Diabetes Care Volume 37, June 2014
e121
Pharmacokinetics of Insulin Aspart in Pregnant Women With Type 1 Diabetes: Every Day Is Different
Robert J.B. Goudie,1 David Lunn,1 Roman Hovorka,2,3 and Helen R. Murphy3
Diabetes Care 2014;37:e121–e122 | DOI: 10.2337/dc13-2535
Suffolk, Norfolk, and Cambridgeshire (study 1) and Essex 2 Research ethics committees (study 2). Participants (n 5 22) had a mean age of 32 (4.5) years; diabetes duration, 18 (8.7) years; gestational age, 22 (6.5) weeks; BMI, 27.0 (3.3) kg/m 2 ; and booking HbA1c, 7.1% (1.0) (54 [10.9] mmol/mol). Each mealtime was considered separately so that the basic unit of study is a time series (5-h profile) of insulin concentration after breakfast or dinner, with 88 profiles from 22 women (40, study 1; 48, study 2). Plasma insulin concentration (n 5 1,302 measurements) was measured by an immunochemiluminometric assay (Invitron, Monmouth, U.K.) with intraassay coefficient of variation (CV) 4.7% and interassay CV 7.2%–8.1%. A twocompartment model estimated timeto-peak plasma insulin concentration (tmax [min]), metabolic clearance rate of insulin (MCR [mL/kg/min]), rate of plasma insulin accumulation (Ia [pmol/L/min]), and postprandial plasma insulin concentration (Ib [pmol/L]). The mean time-to-peak postprandial aspart concentration was 55 min, which was reduced to 40 min after study 2 breakfast (Table 1). This suggests that moderate intensity physical activity may speed up prandial insulin absorption. There was strong evidence of
delayed aspart absorption with advancing pregnancy. The time-to-peak aspart concentration was delayed by 1.6% per week, meaning that absorption is approximately 50% slower at 38 weeks compared with 8 weeks of gestation. Interestingly, the time-to-peak was faster (1.1% per year) in women with longer duration of type 1 diabetes. The between-patient variability was less than expected from our comparable data set outside pregnancy (CV for tmax 12% and MCR 14%), compared with 33% and 44%, respectively, outside pregnancy (5). During pregnancy, the within-patient variability was striking (CV for t max 29% and MCR 29% and 23%). The percentage of inter-occasion variation out of total variation is high (t max 83% and MCR 71%), implying most variability is occasion-specific rather than individual-specific. This suggests that aspart pharmacokinetics is considerably less reproducible in pregnancy. In summary, our observations highlight the day-to-day challenges of optimal prandial dosing in type 1 diabetic pregnancy. They suggest that earlier premeal boluses are required as pregnancy advances and that physical activity is a potentially modifiable means for speeding up insulin absorption in pregnancy.
1
MRC Biostatistics Unit, Institute of Public Health, Cambridge, U.K. Department of Paediatrics, University of Cambridge, Cambridge, U.K. 3 University of Cambridge Wellcome Trust-MRC Institute of Metabolic Science, Level 4 Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge, U.K. 2
Corresponding author: Helen R. Murphy, [email protected]. Clinical trial reg. nos. ISRCTN62568875 and ISRCTN50385583, http://isrctn.org. © 2014 by the American Diabetes Association. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
eLETTERS – OBSERVATIONS
Rapid-acting insulin analogs are increasingly used during type 1 diabetic pregnancy. They may assist women to safely optimize glucose control (1,2), but little is known about their pharmacokinetics and reproducibility in pregnancy. Using a unique data set of 1,300 plasma insulin samples collected under strictly observed experimental conditions, we explored the relationship between aspart pharmacokinetics and clinical and demographic factors. We also assessed reproducibility both within and between pregnant women using continuous subcutaneous insulin infusion (CSII). In study 1 (ISRCTN62568875), 10 women were studied on two occasions under sedentary conditions with prandial boluses administered before standardized evening and breakfast meals in early (12–16 weeks) and in late (28–32 weeks) gestation (3). In study 2 (ISRCTN50385583), 12 women were studied on two occasions in midgestation (19 and 23 weeks) (4). The boluses were administered before standardized evening and breakfast meals (60-g carbohydrate dinner, 50-g carbohydrate breakfast). Physical activity was encouraged with postprandial walking (20 min after each meal) with 50 min of brisk treadmill walking (3.9 km/h) after breakfast (4). Ethics approval was obtained from
