Last updated 9 August 2020
The RE-LY PK model (Liesenfeld, T. et al. 2011) and the pooled PK model (Dansirikul, Lehr et al. 2012) have been implemented with some modifications. An allometric size effect using total body weight is used to scale clearance, intercompartmental clearance, central volume of distribution and peripheral volume of distribution. Size standardized (70 kg) parameters have been calculated from the reported values using the median total body weight for each study population. The reported effects of female sex (smaller clearance) and South-East Asian race (smaller central volume) have not been implemented because it is likely that these differences can be explained by smaller total body weight. The empirical association of increasing age with decreasing clearance has been retained for ages greater than or equal to 20 y. The effect of heart failure or atrial fibrillation on clearance are included. The reported effect of haemoglobin on volume of distribution have not been implemented. Instead, predicted concentrations are adjusted to the observed hematocrit relative to a standard hematocrit of 45% and the target concentration is standardized to a hematocrit of 45%.
Creatinine clearance (CLcr) is used to predict dabigatran clearance using the sigmoid Emax model proposed by (Liesenfeld, T. et al. 2011). In the Leisenfeld and Dansirikul studies CLcr was calculated using the Cockcroft & Gault method (Cockcroft and Gault 1976). In the NextDose model CLcr is predicted using the method described by Matthews (Matthews, Kirkpatrick et al. 2004) in adults and the Schwartz method in children (Schwartz 1992) assuming serum creatinine observations are at steady state. The Matthews method is essentially equivalent to Cockcroft & Gault but is based on a large population of patients treated with aminoglycosides rather than healthy veteran soldiers.
With a peak to trough ratio of 2:1 reported in RE-LY (Reilly, Lehr et al. 2014) the dabigatran Cssavg would be about 50% higher than the typical trough concentration. The acceptable trough plasma total (dabigatran+ acyl-glucuronide) conc range proposed by Chin et al. is 30-130 mcg/L. A trough target of 80 mcg/L can be assumed in the middle of this range and used to propose a steady state average target of 120 mcg/L.
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Cockcroft, D. W. and M. H. Gault (1976). "Prediction of creatinine clearance from serum creatinine." Nephron 16: 31-41.
Dansirikul, C., T. Lehr, K.-H. Liesenfeld, S. Haertter and A. Staab (2012). "A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery." Thromb Haemost 107(04): 775-785.
Liesenfeld, K.-H., L. T., C. Dansirikul, P. A. Reilly, S. J. Connolly, M. D. Ezekowitz, S. Yusuf, L. Wallentin, S. Haertter and A. Staab (2011). "Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial." Journal of Thrombosis and Haemostasis 9(11): 2168-2175.
Matthews, I., C. Kirkpatrick and N. Holford (2004). "Quantitative justification for target concentration intervention--parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides." Br J Clin Pharmacol 58(1): 8-19.
Reilly, P. A., T. Lehr, S. Haertter, S. J. Connolly, S. Yusuf, J. W. Eikelboom, M. D. Ezekowitz, G. Nehmiz, S. Wang, L. Wallentin and R.-L. Investigators (2014). "The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy)." J Am Coll Cardiol 63(4): 321-328.
Schwartz, G. J. (1992). "Does kL/PCr estimate GFR, or does GFR determine k?" Pediatr Nephrol 6(6): 512-515.