Bioequivalence Studies of Omnitrope, the First Biosimilar/rhGH Follow‐on Protein: Two Comparative Phase 1 Randomized Studies and Population Pharmacokinetic Analysis

Abstract

This article discusses the bioequivalence of Omnitrope (Sandoz's rhGH biosimilar) and Genotropin (reference rhGH product), assessed in the first 2 clinical phase 1 studies conducted during the development of Omnitrope. Both of these phase 1 studies were randomized, double-blind, crossover studies, each involving 24 healthy volunteers who underwent pituitary somatrope cell down-regulation using octreotide. Three different formulations of recombinant human growth hormone (rhGH) were compared: Omnitrope lyophilisate, Omnitrope liquid and Genotropin (lyophilized powder for injection). Both pharmacokinetics (area under the curve [AUC], C(max), t(max) and t(1/2)) and pharmacodynamics (serum levels of insulin-like growth factor 1, insulin-like growth factor binding protein-3 and non-esterified fatty acid) were assessed after a single subcutaneous injection of 5 mg rhGH. The 3 formulations had comparable pharmacokinetics and pharmacodynamics. All the 90% confidence intervals of the ratios of the least squares means for the pharmacokinetic and pharmacodynamic parameters AUC and C(max) were within the predefined FDA and EMEA acceptance range of 80%-125% for bioequivalence. In addition, a comparative population pharmacokinetic analysis further supports that Omnitrope lyophilisate, Omnitrope liquid and Genotropin can be regarded as equivalent in terms of pharmacokinetics. Therefore, Omnitrope lyophilisate was demonstrated to be bioequivalent to both Genotropin and the Omnitrope liquid formulation.

Pharmacokinetic Similarity of Biologics: Analysis Using Nonlinear Mixed-Effects Modeling

“…For somatropin, a one‐compartment model with first‐order absorption and first‐order elimination was used with and without a lag time for the absorption 37 . The PK parameters estimated were CL/F, apparent clearance of elimination, expressed as l/h; V/F, the apparent volume of distribution, expressed in liters; k a , the absorption rate constant, expressed in h −1 ; and t lag , the absorption lag time, expressed in h.…”

Comparative Pharmacokinetics of HD203, a Biosimilar of Etanercept, with Marketed Etanercept (Enbrel®)

“…[2] Since the substantial cost of the treatments based on these biosynthetic products, including etanercept, limits access to these therapeutic agents, the patent expiry of the original biologic products creates opportunities for the abbreviated development of biosimilars. [3][4][5] A biosimilar etanercept is already marketed in China as Yisaipu, and in Colombia as Etanar, by CP Guojian Pharmaceutical Co., Ltd (Shanghai, China). Several other biotechnology companies are developing biosimilars of etanercept as well.…”

A phase 1, randomized study to assess the pharmacokinetic comparability of siltuximab derived from two different cell lines in healthy subjects

“…A crossover design suggested by US FDA for bioequivalence comparison based on its statistical superiority was also recommended for biologics . This design has been applied for biologics with shorter half‐lives . However, monoclonal antibodies usually have much longer half‐lives and require much longer washout periods between dosing sessions in addition to prolonged sampling periods.…”

“…2,6 This design has been applied for biologics with shorter half-lives. 7,8 However, monoclonal antibodies usually have much longer half-lives and require much longer washout periods between dosing sessions in addition to prolonged sampling periods. Even though the level of immunogenicity may be low for monoclonal antibodies, anti-drug antibodies may develop in humans after the administration of a biological product.…”