The impact of body weight on rivaroxaban pharmacokinetics.

BACKGROUND: There is concern amongst clinicians that the fixed dosing strategy of rivaroxaban for the treatment of venous thromboembolism (VTE) might not be optimal in those patients under or overweight. OBJECTIVE: To develop a pharmacokinetic model for rivaroxaban, based on real-world patients, specifically focusing on the impact of patients' body weight on rivaroxaban pharmacokinetics. PATIENTS/METHODS: One hundred and one patients prescribed rivaroxaban prophylactic or treatment doses for the prevention or treatment of VTE were recruited at a London teaching hospital. Subjects had up to 3 rivaroxaban concentrations measured during a single dosing period (trough, 1 and 3 hours post dose). Population pharmacokinetic analyses was conducted to develop a rivaroxaban model, which was subsequently evaluated. RESULTS: A one-compartment model with between-subject variability on rivaroxaban clearance and volume of distribution, with a combined (additive and proportional) error model, best fitted the data. Following a full covariate analysis, creatinine clearance on rivaroxaban clearance was found to be the significant covariate impacting on the pharmacokinetic profile of rivaroxaban in the dataset. CONCLUSIONS: Our results suggest that the most important covariate impacting on rivaroxaban pharmacokinetics is creatinine clearance and the weight alone has little effect. These findings are in line with previous studies for rivaroxaban. Larger datasets, from real-world patients who are followed longitudinally, should be conducted to provide front-line clinicians with further reassurance when prescribing rivaroxaban for the acute management of VTE.

Anticoagulation for prevention and treatment of cancer-related venous thromboembolism.

The close relationship between malignancy and venous thromboembolism (VTE) is well established, with malignancy increasing VTE risk and accounting for a substantial proportion of presentations with VTE. Moreover, VTE impacts significantly on morbidity and mortality in cancer patients. Anticoagulation for prevention and treatment of VTE requires a patient-centred approach due to the heterogeneous patient population and inherent increased thrombotic and bleeding risks. In recent years, low molecular weight heparin (LMWH) injections have come to be the mainstay for treatment and prevention of cancer-related VTE. For treatment, this is usually administered for at least 6 months and continued in patients with active cancer or those receiving treatment for cancer. The use of LMWH for thromboprophylaxis in hospitalised cancer patients is also well accepted, but out-of-hospital prophylaxis remains contentious. The development of risk assessment models may help identify the patients at highest risk. The role of the new oral factor Xa and thrombin inhibitors in this setting remains to be determined.

Platelet production and platelet destruction: assessing mechanisms of treatment effect in immune thrombocytopenia.

This study investigated the immature platelet fraction (IPF) in assessing treatment effects in immune thrombocytopenia (ITP). IPF was measured on the Sysmex XE2100 autoanalyzer. The mean absolute-IPF (A-IPF) was lower for ITP patients than for healthy controls (3.2 vs 7.8 × 109/L, P < .01), whereas IPF percentage was greater (29.2% vs 3.2%, P < .01). All 5 patients with a platelet response to Eltrombopag, a thrombopoietic agent, but none responding to an anti-FcγRIII antibody, had corresponding A-IPF responses. Seven of 7 patients responding to RhoD immuneglobulin (anti-D) and 6 of 8 responding to intravenous immunoglobulin (IVIG) did not have corresponding increases in A-IPF, but 2 with IVIG and 1 with IVIG anti-D did. This supports inhibition of platelet destruction as the primary mechanism of intravenous anti-D and IVIG, although IVIG may also enhance thrombopoiesis. Plasma glycocalicin, released during platelet destruction, normalized as glycocalicin index, was higher in ITP patients than controls (31.36 vs 1.75, P = .001). There was an inverse correlation between glycocalicin index and A-IPF in ITP patients (r² = -0.578, P = .015), demonstrating the relationship between platelet production and destruction. Nonresponders to thrombopoietic agents had increased megakaryocytes but not increased A-IPF, suggesting that antibodies blocked platelet release. In conclusion, A-IPF measures real-time thrombopoiesis, providing insight into mechanisms of treatment effect.