Pharmacokinetics of teriparatide (rhPTH[1-34]) and calcium pharmacodynamics in postmenopausal women with osteoporosis

Abstract

Teriparatide (rhPTH[1-34]) affects calcium metabolism in a pattern consistent with the known actions of endogenous parathyroid hormone (PTH). This report describes the pharmacokinetics and resulting serum calcium response to teriparatide in postmenopausal women with osteoporosis. Pharmacokinetic samples for this analysis were obtained from 360 women who participated in the Fracture Prevention Trial. Postmenopausal women with osteoporosis received daily subcutaneous injections of either teriparatide 20 μg (4.86 μmol) or placebo, median 21 months' treatment. Serum teriparatide and calcium concentrations were measured throughout the study. An indirect-response model was developed to describe the pharmacokinetic-pharmacodynamic relationship between teriparatide concentrations and serum calcium response. The pharmacokinetics of teriparatide were characterized by rapid absorption (maximum concentration achieved within 30 min) and rapid elimination (half-life of 1 h), resulting in a total duration of exposure to the peptide of approximately 4 h. Teriparatide transiently increased serum calcium, with the maximum effect observed at approximately 4.25 h (median increase 0.4 mg/dl [0.1 mmol/l]). Calcium concentrations returned to predose levels by 16-24 h after each dose. Persistent hypercalcemia was not observed; one teriparatide 20 μg-treated patient had a predose serum calcium value above the normal range but <11.0 mg/dl (2.75 mmol/l). Following once-daily subcutaneous administration, teriparatide produces a modest but transient increase in serum calcium, consistent with the known effects of endogenous PTH on mineral metabolism. The excursion in serum calcium is brief, due to the short length of time that teriparatide concentrations are elevated.

Fig. 1

Serum calcium concentrations vs. time since last teriparatide 20 μg (a) or placebo (b) dose. The upper (10.6 mg/dl, 2.64 mmol/l) and lower (8.2 mg/dl) limits of normal for serum calcium are shown by the horizontal lines

Fig. 2

Visual predictive check of final PK–PD model. Solid lines represent the 90% confidence intervals for the 5th, median, and 95th percentiles of model simulated results. Dotted lines represent the 5th, median, and 95th percentiles calculated from the observed data. Data were binned in ranges of 0–2, 2–4, 4–6, 6–24, and 24–30 h for the calculation of percentiles. The observed data are overlaid for reference

Fig. 3

Model predicted teriparatide concentration–time profile and the resulting serum calcium response following teriparatide 20 μg injection. Upper (10.6 mg/dl, 2.64 mmol/l) and lower (8.2 mg/dl) limits of normal for serum calcium are shown by the horizontal lines. IQR interquartile range