Evaluation of Population PK/PD for Osteoporosis during a Vitamin D3 (1,25(OH)2D3) Derivative Therapy
Yumi Emoto, Satofumi Iida, Hidenobu Aso, Haruki Kinoshita
Dept. of Clinical Pharmacology, Chugai Clinical Research Center, Tokyo, Japan
Objectives: The purpose of this analysis was to characterize the relationship between pharmacokinetics (PK, concentration of Vitamin D3 (1,25(OH)2D3) derivative) and pharmacodynamics (PD, Lumbar Bone Mineral Density; BMD) in the treatment of osteoporosis with a vitamin D3 (1,25(OH)2D3) derivative.
Methods: Data from four clinical studies were used in this analysis: 1) An open-label cross-over study in 12 healthy volunteers at 1 ug; 2) An open-label daily oral administration study in 24 healthy volunteers at a dosage of 0.1, 0.25, 0.5 and 1 ug; 3) An open-label daily administration, 24 week study in 106 patients with osteoporosis (dosage of 0.25, 0.5, 0.75 and 1 ug); and 4) A double-blind placebo control daily administration 48 week study in 158 patients with osteoporosis at 0.75 ug. In total, 1397 plasma samples from 300 subjects were obtained for PK analysis from all four studies and 680 BMD data from 264 patients were obtained for PD analysis from two clinical studies where osteoporosis patients were enrolled. The plasma drug concentrations were determined by LC/MS/MS and BMD data were measured by dual-energy-X-ray absorptiometry (DXA) to assess PD. This population PK/PD model analysis was performed by sequential methods using NONMEM VI.
Results: The final PK/PD model consists of a one compartment model with first order absorption and a turnover PD model in which the plasma drug concentration inhibits bone loss (Kout). A linear disease progression model including the initial value of endogenous vitamin D3 as a covariate best described the BMD decrease profile. The PK/PD model was validated both by a visual predictive check and by a numerical predictive check. Additionally, the PK/PD model was explained biologically by dose-dependent suppression of the bone loss markers (tDPD, CTx, NTx) and the linear disease progression model was confirmed by analysis using placebo data.
Conclusions: A PK/PD model has been developed which shows linear disease progression during 48 weeks treatment with a vitamin D3 (1,25(OH)2D3) derivative. The model is likely to be useful for predicting the percentage change in BMD after administration of a vitamin D3 (1,25(OH)2D3) derivative.
 Matsumoto T, et al. A new active vitamin D, ED-71, increases bone mass in osteoporotic patients under vitamin D supplementation: a randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab (2005) 90(9):5031-6.