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Calcified Tissue International (1)
The AAPS Journal (1)
Chien, Jenny Y. (1)
Dobnig, Harald (1)
Friedrich, Stuart (1)
Glass, Emmett V. (1)
Heathman, Michael (1)
Heathman, Michael A. (1)
Marín, Fernando (1)
Miller, Paul D. (1)
Satterwhite, Julie (1)
Sinha, Vikram (1)
de Alwis, Dinesh P. (1)
Year of Publication
Pharmacokinetics of Teriparatide (rhPTH[1–34]) and Calcium Pharmacodynamics in Postmenopausal Women with Osteoporosis
Miller, Paul D.
Glass, Emmett V.
Calcified Tissue International
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.
Anabolic agent; Osteoporosis therapy; Peptide hormone; Parathyroid hormone; Teriparatide pharmacokinetics; Calcium pharmacodynamics
Pharmacokinetics/pharmacodynamics and the stages of drug development: Role of modeling and simulation
Chien, Jenny Y.
de Alwis, Dinesh P.
The AAPS Journal
Pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation (M&S) are well-recognized powerful tools that enable effective implementation of the learn-and-confirm paradigm in drug development. The impact of PK/PD M&S on decision making and drug development risk management is dependent on the question being asked and on the availability and quality of data accessible at a particular stage of drug development. For instance, M&S methodologies can be used to capture uncertainty and use the expected variability in PK/PD data generated in preclinical species for projection of the plausible range of clinical dose; clinical trial simulation can be used to forecast the probability of achieving a target response in patients based on information obtained in early phases of development. Framing the right question and capturing the key assumptions are critical components of the “learn-and-confirm” paradigm in the drug development process and are essential to delivering high-value PK/PD M&S results. Selected works of PK/PD modeling and simulation from preclinical to phase III are presented as case examples in this article.
drug development; modeling and simulation; pharmacokinetics/pharmacodynamics; NONMEM; design optimization
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