e122
Diabetes Care Volume 37, June 2014
Insulin Pharmacokinetics in Pregnancy
Table 1—Insulin aspart pharmacokinetics in type 1 diabetic pregnancy Aspart pharmacokinetic parameter Factor
MCR
Time to peak tmax
Accumulation rate Ia
Postprandial concentration Ib
Association with clinical and demographic factors* Study 2 breakfast 0.97 0.37 0.79 Gestation (weeks) 0.76 0.16 0.13 Diabetes duration 0.68 0.20 0.12 Peak bolus rate 0.15 0.14 0.64 Total daily dose 0.23 0.38 0.52 Point estimates (accuracies) of the mean for each study and meal-time combination§ min mL/kg/min pmol/L/min Study 2 breakfast Study 2 dinner Study 1 breakfast Study 1 dinner
40 (3.4) 55 (4.0) 55 (4.7) 55 (4.7)
0.027 (0.0025) 0.022 (0.0025) 0.024 (0.0019) 0.025 (0.0019)
Point estimates (accuracies) of the effect sizes§** Gestation (weeks) 1.6 (0.64)% Diabetes duration 21.1 (0.49)% Peak bolus rate 0.16 (1.0)% Total daily dose 0.31 (0.29)%
20.62 (0.75)% 0.68 (0.56)% 20.18 (1.2)% 20.45 (0.25)%
0.24 0.12 0.10 0.12 0.11 pmol/L
0.058 (0.043) 20.037 (0.027) 20.032 (0.024) 20.029 (0.024) 20.0032 (0.0029) 0.0021 (0.0021) 0.011 (0.0045) 20.0025 (0.0011)
36 (14) 29 (11) 27 (11) 28 (11) 0.75 (1.1) 20.017 (0.80) 0.46 (1.6) 20.090 (0.45)
Significant associations are indicated in boldface type. *Estimated probability of association. Only the clinical/demographic factors for which the probability of an association $0.5 are shown. §Accuracy is measured by posterior standard deviation (the Bayesian analog of a standard error). **For tmax and MCR, the estimated expected percentage change is shown; for Ia and Ib, the estimated expected absolute change is shown.
Acknowledgments. The authors are grateful
to the research staff at the Wellcome Trust clinical research centre (Addenbrooke’s Hospital, Cambridge, U.K.) for their excellent clinical care, Dr. Paul Luzio and colleagues (University of Cardiff, Wales, U.K.) for plasma insulin measurements, and to all the study participants for their generous and enthusiastic support. Funding. R.J.B.G. and D.L. are funded by the UK Medical Research Council (U105260557). H.R.M. is funded by a National Institute for Health Research research fellowship (CDF-2013-06-035). The clinical studies were funded by a Diabetes UK project grant (BDA07/003551). The research was conducted with support from JDRF, Medical Research Council Centre for Obesity and Related Metabolic Diseases, National Institute for Health Research Biomedical Research Centre (Cambridge, U.K.), and Addenbrooke’s Clinical Research Centre (Cambridge, U.K.). No funder had any role in the study design; data collection, analysis, and interpretation; or manuscript preparation.
Duality of Interest. H.R.M. has received hono-
References
raria for speaking engagements from Medtronic, Roche, and Novo Nordisk; and is a member of the Medtronic European Advisory Board. R.H. reports speaker honoraria from MiniMed Medtronic, LifeScan, Eli Lilly, B. Braun, and Novo Nordisk; service on advisory panels for Animas, MiniMed Medtronic, and Eli Lilly; license fees from B. Braun and Becton, Dickinson and Company; and having served as a consultant to Becton, Dickinson and Company, B. Braun, Sanofi, and Profil. No other potential conflicts of interest relevant to this article were reported. Author Contributions. R.J.B.G., D.L., R.H., and H.R.M. designed the studies. H.R.M. performed the studies. R.J.B.G., D.L., and R.H. analyzed the data. R.J.B.G., D.L., R.H., and H.R.M. interpreted the data. R.J.B.G. and H.R.M. drafted the manuscript. R.J.B.G., D.L., R.H., and H.R.M. reviewed and edited the manuscript. All authors approved final version. H.R.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
