Calcimimetics

Calcimimetics lower parathyroid hormone by increasing parathyroid sensitivity to calcium. Cinacalcet is oral; etelcalcetide is given intravenously at dialysis. They treat secondary hyperparathyroidism in dialysis and selected primary hyperparathyroidism and parathyroid carcinoma.

Mechanism. They are positive allosteric modulators of the calcium-sensing receptor on parathyroid chief cells, so a lower calcium concentration is needed to suppress PTH. PTH falls, along with serum calcium, and parathyroid hyperplasia is reduced.

Pharmacokinetics. Cinacalcet absorption is raised by food; it is metabolised by CYP3A4, CYP2D6 and CYP1A2, with a half-life of 30 to 40 hours. Etelcalcetide is cleared by dialysis and given after it.

Differences. Etelcalcetide gives a guaranteed dose with dialysis and less nausea; cinacalcet causes more vomiting. Evocalcet and upacicalcet are used in some Asian markets.

• Secondary hyperparathyroidism in dialysis: after phosphate and vitamin D control, aim for PTH 2 to 9 times the upper limit of normal.
• Primary hyperparathyroidism: for patients who cannot or will not have surgery, with symptomatic hypercalcaemia (corrected calcium over 3.0 mmol/L).
• Parathyroid carcinoma: to control hypercalcaemia.
• Not for non-dialysis chronic kidney disease, because of hypocalcaemia and low efficacy.
• Hold or reduce if corrected calcium falls under 2.0 mmol/L (8.4 mg/dL) or hypocalcaemia symptoms appear.

Special groups. Pregnancy: avoid. Breastfeeding: avoid. Children: cinacalcet is used in dialysis in specialist centres. Older adults: nausea and vomiting limit tolerance. Kidney impairment: designed for use here. Liver impairment: moderate to severe disease raises exposure, so monitor closely. Regional: dialysis access is limited, so parathyroidectomy is often the practical option.

Adverse effects. Nausea and vomiting (up to 30%), hypocalcaemia with paraesthesia, cramps, tetany, seizures, QT prolongation, upper gastrointestinal bleeding (etelcalcetide), and low PTH with adynamic bone disease.

Interactions. Cinacalcet strongly inhibits CYP2D6 (raising tricyclics, flecainide and metoprolol). Ketoconazole and other CYP3A4 inhibitors raise cinacalcet levels.

Monitoring. Corrected calcium within 1 week of starting or changing the dose (every 2 weeks for etelcalcetide initially), then monthly; PTH 1 to 4 weeks after a change, then every 1 to 3 months; ECG with hypocalcaemia.

Referral and escalation. Persistent hypocalcaemia, PTH under 2 times the upper limit, refractory hyperparathyroidism needing parathyroidectomy.