Evaluation of IPPSE, an alternative method for sequential population PKPD analysis.

The aim of this study is to present and evaluate an alternative sequential method to perform population pharmacokinetic-pharmacodynamic (PKPD) analysis. Simultaneous PKPD analysis (SIM) is generally considered the reference method but may be computationally burdensome and time consuming. Evaluation of alternative approaches aims at speeding up the computation time and stabilizing the estimation of the models, while estimating the model parameters with good enough precision. The IPPSE method presented here uses the individual PK parameter estimates and their uncertainty (SE) to propagate the PK information to the PD estimation step, while the IPP method uses the individual PK parameters only and the PPP&D method utilizes the PK data. Data sets (n = 200) with various study designs were simulated according to a one-compartment PK model and a direct Emax PD model. The study design of each dataset was randomly selected. The same PK and PD models were fitted to the simulated observations using the SIM, IPP, PPP&D and IPPSE methods. The performances of the methods were compared with respect to estimation precision and bias, and computation time. Estimated precision and bias for the IPPSE method were similar to that of SIM and PPP&D, while IPP had higher bias and imprecision. Compared with the SIM method, IPPSE saved more computation time (61%) than PPP&D (39%), while IPP remained the fastest method (86% run time saved). The IPPSE method is a promising alternative for PKPD analysis, combining the advantages of the SIM (higher precision and lower bias of parameter estimates) and the IPP (shorter run time) methods.