Assessment of the nlmixr R package for population pharmacokinetic modeling: A metformin case study

Aim nlmixr offers first-order conditional estimation (FOCE), FOCE with interaction (FOCEi) and stochastic approximation estimation-maximisation (SAEM) to fit nonlinear mixed-effect models (NLMEM). We modelled metformin's pharmacokinetic data using nlmixr and investigated SAEM and FOCEi's performance with respect to bias and precision of parameter estimates, and robustness to initial estimates. Method Compartmental models were fitted. The final model was determined based on the objective function value and inspection of goodness-of-fit plots. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re-estimated as the initial estimates were perturbed 100 times and resultant changes evaluated. Results The absorption kinetics of metformin depend significantly on food status. Under the fasted state, the first-order absorption into the central compartment was preceded by zero-order infusion into the depot compartment, whereas for the fed state, the absorption into the depot was instantaneous followed by first-order absorption from depot into the central compartment. The means of relative mean estimation error (rMEE) (MEESAEMMEEFOCEi$$ \frac{\mathrm{ME}{\mathrm{E}}_{\mathrm{SAEM}}}{\mathrm{ME}{\mathrm{E}}_{\mathrm{FOCEi}}} $$) and rRMSE (RMSESAEMRMSEFOCEi$$ \frac{\mathrm{RMS}{\mathrm{E}}_{\mathrm{SAEM}}}{\mathrm{RMS}{\mathrm{E}}_{\mathrm{FOCEi}}} $$) were 0.48 and 0.35, respectively. All parameter estimates given by SAEM appeared to be narrowly distributed and were close to the true value used for simulation. In contrast, the distribution of estimates from FOCEi were skewed and more biased. When initial estimates were perturbed, FOCEi estimates were more biased and imprecise. Discussion nlmixr is reliable for NLMEM. SAEM was superior to FOCEi in terms of bias and precision, and more robust against initial estimate perturbations.