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.

Objective: This study aimed to assess effectiveness and safety outcomes of antiplatelet therapy for secondary prevention among patients with ischaemic stroke or transient ischaemic attack (TIA) in Malaysia. Method: Patients with a first ischaemic stroke/TIA between 2014 and 2017 were identified from stroke registry and data was linked with other data sources for information on antiplatelet exposure and outcome events. Exposure was defined as antiplatelet therapy at discharge from the index stroke hospitalisation and categorised into single antiplatelet therapy (SAPT) and dual antiplatelet therapy (DAPT) groups. Primary outcome was composite events of stroke, myocardial infarction, and all-cause death at up to one year after the index stroke in an intention-to-treat analysis. Results: Of 4434 patients included in the analysis, 6.7% were treated with DAPT and 93.3% were in SAPT group. During the 1-year follow-up, composite events occurred in 5.7% of patients in DAPT group and in 12.3% of SAPT (p<0.001). The rates of individual events were lower in DAPT group compared to SAPT: recurrent stroke (3.4% versus 4.8%), myocardial infarction (0.7% versus 1.9%), and all-cause death (1.7% versus 6.0%). Bleeding occurred in 1.3% of the DAPT group versus 1.6% of the SAPT. Multivariable-adjusted Cox regression analysis showed that rates of composite outcome was lower in the DAPT group compared to SAPT (HR 0.53, 95%CI 0.32, 0.86). Conclusion: In patients with ischaemic stroke/TIA, treatment with DAPT following the index stroke was associated with reduced risk of the composite events of stroke, myocardial infarction, and death. There appears to be similar risk of bleeding with DAPT versus SAPT.