature. This review focuses on the process of TDM to inform health care workers on the fundaments and prerequisites that safeguard the good application of TDM. Knowledge on the complete process of TDM including pharmacokinetics (and relevant covariates), pharmacodynamic aspects, trials that are necessary to provide us with evidence, translation of knowledge to other populations and pathogens, and implications for the pre-analytical, analytical, and post-analytical phases (the process of TDM) are discussed in relevant detail. For each individual step, recommendations are made for the readers. We believe this will be a valuable resource and to be of added value to the many papers that focus on relations between exposure and efficacy or toxicity. It will help to achieve greater benefit of TDM
Pros and cons of therapeutic drug monitoring of antiretroviral agents.
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119505.pdf (Publisher’s version ) (Closed access)Therapeutic drug monitoring has the promise to become a part of routine patient care in the treatment of HIV infection. It is known that plasma drug concentrations of protease inhibitors and non-nucleoside reverse transcriptase inhibitors are better predictors of antiviral response or toxicity than drug dose is. Furthermore, high interpatient variability is significant. In addition, therapeutic drug monitoring may be used as a direct and objective instrument to measure non-adherence. This review describes possibilities and limitations of therapeutic drug monitoring in HIV treatment
A Model-Informed Method for the Purpose of Precision Dosing of Isoniazid in Pulmonary Tuberculosis
No full textBackground and Objective This study aimed to develop and evaluate a population pharmacokinetic model and limited sampling strategy for isoniazid to be used in model-based therapeutic drug monitoring. Methods A population pharmacokinetic model was developed based on isoniazid and acetyl-isoniazid pharmacokinetic data from seven studies with in total 466 patients from three continents. Three limited sampling strategies were tested based on the available sampling times in the dataset and practical considerations. The tested limited sampling strategies sampled at 2, 4, and 6 h, 2 and 4 h, and 2 h after dosing. The model-predicted area under the concentration–time curve from 0 to 24 h (AUC24) and the peak concentration from the limited sampling strategies were compared to predictions using the full pharmacokinetic curve. Bias and precision were assessed using the mean error (ME) and the root mean square error (RMSE), both expressed as a percentage of the mean model-predicted AUC24 or peak concentration on the full pharmacokinetic curve. Results Performance of the developed model was acceptable and the uncertainty in parameter estimations was generally low (the highest relative standard error was 39% coefficient of variation). The limited sampling strategy with sampling at 2 and 4 h was determined as most suitable with an ME of 1.1% and RMSE of 23.4% for AUC24 prediction, and ME of 2.7% and RMSE of 23.8% for peak concentration prediction. For the performance of this strategy, it is important that data on both isoniazid and acetyl-isoniazid are used. If only data on isoniazid are available, a limited sampling strategy using 2, 4, and 6 h can be employed with an ME of 1.7% and RMSE of 20.9% for AUC24 prediction, and ME of 1.2% and RMSE of 23.8% for peak concentration prediction. Conclusions A model-based therapeutic drug monitoring strategy for personalized dosing of isoniazid using sampling at 2 and 4 h after dosing was successfully developed. Prospective evaluation of this strategy will show how it performs in a clinical therapeutic drug monitoring setting
Clofazimine as a Treatment for Multidrug-Resistant Tuberculosis: A Review
No full textMultidrug-resistant tuberculosis (MDR-TB) is an infectious disease caused by Mycobacterium tuberculosis which is resistant to at least isoniazid and rifampicin. This disease is a worldwide threat and complicates the control of tuberculosis (TB). Long treatment duration, a combination of several drugs, and the adverse effects of these drugs are the factors that play a role in the poor outcomes of MDR-TB patients. There have been many studies with repurposed drugs to improve MDR-TB outcomes, including clofazimine. Clofazimine recently moved from group 5 to group B of drugs that are used to treat MDR-TB. This drug belongs to the riminophenazine class, which has lipophilic characteristics and was previously discovered to treat TB and approved for leprosy. This review discusses the role of clofazimine as a treatment component in patients with MDR-TB, and the drug’s properties. In addition, we discuss the efficacy, safety, and tolerability of clofazimine for treating MDR-TB. This study concludes that the clofazimine-containing regimen has better efficacy compared with the standard one and is also well-tolerated. Clofazimine has the potential to shorten the duration of MDR-TB treatment
