Background and objective: Pasireotide (SOM230, Signifor®) is a somatostatin analog approved in a subcutaneous formulation for the treatment of Cushing's disease. This analysis characterizes the population pharmacokinetics (PopPK) of subcutaneous pasireotide jointly in healthy volunteers (HVs) and Cushing's disease patients (CDPs), evaluating the effects of age, body size, and population on pasireotide pharmacokinetics.
Methods: The analysis dataset included five phase I studies and one each from phase II and phase III. A three-compartment, linear structural pharmacokinetic model was used. Models were specified a priori that varied in the relationship between HVs and CDPs, and the model with the lowest value of the Bayes Information Criterion (BIC) was selected. It was then used to illustrate various features of pasireotide pharmacokinetics.
Results and conclusions: In the final model, the estimated values of apparent clearance (CL/F), central volume of distribution, and deep peripheral volume of distribution of pasireotide in CDP were 59, 43, and 225% those of HVs at the same age and body size. Clearance increased with body size and decreased with age similarly for CDPs and HVs. The estimated CL/F for a typical CDP (40 years old, lean body weight [LBW] 49 kg) was 3.72 L/h, and for a typical HV (29 years old, LBW 61 kg) was 7.96 L/h. The model was judged adequate by visual predictive checks and diagnostic plots separately for HVs and CDPs and can be used for simulations for deriving exposure-response metrics for pharmacokinetic/pharmacodynamic analyses.