2011 - Athens - Greece

PAGE 2011: Cardiovascular, QT-prolongation
Jeroen Diepstraten

Pharmacodynamics of nadroparin using anti-Xa levels in morbidly obese patients upon subcutaneous administration of 5700 IU

Jeroen Diepstraten, Esther J.H. Janssen, Christian M. Hackeng, Simone van Kralingen, Mariska Y.M. Peeters, Eric P.A. van Dongen, René J. Wiezer, Bert van Ramshorst, Catherijne A.J. Knibbe

St. Antonius Hospital, Nieuwegein, The Netherlands

Objectives: Morbidly obese patients (body mass index (BMI) > 40 kg/m2) are at increased risk for thromboembolism, especially after surgery. In clinical practice a double dose of nadroparin for thrombosis prophylaxis is often used in (morbidly) obese patients, without proper pharmacodynamic studies. The aim of this study was to develop a population pharmacodynamic (PD) model of nadroparin used for thrombotic prophylaxis in morbidly obese patients, using anti Xa-levels as a PD endpoint.

Methods: Twenty morbidly obese patients were included with a median body weight of 144 kg (range 112 - 260 kg), a median BMI of 51 kg/m2 (range 38-79 kg/m2) and median lean body weight of 66 kg (range 54 – 100 kg). At induction of anaesthesia for bariatric surgery, 5700 IU (= 0.6 ml) nadroparin was administered subcutaneously. Chromogenic anti-Xa levels were measured just before and 10, 30, 60, 90, 120, 180, 240, 300 and 420 minutes after nadroparin injection and the next morning within 24 hours after administration. Population PD modelling was performed using NONMEM VI. A step-wise covariate analysis was performed for body weight, lean body weight, ideal body weight, BMI, age, sex, creatinine and bilirubin.

Results: In a two-compartment pharmacodynamic disposition model, the pharmacodynamic effect of nadroparin was found to be delayed and could be best described using a single transit compartment with parameters ktr and ka. Body weight (BW) proved to be the most predictive covariate for clearance (CL = 47.6 mL/min *(BW/144)**1.5) while lean body weight (LBW) was the most predictive covariate for volume of distribution (Vss = 12.6 L * (LBW/66)**1.5).

Conclusions:We developed a pharmacodynamic model for nadroparin using anti-Xa levels in morbidly obese patients with delayed effect, in which body weight and lean body weight proved to be the major determinant for clearance and volume of distribution, respectively.

Reference: PAGE 20 (2011) Abstr 2086 [www.page-meeting.org/?abstract=2086]
Poster: Cardiovascular, QT-prolongation