British journal of clinical pharmacology · 2019
Bridging adults and paediatrics with secondary hyperparathyroidism receiving haemodialysis: a pharmacokinetic-pharmacodynamic analysis of cinacalcet.
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Chen Ping, Sohn Winnie, Narayanan Adimoolam, Gisleskog Per Olsson, Melhem Murad
Аннотация
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).
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).