A systematic review and meta-analysis of dabigatran peak and trough concentration in adults.

Dabigatran etexilate is an oral direct thrombin inhibitor used in preventing thromboembolism in patients with atrial fibrillation and several other conditions. Routine dabigatran concentration monitoring is not recommended in clinical practice; however, measurement of dabigatran concentration may be required in several conditions. This study aims to pool the peak and trough dabigatran concentration from real-world studies. A systematic review was performed to identify studies that measured the peak and trough dabigatran concentrations. Observational studies reporting dabigatran peak or trough concentrations and patients' clinical characteristics of either sex, age or weight were included. Random-effect meta-analyses and metaregression were conducted to pool dabigatran concentrations and to identify the correlation between factors affecting dabigatran concentrations. Fifteen studies with a total of 1226 patients were included. The pooled peak dabigatran concentration was 133 ng/mL (95% CI: 113-154, I2  = 86%, n = 655), while the pooled dabigatran trough concentration was 80 ng/mL (95% CI: 69-91, I2  = 93%, n = 1010). Metaregression analyses suggested that age is significantly correlated to trough concentration, while body weight and creatinine clearance significantly correlated to peak concentration. Subgroup results revealed that dabigatran concentration when measured with liquid chromatography-tandem mass spectrometry was higher than haemoclot thrombin inhibitor assay. Several guidelines have proposed dabigatran concentrations target range and the pooled dabigatran concentrations were in line with the suggested range. Further studies to correlate dabigatran concentrations and clinical outcomes is warranted to improve the safety and efficacy monitoring of dabigatran therapy.

Pharmacogenetics of Statin-Induced Myotoxicity.

Statins, a class of lipid-lowering medications, have been a keystone treatment in cardiovascular health. However, adverse effects associated with statin use impact patient adherence, leading to statin discontinuation. Statin-induced myotoxicity (SIM) is one of the most common adverse effects, prevalent across all ages, genders, and ethnicities. Although certain demographic cohorts carry a higher risk, the impaired quality of life attributed to SIM is significant. The pathogenesis of SIM remains to be fully elucidated, but it is clear that SIM is multifactorial. These factors include drug-drug interactions, renal or liver dysfunction, and genetics. Genetic-inferred risk for SIM was first reported by a landmark genome-wide association study, which reported a higher risk of SIM with a polymorphism in the SLCO1B1 gene. Since then, research associating genetic factors with SIM has expanded widely and has become one of the foci in the field of pharmacogenomics. This review provides an update on the genetic risk factors associated with SIM.

Routine Therapeutic Drug Monitoring of Dabigatran: Experience at a Tertiary Center.

BACKGROUND: A liquid chromatography-mass spectrometry assay to determine plasma dabigatran concentrations has been available for routine clinical use at our tertiary institutions since 2017. The aim of the study was to describe (1) the use of the assay over time; (2) the indications for testing; and (3) subsequent dabigatran prescribing decisions. METHODS: Patients for whom dabigatran concentrations were measured were identified using the laboratory database, and clinical data were extracted from the associated electronic health records. RESULTS: There were 233 samples in 24 months. The use of dabigatran increased over time, with a mean (95% confidence interval) increase of +0.5 (0.3-0.7) samples per month. Dabigatran concentrations ranged from <1 to 1060 mcg/L. The main reasons for testing were uncertainty about impact on renal function and drug interactions (39%), to inform prescribing decisions after thromboembolic or bleeding events (21%), and for investigation following dose-adjustment (16%). Dabigatran dose was changed after 30% (68/233) of assay results. CONCLUSIONS: The clinical use of the dabigatran assay has increased, with almost one-third of results associated with a subsequent change in dabigatran prescribing.

Total flucloxacillin plasma concentrations poorly reflect unbound concentrations in hospitalized patients with Staphylococcus aureus bacteraemia.

AIMS: Flucloxacillin dosing may be guided by measurement of its total plasma concentrations. Flucloxacillin is highly protein bound with fraction unbound in plasma (fu ) of around 0.04 in healthy individuals. The utility of measuring unbound flucloxacillin concentrations for patients outside the intensive care unit (ICU) is not established. We aimed to compare flucloxacillin fu in non-ICU hospitalised patients against healthy volunteers, and to examine the performance of a published model for predicting unbound concentrations, using total flucloxacillin and plasma albumin concentrations. METHODS: Data from 12 healthy volunteers (248 samples) and 47 hospitalized patients (61 samples) were examined. Plasma flucloxacillin concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Flucloxacillin fu for the two groups was compared using a generalized estimating equation model to account for clustered observations. The performance of the single protein binding site prediction model in hospitalized patients was compared with measured unbound concentrations using Bland-Altman plots. RESULTS: The median (range) flucloxacillin fu for healthy (median albumin 45 g l-1 ) and hospitalized individuals (median albumin 30 g l-1 ) were 0.04 (0.02-0.07) and 0.10 (0.05-0.37), respectively (P < 0.0001). The prediction model underpredicted unbound flucloxacillin concentrations with a mean bias (95% limits of agreement) of -54% (-137%, +30%). CONCLUSIONS: The flucloxacillin fu values observed in our cohort of hospitalized patients had a wide range and were greater than those of healthy individuals. Unbound flucloxacillin plasma concentrations were predicted poorly by the model. Instead, unbound concentrations should be measured to guide dosing.

