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IMP was more sensitive to model misspecification without pre-systemic metabolism, IMP analysis failed to converge. For the most complex model (i.e., model of all three analytes, one of which having high level of data below quantification limit), FOCE failed to reliably assess parameter precision, while parameter precision obtained by IMP and SAEM was similar with SAEM being the faster method. FOCE FAST was about two times faster than FOCE but it was prone to premature termination. For simpler models (i.e., models of oxfendazole and/or oxfendazole sulfone), FOCE and FOCE FAST were more efficient than EM methods with shorter run time and comparable parameter precision. All methods yielded similar parameter estimates, but great differences were observed in parameter precision and modeling time. In this study, we compared the performance of FOCE, FOCE FAST, and two EM methods, namely importance sampling (IMP) and stochastic approximation expectation–maximization (SAEM), utilizing the rich pharmacokinetic data of oxfendazole and its two metabolites obtained from the first-in-human single ascending dose study in healthy adults.
![nonmem method 1 vs conditional nonmem method 1 vs conditional](https://www.researchgate.net/profile/Jasper-Stevens/publication/301686105/figure/fig2/AS:410960381661184@1474991998225/Post-hoc-individual-clearance-versus-weight-and-eta-distribution-versus-clearance-A_Q320.jpg)
In NONMEM 7, expectation–maximization (EM) estimation methods and FOCE with FAST option (FOCE FAST) were introduced.
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However, with growing data complexity, the performance of FOCE is challenged by long run time, convergence problem and model instability. First-order conditional estimation (FOCE) has been the most frequently used estimation method in NONMEM, a leading program for population pharmacokinetic/pharmacodynamic modeling.