Population Pharmacokinetic and Exposure–Response Analysis of Weekly Teriparatide in Osteoporosis Patients

Abstract

Teriparatide is a potent therapeutic agent for the treatment of osteoporosis. One of the aims of this analysis was to develop a population pharmacokinetic (PPK) model to understand the pharmacokinetic characteristics of the once-weekly formulation of teriparatide. Another aim was to develop an exposure-response model to describe the relationship between change in bone mineral density (BMD) and teriparatide exposure after weekly subcutaneous administration. The PPK analysis showed that apparent total body clearance was significantly influenced by estimated creatinine clearance and the presence of osteoporosis. A data set consisting of lumbar spine BMD values for 513 osteoporosis patients whose area under the concentration-time curve (AUC) of teriparatide acetate was estimated by the developed PPK model was then compiled. Exposure-response analysis showed that the percentage change from baseline of BMD was well described by a function of the AUC of teriparatide acetate, time, and coadministration of alfacalcidol and a calcium preparation. The analysis indicated that AUC is an important parameter for predicting BMD response to once-weekly teriparatide in osteoporosis patients.

Safety Profiles, Pharmacokinetics, and Changes in Bone Turnover Markers After Twice‐Weekly Subcutaneous Administration of Teriparatide in Healthy Japanese Postmenopausal Women: A Single‐Blind Randomized Study

“…Therefore, the pharmacokinetic parameter related to the efficacy of teriparatide in the once‐weekly 56.5‐μg and twice‐weekly 28.2‐μg injection treatments was weekly AUC, not C max . This is consistent with a previous study …”

“…This is consistent with a previous study. 3 Commonly reported adverse events in the onceweekly 56.5-μg injections were nausea, vomiting, and headache. 1 Incidences of these adverse events in the twice-weekly 28.2-μg injection group were lower than Figure 4.…”

“…Similarly, population pharmacokinetic analysis of weekly teriparatide revealed that renal function significantly influenced apparent total body clearance. 3 In a study giving 24 weeks' treatment with once-weekly 56.5μg teriparatide, maximum plasma concentration (C max ) value and area under the concentration-time curve from time zero to infinity (AUC inf ) value were almost the same compared to those with single dose. 4 In the TOWER trial, a phase 3 trial of onceweekly 56.5-μg teriparatide injections, the drug showed a high reduction of fracture incidence in patients with osteoporosis.…”

“…Imai et al reported that the elimination half‐life of weekly teriparatide was significantly prolonged in subjects with severe renal impairment (estimated glomerular filtration rate, 15.0–29.9 mL/min/1.73 m 2 ). Similarly, population pharmacokinetic analysis of weekly teriparatide revealed that renal function significantly influenced apparent total body clearance . In a study giving 24 weeks’ treatment with once‐weekly 56.5‐μg teriparatide, maximum plasma concentration (C max ) value and area under the concentration‐time curve from time zero to infinity (AUC inf ) value were almost the same compared to those with single dose …”

Talazoparib Exposure‐Efficacy Analysis in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations in the EMBRACA Trial

“…Using a fixed C avg as the exposure metric in the E-R analyses tends to underestimate the E-R relationship or lead to an inverse E-R relationship for efficacy end points, as demonstrated here; on the contrary, it could also lead to the overestimation of the E-R relationship for safety end points for drugs with frequent dose modifications. 11 Thus, although fixed exposure metrics (ie, only 1 value for each patient), such as C avg , minimum concentration, maximum concentration, and area under the concentration-time curve, which are routinely used in E-R analyses, are considered appropriate for drugs without significant dose modification during treatment, [12][13][14] for drugs associated with frequent dose modification, a dynamic time-varying exposure metric (eg, C avg,t ) should be used instead. 15 The results of these analyses support the use of the maximum tolerated dose of 1 mg once daily as the starting dose for talazoparib treatment to ensure optimal exposure and efficacy.…”