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

ABSTRACT: AIMS:Congenital 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. METHODS:A 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. RESULTS:Observed 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. CONCLUSIONS:This 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.

SUBMITTER: Ng CM

PROVIDER: S-EPMC5809353 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Ng Chee M CM Tang Fei F Seeholzer Steven H SH Zou Yixuan Y De León Diva D DD

British journal of clinical pharmacology 20171206 3

<h4>Aims</h4>Congenital 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.<h4>Methods</h4>A total of 182 pharmac ...[more]

PMID: 29077992

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Project description:Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum β-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to <18 years old) with proven/suspected Gram-negative bacterial infections, along with pharmacokinetic data from 12 adult studies, were integrated into a population pharmacokinetic (popPK) analysis. Two-compartment linear models with first-order elimination described the concentration-time profiles of ceftolozane and tazobactam in pediatric patients well. Renal function and body weight were identified to be significant predictors of ceftolozane-tazobactam pharmacokinetics. Renal function, as measured by the estimated glomerular filtration rate (eGFR), significantly affected the clearance of both ceftolozane and tazobactam. Body weight significantly affected clearance and the distribution volume, also of both ceftolozane and tazobactam. Patients with infections had a 32.3% lower tazobactam clearance than healthy volunteers. Using the final popPK models, simulations of various dosing regimens were conducted to assess each regimen's plasma exposure and the probability of pharmacokinetic/pharmacodynamic target attainment. Based on these simulations, the following doses are recommended for further clinical evaluation in phase 2 pediatric trials for cUTI and cIAI (in patients with an eGFR of ≥50 ml/min/1.73 m2 only): for children ≥12 years old, 1.5 g ceftolozane-tazobactam (1 g ceftolozane with 0.5 g tazobactam), and for neonates/very young infants, infants, and children <12 years old, 20/10 mg/kg of body weight ceftolozane-tazobactam, both via a 1-h intravenous infusion every 8 h.

Project description:IntroductionCongenital hyperinsulinism is a rare inherited disease caused by mutations in genes responsible for β-cell's function in glucose hemostasis leading to profound and recurrent hypoglycemia. The incidence of the disease is about 1 in 50000 newborns. Mutations in at least 8 genes have been reported to cause congenital hyperinsulinism. Mutations in ABCC8 gene are the most common cause of the disease that account for approximately 40% of cases. Less frequently KCNJ11 gene mutations are responsible for the disease. Mutations in other genes such as HADH account for smaller fractions of cases. In nearly half of the cases the cause remains unknown.Case presentationDuring the period between 2005 and 2010, a total of six patients with persistent hyperinsulinism were investigated at Mofid Children's Hospital. In this study all of the patients had early onset hyperinsulinemia. Five patients had consanguineous parents. After failure of medical treatment in three patients, They were undergone pancreatectomy. Two diffuse types and one focal type had been recognized in pathological analysis of intra-operative frozen specimens of pancreas in these patients. Genetic analysis was performed using polymerase chain reaction followed by Sanger sequencing for ABCC8, KCNJ11and HADH genes. In five patients homozygous mutations in these genes were identified that indicated an autosomal recessive pattern of inheritance. In one patient a heterozygous mutation in ABCC8 was identified, indicating possible autosomal dominant inheritance of the disease.ConclusionsCongenital hyperinsulinism can have different inheritance pattern. Autosomal recessive inheritance is more common but less frequently autosomal dominant inheritance can be seen. It appears that mutations in ABCC8 gene can show both autosomal recessive and autosomal dominant inheritance of the disease. PCR followed by Sanger sequencing proved to be an efficient method for mutation detection in three investigated genes. Despite early diagnosis, psychomotor retardation was seen in two patients.

Dataset Information

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

Publications

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

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