Dataset Information

Population Pharmacokinetics, Pharmacodynamics, and Exploratory Exposure-Response Analyses of Apixaban in Subjects Treated for Venous Thromboembolism.

ABSTRACT: Apixaban is approved for treatment of venous thromboembolism (VTE) and prevention of recurrence. Population pharmacokinetics, pharmacokinetics-pharmacodynamics (anti-FXa activity), and exposure-response (binary bleeding and thromboembolic endpoints) of apixaban in VTE treatment subjects were characterized using data from phase I-III studies. Apixaban pharmacokinetics were adequately characterized by a two-compartment model with first-order absorption and elimination. Age, sex, and Asian race had less than 25% impact on exposure, while subjects with severe renal impairment were predicted to have 56% higher exposure than the reference subject (60-year-old non-Asian male weighing 85 kg with creatinine clearance of 100 mL/min). The relationship between apixaban concentration and anti-FXa activity was described by a linear model with a slope estimate of 0.0159 IU/ng. The number of subjects with either a bleeding or thromboembolic event was small, and no statistically significant relationship between apixaban exposure and clinical endpoints could be discerned with a logistic regression analysis.

SUBMITTER: Byon W

PROVIDER: S-EPMC5445237 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Population Pharmacokinetics, Pharmacodynamics, and Exploratory Exposure-Response Analyses of Apixaban in Subjects Treated for Venous Thromboembolism.

Byon W W Sweeney K K Frost C C Boyd R A RA

CPT: pharmacometrics & systems pharmacology 20170501 5

Apixaban is approved for treatment of venous thromboembolism (VTE) and prevention of recurrence. Population pharmacokinetics, pharmacokinetics-pharmacodynamics (anti-FXa activity), and exposure-response (binary bleeding and thromboembolic endpoints) of apixaban in VTE treatment subjects were characterized using data from phase I-III studies. Apixaban pharmacokinetics were adequately characterized by a two-compartment model with first-order absorption and elimination. Age, sex, and Asian race had ...[more]

PMID: 28547774

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Project description:IntroductionAs a result of limited clinical data, guidelines do not recommend the use of non-vitamin K antagonist oral anticoagulants in patients who weigh > 120 kg or have a body mass index (BMI) > 40 kg/m2.MethodsThis post hoc analysis of the AMPLIFY trial evaluated the efficacy (venous thromboembolism [VTE]/VTE-related death), safety (major and composite of major and clinically relevant non-major [CRNM] bleeding), and exposure of apixaban compared with enoxaparin followed by warfarin for the treatment of VTE by body weight (≤ 60, > 60 to < 100, ≥ 100 to < 120, ≥ 120 kg) and BMI (≤ 25, > 25 to 30, > 30 to 35, > 35 to 40, > 40 kg/m2).ResultsAmong the AMPLIFY safety population, 5384 and 5359 patients had recorded body weight (range 28.9 to 222.0 kg; ≥ 120 kg, n = 290) and BMI (range 12.5-71.8 kg/m2; > 40 kg/m2, n = 263), respectively. The rates of recurrent VTE/VTE-related death for apixaban versus enoxaparin/warfarin were similar across body weight subgroups: relative risks (RR; 95% confidence intervals [CI]) were 0.63 (0.23, 1.72), 0.99 (0.65, 1.50), 0.77 (0.34, 1.72), and 0.20 (0.02, 1.72) for the ≤ 60, > 60 to < 100, ≥ 100 to < 120, and ≥ 120 kg groups, respectively (Pinteraction = 0.44). The rates of major bleeding were lower with apixaban versus enoxaparin/warfarin; RRs (95% CI) were 0.15 (0.02, 1.15), 0.41 (0.21, 0.77), not estimable, and 0.34 (0.04, 3.22), respectively (Pinteraction = not estimable). The rates of major/CRNM bleeding were significantly lower for apixaban versus enoxaparin/warfarin; RRs (95% CI) were 0.46 (0.24, 0.89), 0.49 (0.38, 0.63), 0.30 (0.16, 0.58), and 0.28 (0.12, 0.66), respectively (Pinteraction = 0.36). Similar trends were seen in the BMI subgroups. There was a modest, not clinically meaningful, decrease (< 30%) in the median predicted exposure with increasing body weight (n = 281).ConclusionsThe findings of this post hoc analysis support the use of apixaban in patients with body weight ≥ 120 kg or BMI > 40 kg/m2.Trial registration numberNCT00643201.

