Population pharmacodynamics in patients receiving tinzaparin for the prevention and treatment of deep vein thrombosis

Objectives: We conducted population anticoagulant pharmacodynamic analysis for patients administered the low-molecular weight heparin tinzaparin. Meth ods: Data from 425 patients (2,631 observations) who participated in 2 Phas e III clinical studies were utilized in an analysis based on a pharmacodyna mic structural model of anti-Xa activity using non-linear mixed effects mod eling techniques. Anti-Xa activity from patients participating in a multice nter, randomized, double-blind clinical trial comparing intravenous once da ily, subcutaneous tinzaparin (175 IU/kg) with heparin for the treatment of deep vein thrombosis (DVT) was first examined using a 2-compartment model w ith first-order absorption and endogenous anti-Xa activity. Covariates incl uded renal function, body weight, age, gender, race, obesity concomitant ad ministration of warfarin, an diabetes. Results: The population estimates an d 90% confidence intervals (CI) for oral clearance (CL) and apparent volume of distribution of the plasma compartment (Vc) were 0.0176 l/h/kg (CI = 0. 012 - 0.023) and 0.098 l/kg (CI = 0.088 - 0.109), respectively. The elimina tion half-life was 3.9 h (CI = 2.5 - 5.2). These estimates are similar to f indings in healthy volunteers. The inter-patient variability in clearance w as related to plasma creatinine and percent above ideal body weight. Cleara nce decreased by 22% for patients with severe renal function impairment (cr eatinine clearance < 30 ml/min), and by about 25% in obese patients (BMI > 30 kg/m(2)). Conclusions: Changes of these magnitudes were not clinically i mportant in pooled clinical trial safety and efficacy analyses. Body weight was not a significant covariate in the model supporting the observations i n earlier well-defined trials, where tinzaparin was dosed on a weight basis (IU/kg). Clearance was not influenced by age, race or gender. The same mod el was applied to data obtained from a prospective, randomized, double-blin d clinical trial comparing tinzaparin (4,500 IU) to enoxaparin (40 mg) once daily in patients undergoing total hip replacement. Model parameters were similar to those previously obtained supporting the extension of these resu lts across dose and indication. Population analysis in patients with diseas e and heterogeneity indicated similar pharmacodynamics as in volunteers, su pporting weight-based dosing and identified the dependence of clearance on obesity and severe renal function, although the magnitude of these effects are probably not clinically significant.