Model building

Data from all 64 patients were included in the model‐building process. Two patients had no recorded value of height, and their height was imputed using multivariate linear regression using the distribution of age, gender and weight in the dataset.

Linear and nonlinear elimination one‐ and two‐compartment disposition models were considered to describe the concentrations of UFH. Maximum response (E _max), sigmoid E _max, linear and log‐linear models were considered to describe the concentration–effect relationship. PD parameters were estimated sequentially using the population pharmacokinetic parameters and data (PPP & D) estimation method 20. A sequential estimation method was chosen in order to avoid introducing bias to the PK model estimation 21.

Censored PD data (above the upper limit of quantification) were accounted for using Beal's M3 likelihood estimation (modified to account for right‐censoring of data) 22. This was implemented in NONMEM using the F‐Flag variable, where the likelihood of an observation being above the upper limit of quantification is calculated and maximized with respect to model parameters.