MU referencing and time-varying covariates

Happy New Year, I hope everybody is ready for a great 2025 ! I'll start my message/question by defining 2 different ways of coding a simple power relationship between body weigh on clearance. * Coding 1 MU_1 = THETA(1) + THETA(2) * LOG(WGT/70) CL = EXP( MU_1 + ETA(1) ) * Coding 2 MU_1 = THETA(1) CL = EXP( MU_1 + ETA(1) ) * ( WGT/70 )**THETA(2) The reference and training materials for NONMEM clearly indicate that MU variables should be time invariant within occasions and recommend using coding 2 when body weight is time varying. Nevertheless, it is possible for an analyst to use coding 1. As far as I can tell from some limited testing, this is not a "fatal" error. Either with FOCE(I) or SAEM/IMP, NONMEM reports a warning but performs the model optimization. The table outputs also report CL as a time varying variable changing as body weight changes. So my questions are the following: when coding 1 is used and body weight is time varying, what is NONMEM actually doing during model optimization? Does NONMEM internally create occasions to break the records by interval of constant body weight and constant MU1? Alternatively, does NONMEM internally calculate an average of MU1? Something entirely different? What's the risk taken by an analyst when using coding 1 versus coding 2? Thank you in advance for you input Sébastien Bihorel Director, Quantitative Pharmacology +1 914-648-9581 [email protected] Regeneron - Internal ******************************************************************** This e-mail and any attachment hereto, is intended only for use by the addressee(s) named above and may contain legally privileged and/or confidential information. If you are not the intended recipient of this e-mail, any dissemination, distribution or copying of this email, or any attachment hereto, is strictly prohibited. If you receive this email in error please immediately notify me by return electronic mail and permanently delete this email and any attachment hereto, any copy of this e-mail and of any such attachment, and any printout thereof. Finally, please note that only authorized representatives of Regeneron Pharmaceuticals, Inc. have the power and authority to enter into business dealings with any third party. ********************************************************************