#1748 Single-dose pharmacokinetics of extended-release calcifediol in healthy Japanese and non-Japanese volunteers

Abstract Background and Aims ERC is currently approved in the United States and certain European countries at a daily dose of 30 mcg, escalating as needed to 60 mcg, for the treatment of secondary hyperparathyroidism (SHPT) in patients with non-dialysis chronic kidney disease (CKD). This study examined, for the first time, racial differences in fasting and fed pharmacokinetic (PK) profiles of serum calcifediol and its primary metabolites after oral administration of extended-release calcifediol (ERC). Method This single-dose, open-label study was conducted at one United States Phase 1 unit to evaluate the PK profiles of serum vitamin D metabolites after oral ERC in 67 healthy male and female Japanese and non-Japanese volunteers having ages of 18 to 55 years. A total of 35 Japanese and 32 non-Japanese participants were randomized with gender balance (at least 8 per group) to ERC doses of 450, 900 and 1,800 mcg (all fasting) and 900 mcg (fed). Participants were housed for 2 days prior to randomization and through the first 48 hours post dose, received standardized and timed meals while in the unit, and provided blood samples at pre-dose baseline, 2-hour intervals through 24 hours, and decreasing frequencies through 28 days. Collected samples were analyzed for serum calcifediol, 24,25-dihydroxyvitamin D3 (24,25D3), total 1,25-dihydroxyvitamin D (1,25D), corrected calcium (Ca) and phosphorus (P). Results Maximum serum concentrations (Cmax) of calcifediol were achieved between 9 and 28 hours (both medians) under fasted conditions, and 9 hours (median) under fed conditions. Dose-related increases were observed in baseline-adjusted Cmax and area under the curve (AUC) in both Japanese and non-Japanese participants in the fasting condition. Cmax was approximately 5-fold higher, and AUC was 3-fold higher under fed conditions. The geometric mean ratios for AUC in Japanese and non-Japanese participants were close to unity after adjustment for body weight. Baseline-adjusted serum Cmax and AUC were not dose-proportional for either nominal dose or dose normalized for body weight. In general, male participants had higher baseline-adjusted AUC and slightly lower clearance compared with female participants of both races. Mean terminal elimination half-life (t1/2) ranged from 10.0 to 16.7 days. Serum 1,25D reached maximum levels on Day 3 then decreased to near baseline levels by Day 7 for both races, and the increases were greater under fed compared to fasting conditions. Serum 24,25D3 concentrations were elevated between Day 1 and Day 28, and were comparable under fasting and fed conditions for both races. Serum Ca and P remained constant after all doses and treatment-emergent adverse events were all mild and unrelated to treatment. Conclusion No racial differences in PK profiles of serum calcifediol and its primary vitamin D metabolites (24,25D3 and 1,25D) were observed between Japanese and non-Japanese participants after single doses of oral ERC in fasting and fed conditions.