Software
Data modeling and simulation were performed primarily in software NONMEM
(ICON, Ellicott City, Maryland, version 7.3) in conjunction with a
gfortran (64-bit) compiler using Pirana (version
2.9.7)16 as an interface. The Laplace integral
approximation with -2 times log-likelihood option was used throughout
the analyses. The R environment17 for statistical
computing version 3.6.2 was used for simulation and plotting.