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.