Project description:BACKGROUND:Currently, there are no direct comparisons of apixaban and rivaroxaban, two new oral direct factor Xa inhibitors approved for management of thromboembolic disorders. OBJECTIVE:Compare the pharmacokinetics and anti-factor Xa activity (AXA) of apixaban and rivaroxaban. METHODS:In this randomized, open-label, two-period, two-treatment crossover study, healthy subjects (N=14) received apixaban 2.5 mg twice daily (BID) and rivaroxaban 10 mg once daily (QD) for 4 days with a ?4.5-day washout. Plasma samples were obtained for pharmacokinetic and AXA assessments; parameters were calculated using noncompartmental methods. RESULTS:Median time-to-maximum concentration was 2 hours for both compounds, and the mean half-life was 8.7 and 7.9 hours for apixaban and rivaroxaban, respectively. Daily exposure, the area under the curve (AUC(0-24)), appeared similar for rivaroxaban (1,094 ng · h/mL) and apixaban (935 ng · h/mL), whereas mean peak-to-trough plasma concentration ratio was 3.6-fold greater for rivaroxaban (16.9) than apixaban (4.7). Coefficient of variation for exposure parameters (AUC0-24, Cmax, Cmin) was 20%-24% for apixaban versus 29%-46% for rivaroxaban. Peak AXA, AXA AUC(0-24), and AXA fluctuation were ~2.5-, 1.3-, and 3.5-fold higher for rivaroxaban than apixaban, respectively. Trough concentrations and AXA were lower for rivaroxaban (10 ng/mL and 0.17 IU/mL vs 17 ng/mL and 0.24 IU/mL for apixaban, respectively). Rivaroxaban exhibited a steeper concentration-AXA response (slope: 0.0172 IU/ng vs 0.0134 IU/ng for apixaban, P<0.0001). CONCLUSION:Apixaban 2.5 mg BID demonstrated less intersubject variability in exposure, lower AXA AUC, and higher trough and smaller peak-to-trough fluctuations in plasma concentration and AXA, suggesting more constant anticoagulation compared with rivaroxaban 10 mg QD. However, the clinical impact of these differences on the relative efficacy and safety of apixaban and rivaroxaban remains to be determined.

Project description:Background and objectiveLysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure-response relationship of oral LSD.MethodsWe analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included. Plasma concentrations of LSD, subjective effects, and vital signs were repeatedly assessed. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling.ResultsGeometric mean (95% confidence interval) maximum plasma concentration values of 1.3 (1.2-1.9) and 3.1 (2.6-4.0) ng/mL were reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. The plasma half-life was 2.6 h (2.2-3.4 h). The subjective effects lasted (mean ± standard deviation) 8.2 ± 2.1 and 11.6 ± 1.7 h for the 100- and 200-µg LSD doses, respectively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. A close relationship was observed between the LSD concentration and subjective response within subjects, with moderate counterclockwise hysteresis. Half-maximal effective concentration values were in the range of 1 ng/mL. No correlations were found between plasma LSD concentrations and the effects of LSD across subjects at or near maximum plasma concentration and within dose groups.ConclusionsThe present pharmacokinetic data are important for the evaluation of clinical study findings (e.g., functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented dose-proportional pharmacokinetics and first-order elimination up to 12 h. The effects of LSD were related to changes in plasma concentrations over time, with no evidence of acute tolerance.Trial registrationNCT02308969, NCT01878942.

Dataset Information

Population Pharmacokinetics, Pharmacodynamics, and Exploratory Exposure-Response Analyses of Apixaban in Subjects Treated for Venous Thromboembolism.

Publications

Population Pharmacokinetics, Pharmacodynamics, and Exploratory Exposure-Response Analyses of Apixaban in Subjects Treated for Venous Thromboembolism.

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