Influence of adult age on the total and free clearance and protein binding of (R)- and (S)-warfarin.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Hepatic drug clearance is thought to be reduced with age. However for highly protein bound drugs, which are cleared by capacity-limited metabolism, studies on total clearance have been conflicting. The hypothesis that protein binding decreases with age has been used to explain this. Warfarin is a highly protein bound drug, which is cleared by capacity-limited metabolism. There are conflicting or little data on the relationship between adult age and total and free clearance and protein binding of (R)- and (S)-warfarin. WHAT THIS STUDY ADDS: In a clinical study of 72 patients (18-89 years) on warfarin therapy, both total and free clearance of (R)-warfarin decreased with age. For (S)-warfarin there was a stronger signal of a decrease in free than total clearance. Protein binding was found not to correlate with age for (R)- and (S)-warfarin. In an ex vivo study, in which warfarin was spiked to plasma samples from 60 healthy subjects (19-87 years), no correlation between protein binding and age was found. These data support the hypothesis that hepatic drug clearance decreases with age. This should be taken into consideration when individualizing dosing, particularly in the elderly. AIMS: To test the hypothesis that the clearance (CL) of warfarin, a very highly protein bound drug with capacity-limited metabolism, decreases with age. METHODS: In a clinical study, a steady-state blood sample was taken from 72 patients (18-89 years) on routine treatment with warfarin. Concentrations of (R)- and (S)-warfarin were determined in plasma (total) and ultrafiltrate (free) by LC-MS/MS. Total and free CL and protein binding were determined and regressed against age and other covariates. In an ex vivo study, warfarin was spiked to plasma samples from 60 healthy subjects (19-87 years) and protein binding was regressed against age and other covariates. RESULTS: For (R)-warfarin a significant decrease with age was found for both total and free CL (P < 0.001). For (S)-warfarin there was a stronger signal of a decrease with age in free CL (P= 0.005) vs. total CL (P= 0.045). The decrease in CL of (R)- and (S)-warfarin was 0.3-0.5% per year. Other covariates influencing CL were lean body weight for both (R)- and (S)-warfarin and CYP2C9 genotype and blood sampling time for (S)-warfarin. Protein binding of (R)- and (S)-warfarin was not found to change significantly with age in either the clinical or the spiked samples, despite a slight decrease in albumin concentration with age. CONCLUSIONS: These data support the hypothesis that the CL of (R)- and (S)-warfarin decreases with age. More accurate information was gained when measuring free CL for (S)-warfarin. Warfarin protein binding did not change significantly with age.

Quantification of total and free concentrations of R- and S-warfarin in human plasma by ultrafiltration and LC-MS/MS.

A sensitive LC-MS/MS assay for quantification of total and free concentrations of R- and S-warfarin in plasma was required to support clinical studies on warfarin enantiomers. Several ultrafiltration devices were evaluated for separation of free warfarin from plasma proteins. The highest precision and lowest non-specific binding was obtained for Centrifree ultrafiltration devices. R- and S-warfarin were extracted from plasma (total) and ultrafiltrate (free) by liquid-liquid extraction with methyl tert-butyl ether using d(6)-warfarin as internal standard. Mean extraction recovery was 68 ± 4%. The enantiomers were separated on a Chirobiotic V column with isocratic elution using 40% methanol and 0.03% acetic acid in water. Negative mode electrospray ionisation was used for MS/MS detection, monitoring the ion transition m/z 307/161. Calibration curves (quadratic, weighted 1/x) were fitted over the range of 20-2,000 ng/ml (r(2)≥0.995) in plasma and 0.5-20 ng/ml (r(2)≥0.998) in ultrafiltrate. The lower limit of quantification for R- and S-warfarin was 0.5 ng/ml in ultrafiltrate. Intra- and interday precision (% RSD) and bias were within 10% in all cases, and matrix effects were negligible. The assay was applied successfully to analysis of samples from clinical studies.