Somapacitan Mechanism of Action

Somapacitan is under investigation in clinical trial NCT01706783 (A Trial Investigating the Safety, Tolerability, Availability and Distribution in the Body of Once-weekly Long-acting Growth Hormone (Somapacitan) Compared to Once Daily Norditropin NordiFlex® in Adults with Growth Hormone Deficiency).

Abstract

Somapacitan is a long‐acting growth hormone (GH) intended for once‐weekly subcutaneous administration. As for GH, the mechanism of action of somapacitan is either directly or indirectly via insulin‐ like growth factor I (IGF‐I). The pharmacokinetics (PK) and pharmacodynamic (PD) properties are potentially suitable for a once‐weekly administration in humans. Somapacitan doses of 0.02‐0.24 mg/kg have been investigated after multiple dosing in adults (healthy and with growth hormone deficiency [GHD]) in phase 1 and somapacitan doses of 0.02‐0.16 mg/kg have been investigated after single dosing in children with GHD. In order to predict the PK and IGF‐I profiles for multiple doses of somapacitan in children and adults, a PK/PD model was developed based on PK and IGF‐I levels from three phase 1 trials. PK were found to be consistent and body‐weight dependent, with little or no accumulation in both children and adults, as described by a non‐linear PK model. IGF‐I increased with higher somapacitan concentrations, with a delay observed between C<inf>max</inf> PK and C<inf>max</inf> IGF‐I. The PK/PD model was based on goodness of fit judged adequate to simulate the expected IGF‐I profiles of intermediate dose levels and to support IGF‐I guided dose selection of multiple dosing in children with GHD. Descriptive IGF‐I exposure‐response analysis of single‐dose data indicated that the dose range 0.04‐0.16 mg/kg in GHD children provided a change in IGF‐I that was comparable to 0.03 mg/kg/day Norditropin, where 0.4 mg/kg was slightly below and 0.16 mg/kg was slightly above that of daily Norditropin. Based on the PK/PD relationship of somapacitan in children, a dose of 0.04 mg/kg is expected to provide C<inf>max</inf> IGF‐I levels around the average daily human GH (hGH) treatment; 0.08 mg/kg is expected to provide Cavg IGF‐I levels around the average daily hGH treatment; and 0.16 mg/kg is expected to provide higher IGF‐I levels, with average concentrations not exceeding +2 SDS after a single dose or at steady state. In conclusion, the PK/PD of somapacitan is well characterized in adults and children in GHD in support of once‐weekly dosing.

Kobe, Japan Clinical Research Trials

GROWTH HORMONES (‘GH) or somatotropin, also referred to as HGH (HGH) in its human type, is certainly a peptide hormone that stimulates development, cell reproduction, and cell regeneration in human beings and other animals. R56. Detection of rhGH misuse poses many issues because GH is a normally occurring substance that includes a short half-lifestyle after subcutaneous and intravenous injection, is certainly released in a pulsatile style, and the levels boost after exercise. Drug assessment involving urine sampling isn’t recommended as this technique of testing is not been shown to be accurate and dependable, whereas repeated bloodstream sampling over 24-hours is certainly neither useful nor feasible in the sports activities setting (Grade A; BEL 1).

Adults with GHD have an elevated threat of cardiovascular morbidity and mortality, and presently, there are no definitive final result data that concur that treating this problem would mitigate this risk as long-term prospective, controlled scientific trials are still lacking. As a result, clinicians should monitor cardiovascular parameters at 6- to 12-month intervals you need to include fasting lipids, systolic and diastolic blood circulation pressure, and heart rate, while more descriptive examinations such as for example electrocardiogram, echocardiogram, and carotid echo-Doppler examinations could be performed if clinically indicated regarding to regional best clinical practice (Quality C; BEL 2; predicated on professional opinion of the committee).

Growth hormones and the gonadotropic axis are inter-related throughout life, you start with the regulation of starting point of puberty ( 211 ). Mechanistic research show that GH and IGF-1 can stimulate the hypothalamic-pituitary-gonadal axis at all amounts ( 212 ) by influencing gonadotropin discharge, estradiol creation by granulosa cells, oocyte maturation, fertility and lactation, and improved ovarian response to gonadotropins ( 212-215 ). Furthermore, dynamic adjustments of various other hormones occur during being pregnant, paralleled by the advancement of the placenta, which secretes placental GH. During being pregnant, circulating placental GH amounts rise, peaking at 36 weeks to levels much like those seen in acromegaly. That is accompanied by a sharpened decline in pituitary GH amounts that become undetectable by the 24th week of gestation ( 216 ). Therefore, the real advantage of rhGH replacement in females with GHD during pregnancy remains unclear.

Octreotide (brand Sandostatin, Novartis Pharmaceuticals) can be an octapeptide that mimics organic somatostatin pharmacologically, though is a far more potent inhibitor of growth hormones, glucagon, and insulin compared to the natural hormone, and includes a a lot longer half-life (about 90 minutes, in comparison to 2-3 minutes for somatostatin). Because it is absorbed badly from the gut, it really is administered parenterally (subcutaneously, intramuscularly, or intravenously). It really is indicated for symptomatic treatment of carcinoid syndrome and acromegaly Additionally it is finding increased make use of in polycystic illnesses of the liver and kidney.

The basic safety of somapacitan and GH was assessed based on data on AEs, scientific laboratory measurements (haematology, biochemistry, urinalysis, fasting blood sugar, fasting bloodstream insulin and antibodies), physical examinations, vital signs, bodyweight, electrocardiogram (ECG) and injection site tolerability. The latter was evaluated by manual, visible inspection of injection sites, assessing the occurrence of discomfort, tenderness, itching, rash, inflammation, induration and any other symptoms of injection site reactions.

Early research utilized rhGH doses along with somapacitan in substitution regimens that took under consideration of bodyweight or body surface, and dose adjustments were predicated on body composition outcomes, analogous to pediatric practice (42-44), but unwanted effects were frequently observed which were mainly because of the fluid-retaining ramifications of rhGH. In light of the observations, rhGH treatment regimens today use dose-titration strategies targeting serum IGF-1 normalization to take into account interindividual distinctions in GH sensitivity that will take into consideration age group, gender, body mass index (BMI), and different other baseline characteristics ( 45-47 ). The use of individualized, stepwise dose adjustments predicated on serum IGF-1 levels has led to improved treatment efficacy, provided the individual is treatment-adherent, and reductions in reported unwanted effects (48, 49).