An open-label, single-dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinacalcet in pediatric subjects aged 28 days to Winnie Y Sohn  1 , Anthony A Portale  2 , Isidro B Salusky  3 , Hao Zhang  4 , Lucy L Yan  4 , Bella Ertik  4 , Shahnaz Shahinfar  5 , Edward Lee  4 , Bastian Dehmel  4 , Bradley A Warady  6 Affiliations Expand Affiliations 1 Amgen, Inc., One Amgen Center Dr. M/S 38-4-A, Thousand Oaks, CA, 91320, USA. wkim@amgen.com. 2 UCSF Benioff Children's Hospital, San Francisco, CA, USA. 3 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 4 Amgen, Inc., One Amgen Center Dr. M/S 38-4-A, Thousand Oaks, CA, 91320, USA. 5 S. Shahinfar Consulting and Childrens Hospital of Philadelphia, Philadelphia, PA, USA. 6 Children's Mercy Hospital, Kansas City, MO, USA. PMID: 30141180 PMCID: PMC6244811 DOI: 10.1007/s00467-018-4054-8 Free PMC article Item in Clipboard

Abstract

Background: Calcimimetics, shown to control biochemical parameters of secondary hyperparathyroidism (SHPT), have well-established safety and pharmacokinetic profiles in adult end-stage renal disease subjects treated with dialysis; however, such studies are limited in pediatric subjects.

Methods: In this study, the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cinacalcet were evaluated in children with chronic kidney disease (CKD) and SHPT receiving dialysis. Twelve subjects received a single dose of cinacalcet (0.25 mg/kg) orally or by nasogastric or gastric tube. Subjects were randomized to one of two parathyroid hormone (PTH) and serum calcium sampling sequences: [(1) 2, 8, 48 h; or (2) 2, 12, 48 h] and assessed for 72 h after dosing.

Results: Median plasma cinacalcet tmax was 1 h (range 0.5-4.0 h); mean (SD) Cmax and AUClast were 2.83 (1.98) ng/mL and 11.8 (8.74) h*ng/mL, respectively; mean (SD) half-life (t1/2) was 3.70 (2.57) h. Dose adjustments, based upon body weight (mg/kg), minimized the effects of age, body weight, body surface area, and body mass index on cinacalcet PK. Reductions in serum PTH levels from baseline were observed at 2 to 8 h post-dose (median 10.8 and 29.6%, respectively), returned towards baseline by 12-72 h and were inversely related to changes in the plasma cinacalcet PK profile. Single-dose cinacalcet was well-tolerated with no unexpected safety findings and a PK/PD, safety profile similar to adults.

Conclusions: In conclusion, a single 0.25 mg/kg dose of cinacalcet was evaluated to be a safe starting dose in these children aged < 6 years.

Trial registration: ClinicalTrials.gov NCT01290029.

Keywords: Calcimimetics; Chronic kidney disease; Cinacalcet; Parathyroid hormone; Pediatric dialysis patients; Secondary hyperparathyroidism.

Conflict of interest statement

Conflict of interest

BE, EL, and WS are all employees and stockholders of Amgen, Inc. HZ is a full-time employee of Amgen, Inc. LY and BD were employees of Amgen, Inc. at the time the research was conducted. SS (S. Shahinfar Consulting, Inc.) and BW are paid consultants for Amgen, Inc. IS has research grants from Amgen, Inc. and Abbvie, Inc. and received consulting fees from Keryx, Inc. AP has nothing to disclose.

Data-sharing agreement

There is a plan to share data. This may include de-identified individual patient data for variables necessary to address the specific research question in an approved data-sharing request and also related data dictionaries, study protocol, statistical analysis plan, informed consent form, and/or clinical study report. Data-sharing requests relating to data in this manuscript will be considered after the publication date, and (1) this product and indication (or other new use) have been granted marketing authorization in both the USA and Europe, or (2) clinical development discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data-sharing request for these data. Qualified researchers may submit a request containing the research objectives, the Amgen product(s), and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labeling. A committee of internal advisors reviews requests. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data-sharing agreement. This may include anonymized patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the following: http://www.amgen.com/datasharing.

Figures

Fig. 1

Study design and treatment schema. Screening was conducted between days − 21 to − 2. Subjects entered the clinical unit on day − 1 to undergo safety laboratory testing and baseline PD sampling and remained in residency until 24-h post-dose procedures were completed. Following pre-dose procedures and dosing on day 1, subjects underwent a 72-h period of PK, PD sampling, and safety monitoring. End of study procedures were conducted on day 4 (72 h post-dose). t SAE follow-up was conducted to day 30. PD pharmacodynamic, PK pharmacokinetic. AE adverse evemt. SAE serious adverse event

Fig. 2

Mean (SD) plasma cinacalcet log concentration-time profiles after administration of cinacalcet at 0.25 mg/kg to pediatric subjects with chronic kidney disease receiving dialysis (n = 10–12)

Fig. 3

Mean (SD) plasma cinacalcet log concentration-time profiles by age group after enteral administration of cinacalcet

Fig. 4

Median parathyroid hormone (PTH) percent change from baseline after administration of cinacalcet at 0.25 mg/kg to pediatric subjects with chronic kidney disease (CKD) receiving dialysis

Fig. 5

Mean (SE) albumin corrected calcium (cCa) over time by age group (n = 4); age ≥ 3 years < 6 years (n = 8); all subjects (n = 12))

Fig. 6

Mean (SE) ionized calcium (cCa) concentrations over time by age group (n = 4); age ≥ 3 years < 6 years (n = 8); all subjects (n = 12))

Fig. 7

Mean (SE) plasma cinacalcet, median (Q1, Q3) parathyroid hormone (PTH) percent change from baseline; mean (SE) total serum Ca concentration-time profiles in pediatric subjects with chronic kidney disease (CKD) receiving dialysis