**5. Conclusions**

In summary, our PBPK model for tramadol and M1 was developed and predicted concentration–time profiles after multiple administrations of a tramadol ER formulation in the Korean population. Di fferences in PK profiles and concentration-dependent toxicities were predicted according to CYP2D6 phenotype and dosage. Most modeling studies of tramadol used a population PK approach, and the literature using PBPK modeling focused on the PK profile of tramadol itself. However, this study developed a model with predictive power for tramadol and M1, the major active

metabolite. This model could be applied to predict concentration-dependent toxicity profiles in cases of tramadol overdose or abuse and also, CYP2D6-related drug interactions.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1999-4923/11/11/618/s1, Figure S1: The predicted mean tramadol and *O*-desmethyltramadol concentration-time profiles after administration of 100 mg tramadol ER tablet twice daily (five times in total) for CYP2D6 poor metabolizer, intermediate metabolizer, extensive metabolizer and ultra-rapid metabolizer, respectively; Figure S2: The predicted mean tramadol and *O*-desmethyltramadol concentration-time profiles after administration of 200 mg tramadol ER tablet twice daily (five times in total) for CYP2D6 poor metabolizer, intermediate metabolizer, extensive metabolizer and ultra-rapid metabolizer, respectively.

**Author Contributions:** J.-W.B., S.L. and K.-H.S. conceived and designed the experiments; H.-C.J., S.H.B. and K.-H.S. performed the experiments, simulations, and analyzed the data; H.-C.J., Y.J., S.H.B., A.K. and K.-H.S. reviewed the data and wrote the paper. All authors approved the final manuscript.

**Funding:** This research was supported by the Bio and Medical Technology Development Program of the National Research Foundation (NRF) and was funded by the Korean governmen<sup>t</sup> (MSIP and MOHW; No. NRF-2015M3A9E1028327) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI17C0927).

**Conflicts of Interest:** The authors declare no conflict of interest.
