Subcutaneous Bioavailability of Taspoglutide at 3 Different Injection Sites in Healthy Overweight/Obese Subjects

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• 作者：Carolina Sturm-Pellanda ; PhD ; Markus Abt ; PhD ; Patricia Sanwald-Ducray ; PhD ; Christophe Schmitt ; PharmD ; ^{christophe.schmitt@roche.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：bioavailability ; GLP-1 agonist ; period effect ; site of injection ; taspoglutide
• 刊名：Clinical Therapeutics
• 出版年：2015
• 出版时间：1 November 2015
• 年：2015
• 卷：37
• 期：11
• 页码：2439-2448
• 全文大小：254 K

文摘

Taspoglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist that has >90% homology with the endogenous GLP-1 while retaining equivalent potency. Once-weekly subcutaneous injections with taspoglutide demonstrated meaningful antihyperglycemic and weight loss effects in patients with type 2 diabetes. The present study was performed to compare the relative bioavailability of taspoglutide injected subcutaneously in the abdomen, upper arm, and thigh.

Methods

Healthy overweight/obese subjects were randomized in an open-label, 3-way crossover study. A single 20-mg dose of taspoglutide was injected subcutaneously on 3 occasions in the abdomen, upper arm, or thigh. Each injection was separated by a 12-week washout period. Blood was sampled up to 12 weeks for the pharmacokinetic evaluation of taspoglutide.

Findings

Sixty subjects were randomized into the study (mean age, 45.5 years; body weight, 97.6 kg; and body mass index, 31.4 kg/m²). AUC_last values (geometric mean) for subcutaneous injections in the abdomen, upper arm, and thigh were 44.2, 61.2, and 50.0 ng·h/mL, respectively. The geometric mean ratio (relative bioavailability) for the upper arm versus the abdomen was 1.41 (90% CI: 1.22–1.62) and for the thigh versus the abdomen was 1.13 (90% CI: 0.98–1.31). Corresponding C_max values for subcutaneous injections in the abdomen, upper arm, and thigh were 0.268, 0.382, and 0.341 ng/mL, respectively, and the geometric mean ratio for the upper arm versus the abdomen was 1.43 (90% CI: 1.24–1.64) and for the thigh versus the abdomen was 1.27 (90% CI: 1.10–1.46). Decreases in taspoglutide exposure were observed with each subsequent period. AUC_last values (geometric mean across injections sites) for periods 1, 2, and 3 were 97.2, 42.6, and 31.5 ng·h/mL, respectively. The geometric mean ratio for period 2 versus 1 was 0.44 (90% CI: 0.38–0.50) and for period 3 versus 1 was 0.32 (90% CI: 0.27–0.37). Analysis of pharmacokinetic data after first injection only (period 1) showed comparable AUC_last across the 3 injection sites and lower initial C_max after injection into the abdomen compared with the other 2 injection sites. Overall, taspoglutide was well tolerated by most subjects in all 3 injection sites, with a lower incidence of nausea and vomiting when injected in the abdomen.

Implications

Regardless of a pronounced period effect, relative bioavailability of taspoglutide was different across injection sites, with the lowest exposure and incidence of nausea and vomiting seen after administration in the abdomen. In the absence of comparable bioavailability, taspoglutide was recommended to be injected into the abdomen.