Extended-release calcifediol identifies a therapeutic vitamin D range in chronic kidney disease stages 3 and 4

Background: Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD) driven by dysregulated vitamin D metabolism. The serum 25-hydroxyvitamin D (25D) levels required for targeted intact parathyroid hormone (iPTH) reductions are poorly defined, and conventional sufficiency thresholds of 20 or 30 ng/ml are inadequate. Exposure-response (E-R) modeling was used to define a 25D range associated with a 30% iPTH reduction during treatment with extended-release calcifediol (ERC). Methods: E-R relationships between 25D and iPTH were evaluated using pooled data from randomized clinical trials of ERC in participants with SHPT, CKD stage 3-4, and vitamin D insufficiency (VDI). Mixed-effects models characterized percent change in iPTH as a function of concurrent 25D. Mechanistic analyses evaluated associations between 25D, its key metabolites, and iPTH. Associations between achieved 25D and markers of mineral metabolism were assessed. Results: E-R modeling demonstrated a nonlinear relationship between 25D and iPTH reduction with a population-average of 84 ng/ml associated with 30% iPTH reduction (ER30), ranging from 67 to 103 ng/ml across the range of kidney function. Baseline body weight and sex significantly influenced achieved 25D concentrations. Higher achieved 25D was not associated with adverse changes in calcium, phosphorus, or fibroblast growth factor 23. Circulating 1,25-dihydroxyvitamin D was not independently associated with iPTH response. Conclusions: Elevation of 25D to 84 ng/ml (range: 66.9-102.6 ng/ml) during ERC treatment was associated with a 30% iPTH reduction in participants with SHPT, CKD stage 3-4, and VDI. This range was unassociated with adverse changes in mineral metabolism.