Bridging adults and paediatrics with secondary hyperparathyroidism receiving haemodialysis: a pharmacokinetic-pharmacodynamic analysis of cinacalcet

Ping Chen, Winnie Sohn, Adimoolam Narayanan, Per Olsson Gisleskog, Murad Melhem, Ping Chen, Winnie Sohn, Adimoolam Narayanan, Per Olsson Gisleskog, Murad Melhem

Abstract

Aims: The aims of this study were to develop a pharmacokinetic (PK) and PK-pharmacodynamic (PK/PD) model of cinacalcet in adults and paediatrics with secondary hyperparathyroidism (SHPT) on dialysis, to test covariates of interest, and to perform simulations to inform dosing in paediatrics with SHPT.

Methods: Cinacalcet PK, intact parathyroid hormone (iPTH) and corrected calcium (cCa) time courses following multiple daily oral doses (1-300 mg) were modelled using a nonlinear mixed effects modelling approach using data from eight clinical studies. Model-based trial simulations, using adult or paediatric titration schemas, predicted efficacy (iPTH change from baseline and proportion achieving iPTH decrease ≥30%) and safety (cCa change from baseline and proportion achieving cCa ≤8.4 mg/dL) endpoints at 24 weeks.

Results: Cinacalcet PK parameters were described by a two-compartment linear model with delayed first-order absorption-elimination (apparent clearance = 287.74 L h-1 ). Simulations suggested that paediatric starting doses (1, 2.5, 5, 10 and 15 mg) would provide PK exposures less than or similar to a 30 mg adult dose. The titrated dose simulations suggested that the mean (prediction interval) proportion of paediatric and adult subjects achieving ≥30% reduction in iPTH from baseline at Week 24 was 49% (36%, 62%), and 70.1% (62.5%, 77%), respectively. Additionally, the mean (confidence interval) proportion of paediatric and adult subjects achieving cCa ≤8.4 mg dL-1 at Week 24 was 8% (2%, 18%) and 23.6% (17.5%, 30.5%), respectively.

Conclusions: Model-based simulations showed that the paediatric cinacalcet starting dose (0.2 mg kg-1 ), titrated to effect, would provide the desired PD efficacy (PTH suppression <30%) while minimizing safety concerns (hypocalcaemia).

Keywords: PK/PD; chronic kidney disease; dialysis; modelling and simulation; paediatrics.

Conflict of interest statement

P.C., W.S. and A.N. are employees of Amgen Inc. M.M., currently with Vertex Pharmaceuticals, was an employee of Amgen at the time the work was completed. P.O.G. was a consultant on this analysis.

© 2019 Amgen Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1
Figure 1
PK/PD model schematic. CaS receptor, calcium‐sensing receptor; cCa, corrected calcium; CL/F, apparent systemic clearance; iPTH, intact parathyroid hormone; Kin cCa, the first order input rate for Ca; Kout cCa, the first order elimination rate for Ca; Q/F, apparent distribution clearance; Tlag, lag time
Figure 2
Figure 2
Prediction‐corrected visual predictive check for the final PK/PD model (combined dataset with additional 5 subjects in Study 20110100) for iPTH A, and corrected calcium B, separated by age group. Note that the bulk of the data fell within prediction‐corrected prediction intervals. cCa, corrected calcium; CI, confidence interval; iPTH, intact parathyroid hormone; Obs, observed; PK/PD, pharmacokinetics/pharmacodynamics; Sim, simulated
Figure 3
Figure 3
Simulated serum iPTH and cCa following Study 20070208 titrated dosing schema with weekly cCa monitoring in paediatric subjects (I), or following study titrated dosing schema in adults (II): A, PTH change from baseline vs time; B, fraction of subjects with iPTH decrease ≥30% vs time; C, corrected Ca change from baseline vs time; D, fraction of subjects with Ca ≤8.4 mg dL−1. Black line and shaded area indicates the mean and 90% prediction interval, respectively; cCa, corrected calcium; iPTH, intact parathyroid hormone
Figure 4
Figure 4
The predicted proportion of subjects to be on each dose level, over the course of the study. Simulations were performed following the design and six step‐wise titrated dosing schema from paediatric Study 20070208 A, or following dosing implemented in study 20000172 in adult subjects B. Subject to maintenance of serum iPTH and serum calcium values, subjects were eligible for a dose increase once every 4 weeks. For paediatric subjects, next dose level was based on subject post‐dialysis weight (see Supporting Information S4.1). cCa, corrected calcium, iPTH, intact parathyroid hormone

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