1. Heller S, Damm P, Mersebach H, et al. Hypoglycemia in type 1 diabetic pregnancy: role of preconception insulin aspart treatment in a randomized study. Diabetes Care 2010;33:473–477 2. Mathiesen ER, Kinsley B, Amiel SA, et al.; Insulin Aspart Pregnancy Study Group. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care 2007;30:771–776 3. Murphy HR, Elleri D, Allen JM, et al. Closed-loop insulin delivery during pregnancy complicated by type 1 diabetes. Diabetes Care 2011;34:406–411 4. Murphy HR, Kumareswaran K, Elleri D, et al. Safety and efficacy of 24-h closed-loop insulin delivery in well-controlled pregnant women with type 1 diabetes: a randomized crossover case series. Diabetes Care 2011;34:2527–2529 5. Haidar A, Elleri D, Kumareswaran K, et al. Pharmacokinetics of insulin aspart in pump-treated subjects with type 1 diabetes: reproducibility and effect of age, weight, and duration of diabetes. Diabetes Care 2013;36:E173–E174
Copyright of Diabetes Care is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
e121
Pharmacokinetics of Insulin Aspart in Pregnant Women With Type 1 Diabetes: Every Day Is Different
Robert J.B. Goudie,1 David Lunn,1 Roman Hovorka,2,3 and Helen R. Murphy3
Diabetes Care 2014;37:e121–e122 | DOI: 10.2337/dc13-2535
Suffolk, Norfolk, and Cambridgeshire (study 1) and Essex 2 Research ethics committees (study 2). Participants (n 5 22) had a mean age of 32 (4.5) years; diabetes duration, 18 (8.7) years; gestational age, 22 (6.5) weeks; BMI, 27.0 (3.3) kg/m 2 ; and booking HbA1c, 7.1% (1.0) (54 [10.9] mmol/mol). Each mealtime was considered separately so that the basic unit of study is a time series (5-h profile) of insulin concentration after breakfast or dinner, with 88 profiles from 22 women (40, study 1; 48, study 2). Plasma insulin concentration (n 5 1,302 measurements) was measured by an immunochemiluminometric assay (Invitron, Monmouth, U.K.) with intraassay coefficient of variation (CV) 4.7% and interassay CV 7.2%–8.1%. A twocompartment model estimated timeto-peak plasma insulin concentration (tmax [min]), metabolic clearance rate of insulin (MCR [mL/kg/min]), rate of plasma insulin accumulation (Ia [pmol/L/min]), and postprandial plasma insulin concentration (Ib [pmol/L]). The mean time-to-peak postprandial aspart concentration was 55 min, which was reduced to 40 min after study 2 breakfast (Table 1). This suggests that moderate intensity physical activity may speed up prandial insulin absorption. There was strong evidence of
delayed aspart absorption with advancing pregnancy. The time-to-peak aspart concentration was delayed by 1.6% per week, meaning that absorption is approximately 50% slower at 38 weeks compared with 8 weeks of gestation. Interestingly, the time-to-peak was faster (1.1% per year) in women with longer duration of type 1 diabetes. The between-patient variability was less than expected from our comparable data set outside pregnancy (CV for tmax 12% and MCR 14%), compared with 33% and 44%, respectively, outside pregnancy (5). During pregnancy, the within-patient variability was striking (CV for t max 29% and MCR 29% and 23%). The percentage of inter-occasion variation out of total variation is high (t max 83% and MCR 71%), implying most variability is occasion-specific rather than individual-specific. This suggests that aspart pharmacokinetics is considerably less reproducible in pregnancy. In summary, our observations highlight the day-to-day challenges of optimal prandial dosing in type 1 diabetic pregnancy. They suggest that earlier premeal boluses are required as pregnancy advances and that physical activity is a potentially modifiable means for speeding up insulin absorption in pregnancy.
