significantly decreased in rats with ethynyl estradiol induced cholestasis through the significant reduction of Oatp1a2 and Mrp2 expression. P218 APPLICATION OF TARGET-MEDIATED DRUG DISPOSITION MODEL TO PREDICT HUMAN PHARMACOKINETICS AND TARGET OCCUPANCY OF GC1118, AN ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODY Wan-Su Park 1, 2 , Seunghoon Han 1, 2 , Jongtae Lee 1, 2 , Taegon Hong 3 , Dong- Seok Yim 1, 2 . 1 PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul, South Korea; 2 Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary’s Hospital, Seoul, South Korea; 3 Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, South Korea GC1118 is an anti-EGFR monoclonal antibody under clinical development. We modeled the pharmacokinetics (PK) of GC1118 in monkeys to predict human PK and receptor occupancy (RO) profiles. Serum concentrations of GC1118 and its comparator (cetuximab) were characterized using non- compartmental analysis (NCA) and a target-mediated drug disposition (TMDD) model following intravenous infusion of 3-25 mg/kg in monkeys. The scaling exponent of the EGFR synthesis rate was determined by sensitivity analysis. Human cetuximab exposures (Cmax and AUC) pre- dicted by differing exponents (0.5-1.0) in the allometric monkey PK model were compared with those reported in literature. A TMDD model well described the monkey PK profile which showed a decrease in clearance (1.2 to 0.4 mL/hr/kg) with increasing doses. The exponents of 0.75 (clear- ance) and 1.0 (volume of distribution) were used for allometric scaling to predict human PK. The allometric coefficient for the EGFR synthesis rate chosen by the sensitivity analysis was 0.85. Based on the predicted con- centration of total target (EGFR) and drug-target complex, we estimated RO values that could not be measured experimentally. TMDD model of GC1118 in monkey was developed and was used to predict the human PK and RO of GC1118. This approach was applied to guide the dose selection in the first-in-human study. P219 BLOOD DISTRIBUTION OF SUBCUTANEOUS BORTEZOMIB AND ITS KINETICS IN MULTIPLE MYELOMA PATIENTS Takashi Osawa , Takafumi Naito, Yasuaki Mino, Junichi Kawakami. Hamamatsu University School of Medicine, Hamamatsu, Japan Bortezomib, a proteasome inhibitor is used for the treatment of multiple myeloma. Subcutaneous bortezomib shows less incidence of peripheral neuropathy than intravenous bortezomib. However, for some patients, it has poor therapeutic effects or causes serious adverse effects. Pharmaco- kinetic data for subcutaneous bortezomib are needed in order to ensure its safe and effective use. To date, the blood distribution of subcutaneous bortezomib remains to be clarified in multiple myeloma patients. Kinetic assessment of the blood disposition of bortezomib could contribute to the dose optimization for patients with multiple myeloma. This study aimed to evaluate the blood distribution of subcutaneous bortezomib and its ki- netics in multiple myeloma patients. The present study was an observation study conducted at a single site at Hamamatsu University Hospital. Twenty-six multiple myeloma patients treated with subcutaneous borte- zomib were enrolled. Subcutaneous bortezomib were administered concomitantly with dexamethasone on days 1, 8, 15, and 22 of each cycle (35 days for cycle). Blood specimens were drawn just before the borte- zomib administration on days 1 and 15 in the cycle n (n  2) and n+1 and after discontinuation. The bortezomib concentrations in the whole blood and plasma were determined using an LC-MS/MS. The relationships be- tween the bortezomib concentration and blood components were inves- tigated. The whole blood concentration of bortezomib on day 15 was significantly higher than that on day 1 in the cycle n. No significant dif- ference was observed in whole blood concentrations of bortezomib on day 15 between the cycle n and n+1. Interindividual variation was observed in whole blood concentrations of bortezomib on day 15 in the cycle n (IQR, 46.167.4 ng/mL) and n+1 (39.752.9 ng/mL). The bortezomib concen- trations in whole blood and blood cells were 2- and 4-fold higher than that in plasma, respectively. Interindividual variation was observed in the blood cell concentration of bortezomib (IQR, 89.4115.5 