S H Ingwersen1, K C Petri2, N Tandon3, K-H Yoon4, L Chen5, J Vora6, W Yang7. 1. Novo Nordisk A/S, Søborg, Denmark. Electronic address: si@novonordisk.com. 2. Novo Nordisk A/S, Søborg, Denmark. 3. All India Institute of Medical Sciences, New Delhi, India. 4. Catholic Medical Center, The Catholic University of Korea, South Korea. 5. Department of Endocrinology, Wuhan Union Hospital, Wuhan, Hubei, China. 6. Royal Liverpool University Hospitals, Liverpool, UK. 7. Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China.
Abstract
AIMS: To investigate the population pharmacokinetics and exposure-response relationship of liraglutide, a human glucagon-like peptide-1 (GLP-1) analogue, in Asian subjects with Type 2 diabetes mellitus. METHODS: Data were derived from a published 16-week, randomized, double-blind, double-dummy, active-controlled, parallel-group trial of liraglutidein China, India and South Korea. The analysis utilized 2061 pharmacokinetic (PK) samples from 605 subjects exposed toliraglutide 0.6, 1.2 or 1.8 mg once daily. Demographic factors (body weight, age, gender, country) of importance for liraglutide clearance were evaluated. An exploratory exposure-response analysis was conducted to investigate effects on glycated haemoglobin (HbA1c) and body weight. RESULTS: Estimated liraglutide exposure (area under the curve; AUC) appeared to increase proportionally with increasing liraglutide dose (0.6-1.8 mg). The covariate analysis confirmed previous findings in a global clinical trial. Body weight was a predictor of liraglutide exposure; compared to a reference subject of 67 kg, exposure was 32% lower for maximum (115 kg) and 54% higher for minimum (37 kg) observed body weights. Gender, age and country had no relevant effect on exposure. Exposure-response analysis supported the use of 1.2mg as maintenance dose with the option of individual dose escalation to 1.8 mg to optimize treatment outcomes. CONCLUSIONS: Exposure appeared to increase proportionally with increasing liraglutide dose in Asian subjects with Type 2 diabetes mellitus. The only PK relevant predictor of exposure was body weight. The exposure-response relationships for HbA1c and body weight in Asian subjects were similar to observations in global populations.
RCT Entities:
AIMS: To investigate the population pharmacokinetics and exposure-response relationship of liraglutide, a humanglucagon-like peptide-1 (GLP-1) analogue, in Asian subjects with Type 2 diabetes mellitus. METHODS: Data were derived from a published 16-week, randomized, double-blind, double-dummy, active-controlled, parallel-group trial of liraglutide in China, India and South Korea. The analysis utilized 2061 pharmacokinetic (PK) samples from 605 subjects exposed to liraglutide 0.6, 1.2 or 1.8 mg once daily. Demographic factors (body weight, age, gender, country) of importance for liraglutide clearance were evaluated. An exploratory exposure-response analysis was conducted to investigate effects on glycated haemoglobin (HbA1c) and body weight. RESULTS: Estimated liraglutide exposure (area under the curve; AUC) appeared to increase proportionally with increasing liraglutide dose (0.6-1.8 mg). The covariate analysis confirmed previous findings in a global clinical trial. Body weight was a predictor of liraglutide exposure; compared to a reference subject of 67 kg, exposure was 32% lower for maximum (115 kg) and 54% higher for minimum (37 kg) observed body weights. Gender, age and country had no relevant effect on exposure. Exposure-response analysis supported the use of 1.2mg as maintenance dose with the option of individual dose escalation to 1.8 mg to optimize treatment outcomes. CONCLUSIONS: Exposure appeared to increase proportionally with increasing liraglutide dose in Asian subjects with Type 2 diabetes mellitus. The only PK relevant predictor of exposure was body weight. The exposure-response relationships for HbA1c and body weight in Asian subjects were similar to observations in global populations.
Authors: Julia K Mader; Lene Jensen; Steen H Ingwersen; Erik Christiansen; Simon Heller; Thomas R Pieber Journal: Clin Pharmacokinet Date: 2016-11 Impact factor: 6.447