Pharmacokinetics of Insulin Aspart and Glucagon in Type 1 Diabetes during Closed-Loop Operation

Haidar, Ahmad; Duval, C.; Legault, Laurent; Rabasa‐Lhoret, Rémi

doi:10.1177/193229681300700610

Cited by 26 publications

(30 citation statements)

References 21 publications

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“…However, using literature informed prior distributions of both tmax and ClF,I and optimizing for all four visits simultaneously we obtained reasonable fits by MAP estimation [28,34].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies showed that a simple two-state model with identical time constants for absorption and elimination could be used to describe the PK of insulin aspart after SC dosing [28]. …”

Section: Insulin Pharmacokinetic Modelmentioning

confidence: 99%

“…Due to missing insulin data around the expected time of maximum insulin concentration both tmax and ClF,I were estimated using maximum a posteriori (MAP) while Ib was estimated using ML. Prior distributions of tmax and ClF,I were reported in [28] and further information regarding tmax was extracted from the product monograph on insulin aspart [34]. Table S2 lists the prior parameter distributions.…”

Section: Model Fittingmentioning

confidence: 99%

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Cross-Validation of a Glucose-Insulin-Glucagon Pharmacodynamics Model for Simulation Using Data From Patients With Type 1 Diabetes

Wendt

Ranjan

Møller

et al. 2017

J Diabetes Sci Technol

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Background: Currently, no consensus exists on a model describing endogenous glucose production (EGP) as a function of glucagon concentrations. Reliable simulations to determine the glucagon dose preventing or treating hypoglycemia or to tune a dual-hormone artificial pancreas control algorithm need a validated glucoregulatory model including the effect of glucagon. Methods: Eight type 1 diabetes (T1D) patients each received a subcutaneous (SC) bolus of insulin on four study days to induce mild hypoglycemia followed by a SC bolus of saline or 100, 200, or 300 µg of glucagon. Blood samples were analyzed for concentrations of glucagon, insulin, and glucose. We fitted pharmacokinetic (PK) models to insulin and glucagon data using maximum likelihood and maximum a posteriori estimation methods. Similarly, we fitted a pharmacodynamic (PD) model to glucose data. The PD model included multiplicative effects of insulin and glucagon on EGP. Bias and precision of PD model test fits were assessed by mean predictive error (MPE) and mean absolute predictive error (MAPE). Results: Assuming constant variables in a subject across nonoutlier visits and using thresholds of ±15% MPE and 20% MAPE, we accepted at least one and at most three PD model test fits in each of the seven subjects. Thus, we successfully validated the PD model by leave-one-out cross-validation in seven out of eight T1D patients. Conclusions: The PD model accurately simulates glucose excursions based on plasma insulin and glucagon concentrations. The reported PK/PD model including equations and fitted parameters allows for in silico experiments that may help improve diabetes treatment involving glucagon for prevention of hypoglycemia.

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“…However, using literature informed prior distributions of both tmax and ClF,I and optimizing for all four visits simultaneously we obtained reasonable fits by MAP estimation [28,34].…”

Section: Discussionmentioning

confidence: 99%

Section: Insulin Pharmacokinetic Modelmentioning

confidence: 99%

Section: Model Fittingmentioning

confidence: 99%

See 1 more Smart Citation

Cross-Validation of a Glucose-Insulin-Glucagon Pharmacodynamics Model for Simulation Using Data From Patients With Type 1 Diabetes

Wendt

Ranjan

Møller

et al. 2017

J Diabetes Sci Technol

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show abstract

“…The model used in the present study was previously employed to study insulin aspart pharmacokinetics in T1D [19,20]. Compared to T1D, t max is longer and MCR I lower in the present study investigating T2D.…”

Section: Fig 2 -Weighted Residuals (Median and Iqr) Representing Difmentioning

confidence: 96%

“…The exogenous plasma insulin concentration is obtained assuming instantaneous equilibration between insulin appearance in plasma and plasma insulin reflecting a short plasma insulin half-life relative to the frequency of plasma insulin measurements [19,20]:…”

Section: Insulin Kineticsmentioning

confidence: 99%

Pharmacokinetics of insulin lispro in type 2 diabetes during closed-loop insulin delivery

Ruan

Thabit

Kumareswaran

et al. 2014

Computer Methods and Programs in Biomedicine

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Pharmacokinetics of diluted (U20) insulin aspart compared with standard (U100) in children aged 3–6 years with type 1 diabetes during closed-loop insulin delivery: a randomised clinical trial

et al. 2014

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Aims/hypothesisThe aim of this study was to compare the pharmacokinetics of two different concentrations of insulin aspart (B28Asp human insulin) in children aged 3–6 years with type 1 diabetes.MethodsYoung children with type 1 diabetes underwent an open-label, randomised, two-period crossover study in a clinical research facility, 2–6 weeks apart. In random order, diluted (1:5 dilution with saline [154 mmol/l NaCl]; 20 U/ml) or standard strength (100 U/ml) insulin aspart was administered via an insulin pump as a meal bolus and then overnight by closed-loop insulin delivery as determined by a model predictive algorithm. Plasma insulin was measured every 30–60 min from 17:00 hours on day 1 to 8:00 hours on day 2. We measured the time-to-peak insulin concentration (tmax), insulin metabolic clearance rate (MCRI) and background insulin concentration (insc) using compartmental modelling.ResultsEleven children (six male; age range 3.75–6.96 years, HbA1c 7.6% ± 1.3% [60 ± 14 mmol/mol], BMI standard deviation score 1.0 ± 0.8, duration of diabetes 2.2 ± 1.0 years, total daily dose 12.9 [10.6–16.5] U, fasting C-peptide concentration 5 [5–17.1] pmol/l; mean ± SD or median [interquartile range]) participated in the study. No differences between standard and diluted insulin were observed in terms of tmax (59.2 ± 14.4 vs 61.6 ± 8.7) min for standard vs diluted, p = 0.59; MCRI (1.98 × 10−2 ± 0.99 × 10−2 vs 1.89 × 10−2 ± 0.82 × 10−2 1/kg/min, p = 0.47), and insc (34 [1–72] vs 23 [3–65] pmol/l, p = 0.66). However, tmax showed less intersubject variability following administration of diluted aspart (SD 14.4 vs 8.7 min, p = 0.047).Conclusions/interpretationDiluting insulin aspart does not change its pharmacokinetics. However, it may result in less variable absorption and could be used in young children with type 1 diabetes undergoing closed-loop insulin delivery.Trial registration: Clinicaltrials.gov NCT01557634Funding: Funding was provided by the JDRF, 7th Framework Programme of the European Union, Wellcome Trust Strategic Award and the National Institute for Health Research Cambridge Biomedical Research Centre.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-014-3483-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Pharmacokinetics of Insulin Aspart and Glucagon in Type 1 Diabetes during Closed-Loop Operation

Abstract: Background:

Cited by 26 publications

References 21 publications

Cross-Validation of a Glucose-Insulin-Glucagon Pharmacodynamics Model for Simulation Using Data From Patients With Type 1 Diabetes

Cross-Validation of a Glucose-Insulin-Glucagon Pharmacodynamics Model for Simulation Using Data From Patients With Type 1 Diabetes

Pharmacokinetics of insulin lispro in type 2 diabetes during closed-loop insulin delivery

Pharmacokinetics of diluted (U20) insulin aspart compared with standard (U100) in children aged 3–6 years with type 1 diabetes during closed-loop insulin delivery: a randomised clinical trial

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