ng/mL). The bortezomib concentration in whole blood was correlated with red blood cell count, but not the other blood components. The median half-life of subcutaneous bortezomib in whole blood was 17 days. In conclusion, subcutaneous bortezomib was taken up into red blood cells to a limited extent. The bortezomib concentration in whole blood was associated with the red blood cell count. Subcutaneous bortezomib was eliminated with the life- span of red blood cells. The turnover of red blood cells can affect the blood disposition of bortezomib in multiple myeloma patients. P220 CIRCADIAN OSCILLATION IN THE INTESTINAL EXPRESSION OF OCTN1/ SLC22A4 UNDERLIES THE DOSING TIME-DEPENDENT CHANGES IN THE ABSORPTION OF PREGABALIN AND ITS ANALGESIC EFFECTS ON DIABETIC NEUROPATHY Satoru Koyanagi 1 , Takahiro Akamine 1 , Erika Wada 1 , Naoki Kusunose 2 , Marie Taniguchi 1 , Naoya Matsunaga 1 , Shigehiro Ohdo 1 . 1 Kyushu University, Fukuoka, Japan; 2 Oita University, Yufu, Japan Introduction: One approach to increase the effect of pharmacotherapy is the administration of drugs at times of day when they are most effective. Circadian variations in biological functions are important factors that affect the efficacy of drugs. Previous study suggested a molecular clock- independent mechanism by which bile acid-regulated peroxisome pro- liferator-activated receptor-a (PPARa) activity governs the circadian expression of intestinal transporter [1]. Recently, we identified that organic cation transporter novel type 1 (Octn1) functions as a bile acid- dependent PPARa-regulated gene [2]. Furthermore, this organic cation transporte was responsible for intestinal absorption of pregabalin (PGN). PGN is now widely used for alleviation of diabetes-induced peripheral neuropathic pain. In this study, we investigated how the time-dependent oscillation in the intestinal expression of Octn1 affects the absorption of PGN and its analgesic effects on diabetic mice [3]. Methods: The oligo- nucleotide microarray analyses was performed using RNA isolated from the intestinal epithelial cells of wild-type and PPARa-null mice which were treated with cholic acids Contribution of Octn1 to the transport of PGN was determined by using immortalized small intestine epithelial cells and jejunal segments of streptozotocin (STZ)-treated mice. STZ- treated mice were used as animal model of diabetes-induced peripheral neuropathic pain and were evaluated the analgesic effects of PGN. Re- sults and Discusion: The result of microarray analysis revealed that in- testinal expression of Octn1/Slc22a4 was controlled by the interaction between bile acids and PPARa. The expression of Octn1 in the small in- testine of healthy mice exhibited a significant circadian oscillation, which caused the dosing time-dependent changes in the intestinal absorption of PGN. Since similar dosing-dependent changes in the PGN absorption was also observed in STZ-treated diabetic mice, we investigated whether optimizing the dosing schedule could enhance the analgesic effect of PGN on diabetes-induced peripheral neuropathic pain. The analgesic effect of PGN on the neuropathic pain in STZ-treated diabetic mice was enhanced by administering the drug at the times of day when protein levels of Octn1 were abundant, suggesting that oscillation in the intestinal expression of Octn1/Slc22a4leads to the dosing time-dependent changes in the analgesic effect of PGN. Conclusion: The present results revealed an important interaction between bile acids and PPARa in the circadian regulation of intestinal Octn1/Slc22a4expression and also suggested that the dosing time-dependent change in the analgesic effect of PGN was attributable to the circadian oscillation in the function of Octn1. 1. Okamura A., et al. J Biol Chem. 289:25296-25305 (2014). 2. Wada E., et al. Mol Pharmacol 87:314-322 (2015). 3. Akamine T., et al. J Pharmacol Exp Ther. 354:65-72 (2015). P221 COMPARATIVE APPROACHES BETWEEN QUANTITATIVE-MSI AND QUANTITATIVE-WBA: APPLICATION TO CHLOROQUINE ADMINISTRATION IN A LONG-EVANS MALE RAT MODEL Guillaume Hochart 1 , Joseph Marini 2 , Aurore Tomezyk 1 , Phil Mantefeul 2 , Bonnie Jung 2 , David Bonnel 1 , Stefan Linehan 1 , Don Abstracts / Drug Metabolism and Pharmacokinetics 32 (2017) S27eS107 S89