Clinical pharmacology

Mechanism of action is detailed under Pharmacology & toxicology; this page covers clinical pharmacodynamics, pharmacokinetics, interactions, and overdosage per the label.

Pharmacodynamics — IGF-1

In pediatric patients with GHD receiving subcutaneous Pegpesen^®, at different doses, IGF-1 concentration reached steady state after about 8 weeks of consecutive dosing; median T_max was 48 hours.

At 0.14 mg/kg once weekly, mean peak IGF-1 (CV) increased from 218 (31.5%) ng/mL after a single dose to 233 (31%) ng/mL at steady state; mean trough (CV) increased from 127 (33.1%) ng/mL to 151 (32.9%) ng/mL. No obvious accumulation of IGF-1 concentration was observed after multiple administrations.

Pharmacokinetics — healthy adults (single dose, label)

In 36 healthy adult males receiving a single subcutaneous dose from 0.01 to 0.2 mg/kg: T_max 12.0–48.0 h; C_max 13.0–1140.3 ng/mL; AUC ranges, apparent V_d/F, CL/F, and terminal half-life as reported for the product (half-life approximately 65–121 h across the cohort).

Pharmacokinetics — PopPK in pediatric GHD

Population PK at 0.14 mg/kg weekly in pediatric GHD: after first dose, C_max at ~24 h; geometric mean C_max 343.0 ng/mL (geoCV 26.0%); AUC_0-t 21,500 ng·h/mL (25.7%). At steady state (~8 weeks): C_max,ss 422.0 ng/mL (27.0%); AUC_0-t,ss 30,900 ng·h/mL (33.9%). No clinically significant accumulation. Geometric mean V_d/F 15.4 L (40.1%); CL/F 65.6 mL/h (53.3%); median effective elimination half-life 96.8 h (range 53.4–200.0 h).

Pharmacogenetics

No pharmacogenetic studies have been conducted.

Drug interactions — in vitro

In vitro, Pegpesen^® does not induce CYP1A2, CYP2B6, or CYP3A4; does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A; and does not inhibit BCRP, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, or MATE2-K.

Drug interactions — clinical considerations

No in vivo drug interaction studies in humans have been conducted.

Glucocorticoids

Pegpesen^® may inhibit 11βHSD-1 and reduce serum cortisol. Patients on glucocorticoid replacement may need higher maintenance or stress doses after starting Pegpesen^®. Glucocorticoids may inhibit the growth-promoting effect of GH; adjust glucocorticoid dose in pediatric replacement settings appropriately.

Estrogen

Oral estrogen may reduce GH-mediated IGF-1 response—patients on oral estrogen may require higher Pegpesen^® dosages.

Insulin / antihyperglycemic agents

GH may decrease insulin sensitivity; diabetes patients may need insulin and/or other antihyperglycemic dose adjustments during Pegpesen^®.

Overdosage

No cases of overdosage have been reported.

Acute overdosage may lead initially to hypoglycaemia and subsequently to hyperglycaemia.

Long-term overdosage may result in signs and symptoms of gigantism or acromegaly consistent with excess endogenous growth hormone.