Population pharmacokinetics of exendin‐(9‐39) and clinical dose selection in patients with congenital hyperinsulinism

Publisher： John Wiley & Sons Inc

E-ISSN： 1365-2125|84|3|520-532

ISSN： 0306-5251

Source： BRITISH JOURNAL OF CLINICAL PHARMACOLOGY (ELECTRONIC), Vol.84, Iss.3, 2018-03, pp. : 520-532

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

Abstract

AimsCongenital hyperinsulinism (HI) is the most common cause of persistent hypoglycaemia in infants and children. Exendin‐(9‐39), an inverse glucagon‐like peptide 1 (GLP‐1) agonist, is a novel therapeutic agent for HI that has demonstrated glucose‐raising effect. We report the first population pharmacokinetic (PopPK) model of the exendin‐(9‐39) in patients with HI and propose the optimal dosing regimen for future clinical trials in neonates with HI.
MethodsA total of 182 pharmacokinetic (PK) observations from 26 subjects in three clinical studies were included for constructing the PopPK model using first order conditional estimation (FOCE) with interaction method in nonlinear mixed‐effects modelling (NONMEM). Exposure metrics (area under the curve [AUC] and maximum plasma concentration [Cmax]) at no observed adverse effect levels (NOAELs) in rats and dogs were determined in toxicology studies.
ResultsObserved concentration–time profiles of exendin‐(9‐39) were described by a linear two‐compartmental PK model. Following allometric scaling of PK parameters, age and creatinine clearance did not significantly affect clearance. The calculated clearance and elimination half‐life for adult subjects with median weight of 69 kg were 11.8 l h−1 and 1.81 h, respectively. The maximum recommended starting dose determined from modelling and simulation based on the AUC0‐last at the NOAEL and predicted AUC0‐inf using the PopPK model was 27 mg kg−1 day−1 intravenously.
ConclusionsThis is the first study to investigate the PopPK of exendin‐(9‐39) in humans. The final PopPK model was successfully used with preclinical toxicology findings to propose the optimal dosing regimen of exendin‐(9‐39) for clinical studies in neonates with HI, allowing for a more targeted dosing approach to achieve desired glycaemic response.

Related content

Efficacy and pharmacokinetics of subcutaneous exendin (9‐39) in patients with post‐bariatric hypoglycaemia

By  

DIABETES OBESITY & METABOLISM (ELECTRONIC), Vol. 20, Iss. 2, 2018-02 ,pp. : 352-361 (10)

John Wiley & Sons Inc

Access to resources Recommend Favorite

Non‐Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics and First‐in‐Human Dose Selection for CNTO 5825, an Anti‐Interleukin‐13 Monoclonal Antibody

By  

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY (ELECTRONIC), Vol. 117, Iss. 4, 2015-10 ,pp. : 219-225 (7)

John Wiley & Sons Inc

Access to resources Recommend Favorite

Population pharmacokinetics of infliximab in patients with inflammatory bowel disease: potential implications for dosing in clinical practice

By  

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Vol. 42, Iss. 5, 2015-09 ,pp. : 529-539 (11)

John Wiley & Sons Inc

Access to resources Recommend Favorite

Population pharmacokinetics of rifampicin in Mexican patients with tuberculosis

By  

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Vol. 269-4727, Iss. 1, 2013-02 ,pp. : 56-61 (6)

John Wiley & Sons Inc

Access to resources Recommend Favorite

Population pharmacokinetics of rifampicin in Mexican patients with tuberculosis

By  

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Vol. 38, Iss. 1, 2013-02 ,pp. : 56-61 (6)

John Wiley & Sons Inc

Access to resources Recommend Favorite