Lonapegsomatropin API Manufacturers

General Description:

Lonapegsomatropin, identified by CAS number 1934255-39-6, is a notable compound with significant therapeutic applications. Lonapegsomatropin, also known as TransCon hGH or ACP 001, is a methoxypegylated prodrug of human growth hormone () indicated for the treatment of children 1 year and older, weighing at least 11.5 kg, with growth failure due to insufficient growth hormone secretion. Unlike somatropin, which requires daily dosing, lonapegsomatropin can be administered as a single weekly dose. Lonapegsomatropin was granted FDA approval on 25 August 2021. It was later approved by the European Commission on 13 January 2022.

Indications:

This drug is primarily indicated for: In the US, lonepegsomatropin is indicated in the treatment of growth failure due to inadequate growth hormone secretion in patients one year and older who weigh at least 11.5 kg. In Europe, lonepegsomatropin is indicated to treat growth failure in children and adolescents aged from three years up to 18 years due to insufficient endogenous growth hormone secretion or growth hormone deficiency. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Lonapegsomatropin undergoes metabolic processing primarily in: Lonapegsomatropin-tcgd is a prodrug that undergoes autocleavage, releasing the active from the methoxypolyethelene glycol carrier. The methoxypolyethelene glycol carrier is cleared by the kidneys, while somatropin is metabolized by non-specific protein catabolic pathways in the liver and kidneys to smaller oligopeptides and individual amino acids. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Lonapegsomatropin are crucial for its therapeutic efficacy: After subcutaneous lonapegsomatropin-tcgd administration, the drug undergoes autocleavage, releasing active from the methoxypolyethylene glycol carrier. 0.24 mg/kg/week dosing in pediatric patients leads to a somatropin C_max of 15.2 ng/mL, with a median T_max of 12 hours, and a mean AUC of 500 h\*ng/mL. Methoxypolyethylene glycol reaches a C_max of 13.1 µg/mL, with a meadian T_max of 36 hours. Human growth hormone () concentrations reach a mean steady C_max of 1230 ng/mL, with a T_max of 25 hours. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Lonapegsomatropin is an important consideration for its dosing schedule: The half life of lonapegsomatropin-tcgd is 30.7 ± 12.7 hours, while the half life of released was approximately 25 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Lonapegsomatropin from the body primarily occurs through: The methoxypolyethelene glycol carrier is cleared by the kidneys, while the active undergoes catabolic processes in the kidneys and liver. However, the exact proportions of lonapegsomatropin recovered in the urine and feces has not been reported. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Lonapegsomatropin is distributed throughout the body with a volume of distribution of: Lonapegsomatropin-tcgd dosing of 0.24 mg/kg/week leads to a mean steady state apparent volume of distribution of 0.13 L/kg. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Lonapegsomatropin is a critical factor in determining its safe and effective dosage: In pediatric patients, the apparent clearance of lonapegsomatropin-tcgd is 3.2 mL/h/kg. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Lonapegsomatropin exerts its therapeutic effects through: Lonapegsomatropin-tcgd is a growth hormone prodrug indicated in the treatment of growth failure due to inadequate growth hormone secretion in patients 1 year and older who weigh at least 11.5 kg. It has a long duration of action as it is given weekly. Patients and carers should be counselled regarding the risks of severe hypersensitivity, neoplasms, glucose intolerance, intracranial hypertension, fluid retention, hypoadrenalism, hypothyroidism, slipped capital femoral epiphysis, progression of preexisting scoliosis, and pancreatitis. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Lonapegsomatropin functions by: Lonapegsomatropin-tcgd undergoes autocleavage to release active from the methoxypolyethylene glycol carrier. Somatropin binds to the growth hormone receptor leading to direct effects and insulin-like growth factor-1 mediated indirect effects. Somatropin has effects on the epiphyses of long bones, leading to growth in pediatric patients. Somatropin also stimulates chondrocyte differentiation and proliferation, release of glucose from the liver, protein synthesis, and lipolysis. Somatotropin mediates its effects both directly by somatotropin and indirectly by insulin-like growth factor-1 (IGF-1), which is upregulated by growth hormone. It binds to the human growth hormone receptor (GHR), which is a dimeric receptor expressed in target cells in the liver and cartilage. Upon binding of growth hormone, GHR dimerizes and interacts with Janus kinase 2 (JAK2), subsequently leading to tyrosine phosphorylation of JAK2 and the GH receptor. The signal transducer activator of transcription (STAT) pathway is initiated, where transcription factors such as STAT1, STAT3, and STAT5 are translocated into the nucleus to stimulate target gene transcription. At the epiphysis or growth plate, growth hormone increases linear growth by promoting differentiation of prechondrocytes and expansion of osteoblasts. Growth hormone binding to its receptor in the liver and cartilage promotes the production of IGF-1, which acts on type 1 IGF receptors to also stimulate linear growth. In the liver, activated growth hormone receptor signalling leads to increased production of IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS), which are proteins that bind to IGF-1 in a ternary complex to increase its half-life. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Lonapegsomatropin is categorized under the following therapeutic classes: Cytochrome P-450 CYP1A2 Inducers, Cytochrome P-450 CYP1A2 Inducers (strength unknown), Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 Inhibitors (weak), Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, P-glycoprotein substrates, Prodrugs, Recombinant Human Growth Hormone, Somatropin and Somatropin Agonists. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Lonapegsomatropin include:

• Molecular Weight: 63000.0