Analytical and Clinical Validation of Assays for Volumetric Absorptive Microsampling (VAMS) of Drugs in Different Blood Matrices: A Literature Review
No full textVolumetric absorptive microsampling (VAMS) is the newest and most promising sample-collection technique for quantitatively analyzing drugs, especially for routine therapeutic drug monitoring (TDM) and pharmacokinetic studies. This technique uses an absorbent white tip to absorb a fixed volume of a sample (10–50 µL) within a few seconds (2–4 s), is more flexible, practical, and more straightforward to be applied in the field, and is probably more cost-effective than conventional venous sampling (CVS). After optimization and validation of an analytical method of a drug taken by VAMS, a clinical validation study is needed to show that the results by VAMS can substitute what is gained from CVS and to justify implementation in routine practice. This narrative review aimed to assess and present studies about optimization and analytical validation of assays for drugs taken by VAMS, considering their physicochemical drug properties, extraction conditions, validation results, and studies on clinical validation of VAMS compared to CVS. The review revealed that the bio-analysis of many drugs taken with the VAMS technique was optimized and validated. However, only a few clinical validation studies have been performed so far. All drugs that underwent a clinical validation study demonstrated good agreement between the two techniques (VAMS and CVS), but only by Bland–Altman analysis. Only for tacrolimus and mycophenolic acid were three measurements of agreement evaluated. Therefore, VAMS can be considered an alternative to CVS in routine practice, especially for tacrolimus and mycophenolic acid. Still, more extensive clinical validation studies need to be performed for other drugs
Electronic monitoring of treatment adherence and validation of alternative adherence measures in tuberculosis patients: a pilot study
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95858.pdf (Publisher’s version ) (Open Access)OBJECTIVE: To assess adherence to community-based directly observed treatment (DOT) among Tanzanian tuberculosis patients using the Medication Event Monitoring System (MEMS) and to validate alternative adherence measures for resource-limited settings using MEMS as a gold standard. METHODS: This was a longitudinal pilot study of 50 patients recruited consecutively from one rural hospital, one urban hospital and two urban health centres. Treatment adherence was monitored with MEMS and the validity of the following adherence measures was assessed: isoniazid urine test, urine colour test, Morisky scale, Brief Medication Questionnaire, adapted AIDS Clinical Trials Group (ACTG) adherence questionnaire, pill counts and medication refill visits. FINDINGS: The mean adherence rate in the study population was 96.3% (standard deviation, SD: 7.7). Adherence was less than 100% in 70% of the patients, less than 95% in 21% of them, and less than 80% in 2%. The ACTG adherence questionnaire and urine colour test had the highest sensitivities but lowest specificities. The Morisky scale and refill visits had the highest specificities but lowest sensitivities. Pill counts and refill visits combined, used in routine practice, yielded moderate sensitivity and specificity, but sensitivity improved when the ACTG adherence questionnaire was added. CONCLUSION: Patients on community-based DOT showed good adherence in this study. The combination of pill counts, refill visits and the ACTG adherence questionnaire could be used to monitor adherence in settings where MEMS is not affordable. The findings with regard to adherence and to the validity of simple adherence measures should be confirmed in larger populations with wider variability in adherence rates
International interlaboratory proficiency testing program for measurement of azole antifungal plasma concentrations.
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80118.pdf (Publisher’s version ) (Open Access)An international interlaboratory proficiency testing program for the measurement of antifungal drugs was initiated in 2007. This first round was limited to azole antifungals: fluconazole, itraconazole and hydroxyitraconazole, voriconazole, and posaconazole. The results demonstrate the need for and utility of an ongoing proficiency testing program to further improve the analytical methods for routine patient management and clinical research
Emerg Infect Dis
No full textTo determine differences in the ability of Mycobacterium tuberculosis strains to withstand antituberculosis drug treatment, we compared the activity of antituberculosis drugs against susceptible Beijing and East-African/Indian genotype M. tuberculosis strains. Beijing genotype strains showed high rates of mutation within a wide range of drug concentrations, possibly explaining this genotype's association with multidrug-resistant tuberculosis
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