Apixaban plasma concentrations in patients with obesity.

PURPOSE: Routine therapeutic drug monitoring of apixaban is currently not recommended but may however be warranted in some situations and for some patient groups to provide better and safer treatment. Due to limited data on apixaban concentrations in different subpopulations, it is still unclear which group of patients could possibly gain from monitoring. The purpose of this study was to examine apixaban exposure in patients with obesity compared with normal-weight patients. METHODS: Forty patients with obesity (mean BMI 39.4 kg/m2) and 40 controls with normal weight (mean BMI 23.4 kg/m2), treated with apixaban 5 mg twice daily were included. The patients were matched for age, sex, and renal function. Trough and peak apixaban concentrations were measured with LC‒MS/MS methodology. RESULTS: The median trough concentrations in patients with obesity (58.7, range 10.7-200.7 ng/ml) were slightly higher than those in patients with normal weight (52.0, range 31.0-150.9 ng/ml) (p < 0.05). Notably, the variability in trough concentration was considerably higher in patients with obesity. Peak concentrations were similar in both groups, with a median of 124.5 ng/ml (range 82.0-277.5) and 113.5 ng/ml (range 75.5-334.6) in patients with obesity and normal weight, respectively. CONCLUSION: Apixaban exposure did not vary substantially between obese and normal weight matched controls, implying that general dose adjustments are not required. However, vast interindividual variability was observed in patients with obesity, suggesting that measuring the concentrations could be valuable for specific patients. Further research is needed to identify which specific patients may benefit from this approach.

Clinical evaluation of laboratory methods to monitor exposure of rivaroxaban at trough and peak in patients with atrial fibrillation.

PURPOSE: The one-dose daily regime of rivaroxaban could cause a pronounced variability in concentration and effect of which a deeper knowledge is warranted. This study aimed to evaluate the typical exposure range and effect of the direct factor Xa (FXa)-inhibitor rivaroxaban in a cohort of well-characterized patients with atrial fibrillation (AF). METHODS: Seventy-one AF patients (72 ± 8 years, 55 % men) were treated with rivaroxaban 15 mg/20 mg (n = 10/61) OD. Trough (n = 71) and peak (n = 30) plasma concentrations determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to the coagulation assays anti-FXa for rivaroxaban, prothrombin time-international normalized ratio (PT-INR) (venous samples and point-of-care assay (POC) CoaguChek XS Pro), and aPTT. RESULTS: Median rivaroxaban plasma concentrations by LC-MS/MS were 34 (range 5-84) and 233 ng/ml (range 120-375) at trough and peak, respectively. A strong correlation between LC-MS/MS and the anti-FXa assay was found (p < 0.001) for both trough (r (2) = 0.92) and peak (r (2) = 0.91) samples. PT-INR results from the POC assay, but not from the conventional PT assay, correlated significantly with LC-MS/MS in peak samples exclusively (r (2) = 0.41, p < 0.001). CONCLUSIONS: In "real-life" AF patients treated with rivaroxaban, we observed a pronounced variability in plasma concentrations at trough and to a lesser extent at peak measured by LC-MS/MS. The anti-FXa assay performed well upon rivaroxaban levels in a normal exposure range, although LC-MS/MS remains the only method that covers the whole concentration range with accuracy. Interestingly, the POC assay for PT-INR could be useful to indicate high exposure to rivaroxaban in emergency situations although further validation is required.

Apixaban trough concentrations in atrial fibrillation patients with reduced renal function.

INTRODUCTION: The direct factor Xa inhibitor apixaban is partially eliminated by the kidneys but is still prescribed at fixed doses without therapeutic drug monitoring across varying levels of renal function. If apixaban accumulates due to renal impairment, this may translate into safety concerns, e.g. the risk for bleeding. The purpose of this study was to measure apixaban trough concentrations in patients with different stages of renal function/renal impairment. METHODS: Apixaban trough concentrations were measured using LC-MS/MS in patients with atrial fibrillation, having normal renal function (apixaban 5 mg BID, n=39), moderate renal impairment (apixaban 5 mg BID, n=40) and severe renal impairment (apixaban 2.5 mg BID, n=6). The median (min-max) relative eGFR values were 84.8 (71.7-111.4), 51.4 (31.3-67.2) and 23.0 (21.9-28.4) mL/min/1.73 m², in the three groups, respectively. RESULTS: Patients with moderate renal impairment had significantly higher apixaban trough concentrations than patients with normal renal function. The median (min-max) trough concentrations were 59.8 ng/mL (15.5-170.9) for normal renal function, 128.9 ng/mL (41.4-295.4) for moderate renal impairment and 81.7 ng/mL (61.8-109.0) for severe renal impairment. The trough concentrations correlated significantly with renal function measured as relative/absolute eGFR creatinine/cystatin C. CONCLUSIONS: The standard dosing regimen of 5 mg apixaban BID renders exposure that is roughly twice as high in patients with moderately reduced renal function compared to patients with normal renal function. We suggest that patients with moderately reduced renal function ought to be monitored. Possibly, a dose reduction may be considered to achieve similar exposure as in patients with normal renal function.

Development of a computerised decisions support system for renal risk drugs targeting primary healthcare.

