Nonclinical pharmacokinetic and pharmacodynamic characterisation of somapacitan: A reversible non-covalent albumin-binding growth hormone

Thygesen, Peter; Andersen, Heidi Lie; Behrens, Carsten; Fels, Johannes; Nørskov-Lauritsen, Leif; Rischel, Christian; Johansen, Niklas Dyrby

doi:10.1016/j.ghir.2017.05.006

Cited by 28 publications

(19 citation statements)

References 22 publications

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“…Somapacitan (Novo Nordisk A/S, Bagsværd, Denmark) is a novel reversible albumin-binding GH derivative in which a fatty acid with non-covalent albumin-binding properties has been conjugated by alkylation to GH. The resulting non-covalent binding to endogenous albumin slows elimination by means of reduced clearance via glomerular filtration, resulting in an extended half-life [11, 12], making once-weekly subcutaneous administration possible.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Once-Weekly Somapacitan in Children and Adults: Supporting Dosing Rationales with a Model-Based Analysis of Three Phase I Trials

et al. 2018

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Background Somapacitan, a long-acting growth hormone (GH) derivative, has been well-tolerated in children with GH deficiency (GHD) and adults (healthy and adult GHD), in phase I, single-and multiple-dose trials, respectively, and has pharmacokinetic and pharmacodynamic properties supporting a once-weekly dosing regimen. Objective In the absence of a multiple-dose phase I trial in children with GHD, the aim was to develop a pharmacokinetic/pharmacodynamic model to predict somapacitan exposure and insulin-like growth factor-I (IGF-I) response after once-weekly multiple doses in both children and adults with GHD. Methods Pharmacokinetic/pharmacodynamic models were developed from pharmacokinetic and IGF-I profiles in three phase I trials of somapacitan (doses: healthy adults, 0.01-0.32 mg/kg; adult with GHD, 0.02-0.12 mg/kg; children with GHD, 0.02-0.16 mg/kg) using non-linear mixed-effects modeling. Pharmacokinetics were described using a non-linear one-compartment model with dual firstand zero-order absorption through a transit compartment, with saturable elimination. IGF-I profiles were described using an indirect response pharmacokinetic/pharmacodynamic model, with sigmoidal-effect relationship. Results The non-linear pharmacokinetic and IGF-I data were well-described in order to confidently predict pharmacokinetic/pharmacodynamic profiles after multiple doses in adults and children with GHD.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Once-Weekly Somapacitan in Children and Adults: Supporting Dosing Rationales with a Model-Based Analysis of Three Phase I Trials

et al. 2018

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“…Forty microliters was transferred to microtiter plates and stored at −80 • C until analyzed. Plasma concentrations of GH analogs were determined by beads-based luminescence oxygen channeling immuno-assays as previously described [6,23]. The dynamic range for GH was 0.6 to 1000 ng/mL and when a reading was below the lower limit of quantification, the values were set to half of the lower limit, in the case of GH to 0.3 ng/mL.…”

Section: Micro Plasma Sampling and Analysismentioning

confidence: 99%

“…The albumin-binding fatty-acid moiety is covalently attached to GH via a specific linker attached to a single amino acid in the GH backbone [6]. The prolonged circulation half-life of somapacitan is attributed by the reversible albumin-binding properties of the molecule [6,7]. More than 2 of 15 99% of the somapacitan molecules are bound to albumin in the circulation and tissue.…”

Section: Introductionmentioning

confidence: 99%

Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative

Petersen

Gandhi

Buchardt

et al. 2020

IJMS

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Somapacitan is a long-acting, once-weekly, albumin-binding growth hormone (GH) derivative. The reversible albumin-binding properties leads to prolonged circulation half-life. Here, we investigated and compared somapacitan with human GH on downstream receptor signaling in primary hepatocytes and hepatocellular models and using isothermal titration calorimetry to characterize receptor binding of somapacitan in the presence or absence of human serum albumin (HSA). With non-invasive fluorescence imaging we quantitatively visualize and compare the temporal distribution and examine the tissue-specific growth hormone receptor (GHR) activation at distribution sites. We found that signaling kinetics were slightly more rapid and intense for GH compared with somapacitan. Receptor binding isotherms were characterized by a high and a low affinity interaction site with or without HSA. Using in vivo optical imaging we found prolonged systemically biodistribution of somapacitan compared with GH, which correlated with plasma pharmacokinetics. Ex vivo mouse organ analysis revealed that the temporal fluorescent intensity in livers dosed with somapacitan was significantly increased compared with GH-dosed livers and correlated with the degree of downstream GHR activation. Finally, we show that fluorescent-labeled analogs distributed to the hypertrophic zone in the epiphysis of proximal tibia of hypophysectomized rats and that somapacitan and GH activate the GHR signaling in epiphyseal tissues.

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“…Novo Nordisk (Bagsvaerd, Denmark) manufactures Somapacitan (previously NNC0195-0092), growth hormone with a single point mutation to which a noncovalent albumin-binding terminal fatty acid is linked. Half-life is predicted to increase through albumin binding and subsequent reduced clearance (29). The same technology is used in the long-acting insulin detemir.…”

Section: Non-covalent Albumin Binding Growth Hormonementioning

confidence: 99%

Perspectives on long-acting growth hormone therapy in children and adults

Lal¹,

Hoffman²

2019

Archives of Endocrinology and Metabolism

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Growth hormone therapy with daily injections of recombinant human growth hormone has been available since 1985, and is shown to be safe and effective treatment for short stature in children and for adult growth hormone deficiency. In an effort to produce a product that would improve patient adherence, there has been a strong effort from industry to create a long acting form of growth hormone to ease the burden of use. Technologies used to increase half-life include depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding growth hormone and growth hormone fusion proteins. At present, two long acting formulations are on the market in China and South Korea, and several more promising agents are under clinical investigation at various stages of development throughout the world.

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Nonclinical pharmacokinetic and pharmacodynamic characterisation of somapacitan: A reversible non-covalent albumin-binding growth hormone

Cited by 28 publications

References 22 publications

Pharmacokinetics and Pharmacodynamics of Once-Weekly Somapacitan in Children and Adults: Supporting Dosing Rationales with a Model-Based Analysis of Three Phase I Trials

Pharmacokinetics and Pharmacodynamics of Once-Weekly Somapacitan in Children and Adults: Supporting Dosing Rationales with a Model-Based Analysis of Three Phase I Trials

Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative

Perspectives on long-acting growth hormone therapy in children and adults

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