Efficacy and safety of paricalcitol in children with stages 3 to 5 chronic kidney disease

Abstract

Background: Elevated intact parathyroid hormone (iPTH) levels can contribute to morbidity and mortality in children with chronic kidney disease (CKD). We evaluated the pharmacokinetics, efficacy, and safety of oral paricalcitol in reducing iPTH levels in children with stages 3-5 CKD.

Methods: Children aged 10-16 years with stages 3-5 CKD were enrolled in two phase 3 studies. The stage 3/4 CKD study characterized paricalcitol pharmacokinetics and compared the efficacy and safety of paricalcitol with placebo followed by an open-label period. The stage 5 CKD study evaluated the efficacy and safety of paricalcitol (no comparator) in children with stage 5 CKD undergoing dialysis.

Results: In the stage 3/4 CKD study, mean peak plasma concentration and area under the time curve from zero to infinity were 0.13 ng/mL and 2.87 ng•h/((or ng×h/))mL, respectively, for 12 children who received 3 μg paricalcitol. Thirty-six children were randomized to paricalcitol or placebo; 27.8% of the paricalcitol group achieved two consecutive iPTH reductions of ≥30% from baseline versus none of the placebo group (P = 0.045). Adverse events were higher in children who received placebo than in those administered paricalcitol during the double-blind treatment (88.9 vs. 38.9%; P = 0.005). In the stage 5 CKD study, eight children (61.5%) had two consecutive iPTH reductions of ≥30% from baseline, and five (38.5%) had two consecutive iPTH values of between 150 and 300 pg/mL. Clinically meaningful hypercalcemia occurred in 21% of children.

Conclusions: Oral paricalcitol in children aged 10-16 years with stages 3-5 CKD reduced iPTH levels and the treatment was well tolerated. Results support an initiating dose of 1 μg paricalcitol 3 times weekly in children aged 10-16 years.

Keywords: Chronic kidney disease–mineral and bone disorder; Hypercalcemia; Paricalcitol; Pediatric; Secondary hyperparathyroidism.

Conflict of interest statement

Funding Sources

AbbVie provided funding for the stage 3/4 and stage 5 studies and was involved in the study designs, study execution, collection, analysis, and interpretation of data, and the writing, review, and approval of the report, as well as the decision to submit the manuscript for publication. All authors had access to study results, and Professor Nicholas J. A. Webb takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors had the final decision to submit the publication. The study was overseen by a data review committee.

Disclosure of potential conflicts of interest

Nicholas J. A. Webb served on advisory boards or data safety monitoring boards for AbbVie, Astellas, Alexion, Quintiles, Raptor, and Takeda. Gary Lerner served on a medical advisory board for AbbVie. Bradley A. Warady served as a consultant for Amgen and Keryx and served on an advisory board for AbbVie. Katherine M. Dell served on an advisory board for AbbVie. Larry A. Greenbaum served as a consultant for and received research support from AbbVie. Gema Ariceta served on advisory boards for AbbVie, Alexion, and Orphan Europe. Bernd Hoppe served as a consultant for AbbVie, Alexion, Alnylam, Dicerna, and Oxthera AB. Peter Linde, Ho-Jin Lee, Ann Eldred, and Matthew B. Dufek are employees of AbbVie and may have stock or stock options.

Research involving human participants

Institutional Review Board approval was received before the distribution of any study drug to a participating study site. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants (and/or their parents or legal guardians) included in the study.

Figures

Fig 1

Disposition of children. CONSORT flow diagrams for the stage 3/4 chronic kidney disease (CKD) study (a) and the stage 5 CKD study (b). *Reasons were not mutually exclusive, †Dose reduction to <1 μg three times per week

Fig 2

Paricalcitol plasma concentration. Mean plasma concentration-time profiles of paricalcitol. SD Standard deviation, CKD chronic kidney disease

Fig 3

Proportion of children achieving final measures within Kidney Disease Outcomes Quality Initiative target ranges (intent-to-treat) for iPTH (a), calcium (b), and phosphorus levels (c). iPTH Intact parathyroid hormone

Fig 4

Changes in laboratory values. a, b Changes in estimated glomerular filtration rate (eGFR; a) and creatinine levels (b) over time. c, d Changes in calcium (c) and phosphorus (d) from baseline over time. BSA Body surface area

Fig 5

Changes in intact parathyroid hormone (iPTH; a), calcium (b), and phosphorus (c) over time in patients with stage 5 chronic kidney disease