OBJECTIVES: To assess general practitioners (GPs) experience from the implementation and use of a renal computerised decision support system (CDSS) for drug dosing, developed for primary healthcare, integrated into the patient's electronic health record (EHR), and building on estimation of the patient's creatinine clearance (ClCG). DESIGN: Qualitative research design by a questionnaire and a focus group discussion. SETTING AND PARTICIPANTS: Eight GPs at two primary healthcare centres (PHCs). INTERVENTIONS: The GP at PHC 1, and the project group, developed and tested the technical solution of the CDSS. Proof-of-concept was tested by seven GPs at PHC 2. They also participated in a group discussion and answered a questionnaire. A web window in the EHR gave drug and dosage in relation to ClCG. Each advice was according to three principles: If? Why? Because. OUTCOME MEASURES: (1) The GPs' experience of 'easiness to use' and 'perceived usefulness' at PHC 2, based on loggings of use, answers from a questionnaire using a 5-point Likert scale, and answers from a focus group discussion. (2) The number of patients aged 65 years and older with an estimation of ClCG before and after the implementation of the CDSS. RESULTS: The GPs found the CDSS fast, simple and easy to use. They appreciated the automatic presentation of the CICG status on opening the medication list, and the ability to actively look up specific drug recommendations in two steps. The CDSS scored high on the Likert scale. All GPs wanted to continue the use of the CDSS and to recommend it to others. The number of patients with an estimated ClCG increased 1.6-fold. CONCLUSIONS: Acceptance of the simple graphical interface of this push and pull renal CDSS was high among the primary care physicians evaluating this proof of concept. The graphical model should be useful for further development of renal decision support systems.

Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation.

INTRODUCTION: The direct factor-Xa inhibitor apixaban is approved e.g. for the prevention of stroke in patients with atrial fibrillation (AF). Although routine monitoring of apixaban therapy is currently not recommended, selective monitoring could be useful to optimize efficacy and safety in certain clinical situations. We studied the exposure and effect of apixaban using different laboratory methods in a clinical setting with a well-defined cohort of AF patients. MATERIAL AND METHODS: Seventy AF patients (72±7.4years, 64 % men, mean CHADS2 score 1.7) treated with apixaban 2.5 (n=10) or 5mg BID (n=60). Trough plasma apixaban concentrations determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to the coagulation assays Anti-factor Xa, PT-INR and aPTT. RESULTS: The apixaban plasma concentration determined by LC-MS/MS varied more than 10-fold overall. The range was between 15-83 and 29-186ng/mL for the 2.5mg BID and 5mg BID respectively, with patients receiving 5mg BID having significantly higher apixaban concentrations (p<0.001). A strong correlation between LC-MS/MS and anti-FXa-assay was found (p<0.001), while aPTT and PT-INR were not sensitive enough. There were no significant correlations between gender, creatinine clearance, body weight or age and apixaban exposure. CONCLUSIONS: Anti-FXa-assay performed well upon apixaban concentrations in a normal exposure range. Still LC-MS/MS remains the "gold standard" method, covering also low concentrations. Compared to clinical trials, we observed relatively lower apixaban exposure and a more pronounced difference between high and low dose. Additional information regarding apixaban exposure and benefit-risk profile is needed in order to individualize treatment.

Differential impact of selective serotonin reuptake inhibitors on platelet response to clopidogrel: a randomized, double-blind, crossover trial.

STUDY OBJECTIVE: To assess the effect of two selective serotonin reuptake inhibitors (SSRIs), fluvoxamine and citalopram, that markedly differ in their level of cytochrome P450 (CYP) 2C19 inhibition, on the laboratory response to clopidogrel, a prodrug requiring metabolism by the CYP system, and especially CYP2C19, to produce its active form. DESIGN: Randomized, double-blind, crossover trial. SETTING: Clinical research unit of an academic medical center. SUBJECTS: Fifteen healthy male volunteers. INTERVENTION: All subjects received clopidogrel as a 300-mg loading dose on day 1, followed by 75 mg/day on days 2 and 3. Platelet function was tested at baseline and then after clopidogrel treatment on day 3. After a washout period of 2 weeks, subjects were randomly assigned in a double-blind manner to receive either citalopram 20 mg/day or fluvoxamine 100 mg/day for 7 days. On day 5, platelet function was tested while receiving the SSRI treatment alone; then, a 300-mg clopidogrel loading dose was administered, followed by clopidogrel 75 mg/day on days 6 and 7. Platelet function was then reassessed on day 7 while receiving the combination of the SSRI and clopidogrel. The treatment protocol was then repeated after a washout period of 2 weeks in all subjects with the other SSRI. MEASUREMENTS AND MAIN RESULTS: The antiplatelet effects of fluvoxamine and citalopram and their interactions with clopidogrel were assessed. The response to these three drugs was assessed by light transmittance aggregometry and vasodilator-stimulated phosphoprotein phosphorylation, reporting P2Y12 receptor reactivity. Both fluvoxamine and citalopram tended to reduce adenosine diphosphate-induced aggregation: 80.8 ± 3.4% at baseline, 67.3 ± 6.3% while receiving citalopram, and 65.8 ± 6.4% while receiving fluvoxamine. All subjects had a good laboratory response to clopidogrel, with a mean aggregation of 23.5 ± 3.2% and a mean platelet reactivity index of 47.7 ± 3.9% (p<0.001 compared with baseline for both methods). Laboratory response to clopidogrel was significantly attenuated in the presence of fluvoxamine compared with the response in the presence of citalopram as tested both by aggregometry (32.3 ± 4.2% vs 23.4 ± 3%, p=0.04) and by vasodilator-stimulated phosphoprotein phosphorylation (52.7 ± 5.1% vs 35.9 ± 4.2%, p=0.02). CONCLUSION: Fluvoxamine attenuated the laboratory response to clopidogrel, possibly through inhibition of CYP2C19, whereas citalopram did not affect this response. These potential drug interactions should be taken into consideration in the selection of the appropriate antidepressant agent for patients who are treated with clopidogrel.