Dataset Information

Population Pharmacokinetics of Semaglutide for Type 2 Diabetes.

ABSTRACT:

Introduction

The aim of the present analysis was to characterise the absorption, distribution and elimination of semaglutide by means of population pharmacokinetic (PK) models using data from nine clinical pharmacology trials conducted in both healthy subjects and those with type 2 diabetes.

Methods

Data were obtained from trials with subcutaneous and intravenous administration of semaglutide that utilised frequent PK sampling and included a total of 353 subjects with 10,573 concentration values.

Results

Semaglutide PK properties across trials, drug product strengths and populations were well characterised by a two-compartment model with first-order absorption and elimination. For a typical subject with type 2 diabetes, clearance was estimated to be 0.0348 L/h [95% confidence interval (CI) 0.0327-0.0369 L/h], and the central and peripheral volumes were estimated to be 3.59 L (95% CI 3.28-3.90 L) and 4.10 L (95% CI 3.78-4.42 L), respectively (i.e. a total volume of distribution of 7.7 L). Interindividual variation was low (~ 15%) for both clearance and volumes of distribution, with low residual error (< 5%). Clearance and the total volume of distribution were approximately proportional to body weight. Minor differences were identified between healthy subjects and subjects with type 2 diabetes with respect to clearance and absorption rate, and between injection sites with respect to bioavailability.

Conclusions

A novel two-compartment model was developed to provide the general characteristics of semaglutide absorption following subcutaneous administration, and of distribution and elimination across administration routes. Semaglutide PK was shown to be predictable across populations and administration routes and within subjects, and was primarily influenced by body weight.

Funding

Novo Nordisk, Bagsværd, Denmark.

SUBMITTER: Overgaard RV

PROVIDER: S-EPMC6437231 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AIMS:To investigate whether the pharmacokinetic characteristics of semaglutide were altered in people with hepatic impairment, assessed using Child-Pugh criteria, vs those with normal hepatic function. METHODS:In this multicentre, open-label, parallel-group trial (sponsor Novo Nordisk, ClinicalTrials.gov ID NCT02210871), four groups of participants with normal hepatic function (n?=?19) or mild (n?=?8), moderate (n?=?10) or severe (n?=?7) hepatic impairment received a single, subcutaneous dose of 0.5 mg semaglutide. Semaglutide plasma concentrations were assessed frequently for 35?days after dosing. The primary endpoint was area under the semaglutide plasma concentration-time curve from time zero to infinity (AUC0-? ). No effect of hepatic impairment was declared if the 90% confidence interval (CI) for the between-group ratio (hepatic impairment/normal function) was within the interval 0.70 to 1.43. RESULTS:Semaglutide exposure was similar across all groups, with AUC0-? treatment ratios for mild impairment/normal function of 0.95 (90% CI 0.77, 1.16), moderate impairment/normal function 1.02 (90% CI 0.93, 1.12), and severe impairment/normal function 0.97 (90% CI 0.84, 1.12). The maximum plasma semaglutide concentration (Cmax ) did not appear to be influenced by hepatic function, with mild impairment/normal function treatment ratios of 0.99 (90% CI 0.80, 1.23), moderate impairment/normal function 1.02 (90% CI 0.88, 1.18) and severe impairment/normal function 1.15 (90% CI 0.89, 1.48; sensitivity analysis excluding one extreme semaglutide concentration: 1.05 [90% CI 0.88, 1.25]). In all, 10 participants reported 12 mild or moderate non-serious adverse events. No unexpected safety or tolerability issues were observed. CONCLUSIONS:Semaglutide exposure did not appear to be affected by hepatic impairment, suggesting that dose adjustment may not be necessary in patients with hepatic impairment. Semaglutide was well tolerated and there were no unexpected safety issues.