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

Abstract

Aim: nlmixr offers first-order conditional estimation with or without interaction (FOCE or FOCEi) and stochastic approximation estimation-maximisation (SAEM) to fit nonlinear mixed-effect models (NLMEM). We modelled metformin’s population pharmacokinetics with flip-flop characteristics within nlmixr framework and investigated SAEM and FOCEi’s performance with respect to bias, precision, and robustness. Method: Compartmental pharmacokinetic models were fitted. The final model was determined based on the lowest objective function value and visual inspection of goodness-of-fit plots. To examine flip-flop pharmacokinetics, k_a values of a typical concentration-time profile based on the final model were perturbed and changes in the steepness of the terminal elimination phase were evaluated. 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: A one-compartment model with transit compartment for absorption best described the data. At low n, Stirling’s approximation of n! over-approximated plasma concentration unlike the log-gamma function. Flip-flop pharmacokinetics were evident as the steepness of the terminal elimination phase changed with k_a. Mean rRMSE for fixed-effect parameters was 0.932. When initial estimates were perturbed, FOCEi estimates of k_a and food effect on k_a appeared bimodal and were upward biased. Discussion: nlmixr is reliable for NLMEM even if flip-flop is present but caution should be exercised when using Stirling’s approximation for n! in the transit compartment model. SAEM was marginally superior to FOCEi in bias and precision, but SAEM was superior against initial estimate perturbations.

Metformin—‘BRAINS & AIMS’ pharmacological/prescribing principles of commonly prescribed (Top 100) drugs: Education and discussion

“… A ltered physiology Modelling shows that the absorption kinetics of metformin depend significantly on food: with fasting, the first‐order absorption into the central compartment is preceded by zero‐order infusion into the depot compartment, whereas for the fed state, the absorption into the depot is instantaneous followed by first‐order absorption from depot into the central compartment. 36 P regnancy Can be used safely in pregnancy for pre‐existing and gestational diabetes. Whilst pregnant women with pre‐gestational diabetes on metformin are at a higher risk for adverse pregnancy outcomes than the general population, this appears to be due to the underlying diabetes since women on metformin for other indications do not present meaningfully increased risks 37 Breastfeeding—Safe to use whilst breastfeeding.…”

“…• Modelling shows that the absorption kinetics of metformin depend significantly on food: with fasting, the first-order absorption into the central compartment is preceded by zero-order infusion into the depot compartment, whereas for the fed state, the absorption into the depot is instantaneous followed by first-order absorption from depot into the central compartment. 36…”