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Bridging adults and paediatrics with secondary hyperparathyroidism receiving haemodialysis: a pharmacokinetic-pharmacodynamic analysis of cinacalcet.
Br J Clin Pharmacol. 2019 06; 85(6):1312-1325.BJ

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).

Authors+Show Affiliations

Amgen Inc., Thousand Oaks, CA, USA.Amgen Inc., Thousand Oaks, CA, USA.Amgen Inc., Thousand Oaks, CA, USA.SGS Exprimo, London, UK.Amgen Inc., Thousand Oaks, CA, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30756425

Citation

Chen, Ping, et al. "Bridging Adults and Paediatrics With Secondary Hyperparathyroidism Receiving Haemodialysis: a Pharmacokinetic-pharmacodynamic Analysis of Cinacalcet." British Journal of Clinical Pharmacology, vol. 85, no. 6, 2019, pp. 1312-1325.
Chen P, Sohn W, Narayanan A, et al. Bridging adults and paediatrics with secondary hyperparathyroidism receiving haemodialysis: a pharmacokinetic-pharmacodynamic analysis of cinacalcet. Br J Clin Pharmacol. 2019;85(6):1312-1325.
Chen, P., Sohn, W., Narayanan, A., Gisleskog, P. O., & Melhem, M. (2019). Bridging adults and paediatrics with secondary hyperparathyroidism receiving haemodialysis: a pharmacokinetic-pharmacodynamic analysis of cinacalcet. British Journal of Clinical Pharmacology, 85(6), 1312-1325. https://doi.org/10.1111/bcp.13900
Chen P, et al. Bridging Adults and Paediatrics With Secondary Hyperparathyroidism Receiving Haemodialysis: a Pharmacokinetic-pharmacodynamic Analysis of Cinacalcet. Br J Clin Pharmacol. 2019;85(6):1312-1325. PubMed PMID: 30756425.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bridging adults and paediatrics with secondary hyperparathyroidism receiving haemodialysis: a pharmacokinetic-pharmacodynamic analysis of cinacalcet. AU - Chen,Ping, AU - Sohn,Winnie, AU - Narayanan,Adimoolam, AU - Gisleskog,Per Olsson, AU - Melhem,Murad, Y1 - 2019/04/25/ PY - 2018/07/20/received PY - 2019/01/31/revised PY - 2019/02/04/accepted PY - 2019/2/14/pubmed PY - 2020/4/14/medline PY - 2019/2/14/entrez KW - PK/PD KW - chronic kidney disease KW - dialysis KW - modelling and simulation KW - paediatrics SP - 1312 EP - 1325 JF - British journal of clinical pharmacology JO - Br J Clin Pharmacol VL - 85 IS - 6 N2 - 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). SN - 1365-2125 UR - https://wwww.unboundmedicine.com/medline/citation/30756425/Bridging_adults_and_paediatrics_with_secondary_hyperparathyroidism_receiving_haemodialysis:_a_pharmacokinetic_pharmacodynamic_analysis_of_cinacalcet_ DB - PRIME DP - Unbound Medicine ER -