Trabalhos Aprovados

Evaluation of semaglutide dose levels in type 2 diabetes based on population pharmacokinetics and exposure-response



Autor(es): Petri KCC; Ingwersen SH; Flint A; Zacho J; Overgaard RV; Penaforte Saboia JG;
Apresentador(a): JAQUELLYNE GURGEL PENAFORTE SABOIA

Background: Semaglutide is a GLP-1 RA with a half-life of around 1 week. Two dose levels, 0.5 mg and 1.0 mg are evaluated across demographic subgroups. Aims: To determine if any demographic factors should be considered with semaglutide treatment. To evaluate if all subgroups (including low weight subjects <40 kg and heavy subjects >200 kg) obtained effective exposure levels at 0.5 mg, and additional benefits for 1.0 mg vs 0.5 mg.Method: The population PK analysis included data from 1612 of 1683 adults from 5 randomised trials. The ER analysis included a subset of these data (1552 adults from 4 of the trials). Blood samples for plasma semaglutide concentrations were taken 4-7 times per subject. The population PK model was predefined as 1-compartment with 1st order absorption and elimination and covariates for sex, age, race, ethnicity, body weight(BW), renal function, dose level and injection site. ER for HbA1c and weight loss was conducted via individual estimates of the average steady-state concentration obtained via population PK, and response was visualised using quantile data plots with model prediction overlays.Results: Baseline mean age (range) was 57 (20-86) years, with HbA1c 8.2 (5.9-13.1)%,BW 86.2 (39.7-198.3) kg and diabetes duration 8.1 (0.1-48.9) years. BW was the only covariate with a relevant effect on semaglutide exposure; for the other covariates, the 90% CIs were all within the equivalence interval, 0.80-1.25. For BW, a 55 kg subject had 40% (90% CI: 38-42%) higher exposure versus a reference subject of 85 kg and a 127 kg subject had 27% (90% CI: 26-28%) lower exposure. ER analysis revealed a clear weight and HbA1c reduction across exposures, irrespective of BW, indicating that all subgroups should benefit from semaglutide 0.5 mg. Furthermore, the ER for HbA1c was influenced by baseline HbA1c, and the ER for BW was influenced by sex, with limited impact of other factors. The exposure, HbA1c reduction and weight reduction for the three relevant subgroups (defined by BW, baseline HbA1c, and sex) indicated that all obtained a relevant benefit for 1.0 mg versus 0.5 mg semaglutide. Discussion:BW was the only relevant covariate for semaglutide exposure. However, although the 10% lightest subjects obtained an exposure approximately twice that of the 10% heaviest subjects, all subgroups obtained a relevant clear effect of 0.5 mg and all subgroups obtained benefit from a dose of 1.0 mg vs 0.5 mg semaglutide.

Palavras-chave: semaglutide; glycaemic control; type 2 diabetes

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