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Drug disposition model of radiolabeled etelcalcetide in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis

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Abstract

Etelcalcetide (AMG 416) is an allosteric activator of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. To characterize the time course of etelcalcetide in different matrices (plasma, dialysate, urine, and feces), a drug disposition model was developed. Nonlinear mixed-effect modeling was used to describe data from six adults with CKD on hemodialysis who received a single intravenous dose of [14C]etelcalcetide (10 mg; 710 nCi) after hemodialysis (study NCT02054572). A three-compartment model with the following attributes adequately described the observed concentration–time profiles of etelcalcetide in the different matrices: biotransformation in the central compartment; elimination in dialysate, urine, and feces; and a nonspecific elimination process. The terminal half-life of total C-14 in plasma was approximately 56 days. The ratio of conjugation–deconjugation rate constants between etelcalcetide and biotransformed products was 11.3. Simulations showed that three hemodialysis sessions per week for 52 weeks would contribute to 60.1% of the total clearance of etelcalcetide following single-dose intravenous etelcalcetide administration. Minimal amounts were eliminated in urine (2.5%) and feces (5.7%), whereas nonspecific elimination accounted for 31.2% of total elimination. In addition to removal of etelcalcetide, ~10% of small-molecular weight biotransformed products was estimated to have been removed through hemodialysis and in urine. This model provided a quantitative approach to describe biotransformation, distribution, and elimination of etelcalcetide, a unique synthetic d-amino acid peptide, in the relevant patient population.

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Acknowledgements

The authors thank James Balwit, MS, CMPP, of Complete Healthcare Communications, LLC, Chadds Ford, PA, whose work was funded by Amgen Inc., and Holly Tomlin, MPH, of Amgen Inc., for assistance in writing this manuscript.

Funding

This study was funded by Amgen Inc.

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Authors and Affiliations

  1. Clinical Pharmacology Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, USA

    Liviawati Wu, Murad Melhem & Benjamin Wu

  2. Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, CA, USA

    Raju Subramanian

Authors
  1. Liviawati Wu
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  2. Murad Melhem
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  3. Raju Subramanian
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  4. Benjamin Wu
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Correspondence to Murad Melhem.

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LW, MM, RS, and BW are employees of and shareholders in Amgen Inc.

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For this type of study, formal consent is not required.

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Informed consent was obtained from all individual participants included in the study.

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Wu, L., Melhem, M., Subramanian, R. et al. Drug disposition model of radiolabeled etelcalcetide in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis. J Pharmacokinet Pharmacodyn 44, 43–53 (2017). https://doi.org/10.1007/s10928-016-9503-z

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  • DOI: https://doi.org/10.1007/s10928-016-9503-z

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