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Moon Hee Lee,1 Seok-Kyu Yoon,1 Hyungsub Kim,2 Yong-Soon Cho,3 Sungpil Han,4 Shi Hyang Lee,1 Kyun-Seop Bae,1 Jina Jung,5 Sung Hee Hong,5 Hyeong-Seok Lim1 1Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; 2Department of Emergency Medical Services, College of Health Sciences, Eulji University, Seongnam, Republic of Korea; 3Department of Pharmacology and Clinical Pharmacology, Inje University College of Medicine, Busan, Republic of Korea; 4Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 5Hanmi Pharmaceutical Co. Ltd., Seoul, Republic of KoreaCorrespondence: Hyeong-Seok Lim, Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea, Tel +82-2-3010-4613, Fax +82-2-3010-4623, Email mdlhs@amc.seoul.krPurpose: The combined administration of bazedoxifene, a tissue-selective estrogen receptor modulator, and cholecalciferol can be a promising therapeutic option for postmenopausal osteoporosis patients. This study aimed to examine the pharmacokinetic interactions between these two drugs and the tolerability of their combined administration in healthy male subjects.Patients and Methods: Thirty male volunteers were randomly assigned to one of the six sequences comprised of three treatments: bazedoxifene 20 mg monotherapy, cholecalciferol 1600 IU monotherapy, and combined bazedoxifene and cholecalciferol therapy. For each treatment, a single dose of the investigational drug(s) was administered orally, and serial blood samples were collected to measure the plasma concentrations of bazedoxifene and cholecalciferol. Pharmacokinetic parameters were calculated using the non-compartmental method. The point estimate and 90% confidence interval (CI) of the geometric mean ratio (GMR) were obtained to compare the exposures of combined therapy and monotherapy. The pharmacokinetic parameters compared were the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast). The safety and tolerability of the combined therapy were assessed in terms of the frequency and severity of adverse events (AEs).Results: For bazedoxifene, the GMR (90% CI) of the combined therapy to monotherapy was 1.044 (0.9263– 1.1765) for Cmax and 1.1329 (1.0232– 1.2544) for AUClast. For baseline-adjusted cholecalciferol, the GMR (90% CI) of the combined therapy to monotherapy was 0.8543 (0.8005– 0.9117) for Cmax and 0.8056 (0.7445– 0.8717) for AUClast. The frequency of AEs observed was not significantly different between the combined therapy and monotherapy, and their severity was mild in all cases.Conclusion: A mild degree of pharmacokinetic interaction was observed when bazedoxifene and cholecalciferol were administered concomitantly to healthy male volunteers. This combined therapy was well tolerated at the dose levels used in the present study.Keywords: bazedoxifene, cholecalciferol, drug-drug interaction, pharmacokinetics, tolerability

Seok Kyu Yoon,1 Kyun-Seop Bae,1 Dong Hyun Hong,2 Seong Su Kim,2 Young Kweon Choi,2 Hyeong-Seok Lim1 1Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea; 2Department of Pharmaceutical Research, iCure Pharmaceutical Incorporated, Seoul, Republic of KoreaCorrespondence: Hyeong-Seok LimDepartment of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Songpa-Gu, Seoul Tel +82-2-3010-4623Fax +82-2-3010-4622Email mdlhs@amc.seoul.krIntroduction: This study characterized the pharmacokinetics (PKs) of a donepezil patch formulation currently under development, using mixed effect modeling analysis, and explored optimal patch dosing regimens in comparison with the donepezil oral formulation.Methods: PK data used in this analysis were from 60 healthy Korean male subjects participating in two Phase I studies, where subjects received single or multiple doses of donepezil of 43.75, 87.5, and 175 mg via patches, and 12 of them received a single oral dose of 10 mg of donepezil, followed by a single dose of donepezil via a patch. Donepezil PKs were analyzed by nonlinear mixed effect modeling using NONMEM software.Results: A well-stirred model with two-compartment distribution and delayed absorption was chosen as the best model for the oral formulation. The PKs of donepezil after the patch applications were best described by a two-compartment linear model with zero-order absorption (D2) and absorption delay. The relative bioavailability (BA) of donepezil after the patch application compared with oral dosing was described to be affected by the duration of patch application.Conclusion: PK simulations based on the chosen PK models suggested that, overall, donepezil exposure in plasma is similar whether with 10 mg of oral donepezil every 24 h or a 175 mg patch every 72 h, and likewise with 5 mg of oral donepezil every 24 h or an 87.5 mg patch every 72 h.Keywords: clinical trial(s), clinical trial simulation(s), pharmacokinetics, pharmacometrics, analysis