Chemical formula: C₃₈H₇₃N₂₁O₁₀S₂ Molecular mass: 1,048.26 g/mol PubChem compound: 71511839
The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Etelcalcetide is a synthetic peptide calcimimetic agent which reduces PTH secretion through binding and activation of the calcium-sensing receptor. The reduction in PTH is associated with a concomitant decrease in serum calcium and phosphate levels.
Following a single intravenous bolus administration of 5 mg etelcalcetide, PTH levels decreased rapidly within 30 minutes post-dose and were maximally decreased for 1 hour, before returning to baseline. The extent and duration of the reduction in PTH increased with increasing dose. Reduction in PTH levels correlated with plasma etelcalcetide concentrations in haemodialysis patients. The effect of reducing PTH levels was maintained throughout the 6-month dosing period when etelcalcetide was administered by intravenous bolus 3 times a week.
In the population pharmacokinetics model, volume of distribution at steady-state was approximately 796 L. Etelcalcetide is predominately bound to plasma albumin by reversible covalent binding. Non- covalent binding of etelcalcetide to plasma proteins is low with a fraction unbound ratio of 0.53. The ratio of blood-to-plasma [14C]-etelcalcetide concentrations is approximately 0.6.
Etelcalcetide is not metabolised by CYP450 enzymes. Etelcalcetide is biotransformed in blood by reversible disulphide exchange with endogenous thiols to predominantly form conjugate with serum albumin. The plasma exposure of biotransformation products was approximately 5-fold higher than that of etelcalcetide and their concentration-time course parallels that of etelcalcetide. The predominant biotransformation product (albumin bound) was minimally active in vitro.
Intravenous administration 3 times per week at the end of a haemodialysis session resulted in an effective half-life of 3 to 5 days. Etelcalcetide is rapidly cleared in subjects with normal renal function, whilst in CKD patients requiring haemodialysis, etelcalcetide was predominantly eliminated by haemodialysis. Etelcalcetide was efficiently removed with a haemodialysis clearance value of 7.66 L/hour. Following a single radiolabelled dose of etelcalcetide in CKD patients with secondary HPT receiving haemodialysis, approximately 60% of dosed [14C]-etelcalcetide was recovered in dialysate and approximately 7% recovered in urine and faeces combined over 175 days of collection period. The inter-subject variability of the system clearance in the patient population is approximately 70%.
The pharmacokinetics of etelcalcetide is linear and does not change over time following single (5 to 60 mg) and multiple intravenous doses (2.5 to 20 mg) in CKD patients with secondary HPT receiving haemodialysis. Following 3 times a week intravenous dosing at the end of each 3 to 4 hour haemodialysis session in CKD patients, etelcalcetide plasma levels reached near steady-state 4 weeks after dosing with an observed accumulation ratio of 2- to 3-fold.
No specific pharmacokinetic studies of etelcalcetide have been conducted in patients with mild to severe kidney impairment. The pharmacokinetics of etelcalcetide was characterised in CKD patients receiving haemodialysis. Etelcalcetide is intended for CKD patients receiving haemodialysis.
No specific study in patients with hepatic impairment was performed.
No body weight, gender, age, or race-related pharmacokinetic differences have been observed in adult patients studied.
The expected pharmacological effect of decreased PTH and calcium in blood were observed in animal studies at clinical exposure levels. Reductions in serum calcium associated with tremoring, convulsions and stress-related findings were observed at clinical exposure levels. All effects were reversible upon cessation of treatment.
Etelcalcetide was mutagenic in some strains of bacteria (Ames), however was not genotoxic in in vitro and in vivo mammalian genotoxicity assays and therefore is considered non-genotoxic in humans. In mouse and rat carcinogenicity studies, there were no etelcalcetide-related tumours up to exposure of 0.4-fold clinical exposure levels.
There was no effect on male or female fertility when etelcalcetide was administered to rats at exposure levels up to 1.8-fold higher than clinical exposures levels achieved in patients receiving etelcalcetide at 15 mg three times per week.
There were no effects on embryo-foetal development in rats and rabbits when exposed to up to 1.8 to 4.3 times clinical exposure levels during organogenesis. In a pre- and post-natal development study in rats there was a minimal increase in perinatal pup mortality, delay in parturition and transient reductions in post-natal growth associated with maternal toxicities of hypocalcaemia, tremoring, and reductions in body weight and food consumption at 1.8 times clinical exposure levels.
Studies in rats showed [14C]-etelcalcetide was excreted in the milk at concentrations similar to plasma.
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