1
MRC Biostatistics Unit, Institute of Public Health, Cambridge, U.K. Department of Paediatrics, University of Cambridge, Cambridge, U.K. 3 University of Cambridge Wellcome Trust-MRC Institute of Metabolic Science, Level 4 Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge, U.K. 2
Corresponding author: Helen R. Murphy, [email protected]. Clinical trial reg. nos. ISRCTN62568875 and ISRCTN50385583, http://isrctn.org. © 2014 by the American Diabetes Association. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
eLETTERS – OBSERVATIONS
Rapid-acting insulin analogs are increasingly used during type 1 diabetic pregnancy. They may assist women to safely optimize glucose control (1,2), but little is known about their pharmacokinetics and reproducibility in pregnancy. Using a unique data set of 1,300 plasma insulin samples collected under strictly observed experimental conditions, we explored the relationship between aspart pharmacokinetics and clinical and demographic factors. We also assessed reproducibility both within and between pregnant women using continuous subcutaneous insulin infusion (CSII). In study 1 (ISRCTN62568875), 10 women were studied on two occasions under sedentary conditions with prandial boluses administered before standardized evening and breakfast meals in early (12–16 weeks) and in late (28–32 weeks) gestation (3). In study 2 (ISRCTN50385583), 12 women were studied on two occasions in midgestation (19 and 23 weeks) (4). The boluses were administered before standardized evening and breakfast meals (60-g carbohydrate dinner, 50-g carbohydrate breakfast). Physical activity was encouraged with postprandial walking (20 min after each meal) with 50 min of brisk treadmill walking (3.9 km/h) after breakfast (4). Ethics approval was obtained from
e122
Diabetes Care Volume 37, June 2014
Insulin Pharmacokinetics in Pregnancy
Table 1—Insulin aspart pharmacokinetics in type 1 diabetic pregnancy Aspart pharmacokinetic parameter Factor
MCR
Time to peak tmax
Accumulation rate Ia
Postprandial concentration Ib
Association with clinical and demographic factors* Study 2 breakfast 0.97 0.37 0.79 Gestation (weeks) 0.76 0.16 0.13 Diabetes duration 0.68 0.20 0.12 Peak bolus rate 0.15 0.14 0.64 Total daily dose 0.23 0.38 0.52 Point estimates (accuracies) of the mean for each study and meal-time combination§ min mL/kg/min pmol/L/min Study 2 breakfast Study 2 dinner Study 1 breakfast Study 1 dinner
40 (3.4) 55 (4.0) 55 (4.7) 55 (4.7)
0.027 (0.0025) 0.022 (0.0025) 0.024 (0.0019) 0.025 (0.0019)
Point estimates (accuracies) of the effect sizes§** Gestation (weeks) 1.6 (0.64)% Diabetes duration 21.1 (0.49)% Peak bolus rate 0.16 (1.0)% Total daily dose 0.31 (0.29)%
20.62 (0.75)% 0.68 (0.56)% 20.18 (1.2)% 20.45 (0.25)%
0.24 0.12 0.10 0.12 0.11 pmol/L
0.058 (0.043) 20.037 (0.027) 20.032 (0.024) 20.029 (0.024) 20.0032 (0.0029) 0.0021 (0.0021) 0.011 (0.0045) 20.0025 (0.0011)
36 (14) 29 (11) 27 (11) 28 (11) 0.75 (1.1) 20.017 (0.80) 0.46 (1.6) 20.090 (0.45)
Significant associations are indicated in boldface type. *Estimated probability of association. Only the clinical/demographic factors for which the probability of an association $0.5 are shown. §Accuracy is measured by posterior standard deviation (the Bayesian analog of a standard error). **For tmax and MCR, the estimated expected percentage change is shown; for Ia and Ib, the estimated expected absolute change is shown.
Acknowledgments. The authors are grateful
to the research staff at the Wellcome Trust clinical research centre (Addenbrooke’s Hospital, Cambridge, U.K.) for their excellent clinical care, Dr. Paul Luzio and colleagues (University of Cardiff, Wales, U.K.) for plasma insulin measurements, and to all the study participants for their generous and enthusiastic support. Funding. R.J.B.G. and D.L. are funded by the UK Medical Research Council (U105260557). H.R.M. is funded by a National Institute for Health Research research fellowship (CDF-2013-06-035). The clinical studies were funded by a Diabetes UK project grant (BDA07/003551). The research was conducted with support from JDRF, Medical Research Council Centre for Obesity and Related Metabolic Diseases, National Institute for Health Research Biomedical Research Centre (Cambridge, U.K.), and Addenbrooke’s Clinical Research Centre (Cambridge, U.K.). No funder had any role in the study design; data collection, analysis, and interpretation; or manuscript preparation.
Duality of Interest. H.R.M. has received hono-
References
raria for speaking engagements from Medtronic, Roche, and Novo Nordisk; and is a member of the Medtronic European Advisory Board. R.H. reports speaker honoraria from MiniMed Medtronic, LifeScan, Eli Lilly, B. Braun, and Novo Nordisk; service on advisory panels for Animas, MiniMed Medtronic, and Eli Lilly; license fees from B. Braun and Becton, Dickinson and Company; and having served as a consultant to Becton, Dickinson and Company, B. Braun, Sanofi, and Profil. No other potential conflicts of interest relevant to this article were reported. Author Contributions. R.J.B.G., D.L., R.H., and H.R.M. designed the studies. H.R.M. performed the studies. R.J.B.G., D.L., and R.H. analyzed the data. R.J.B.G., D.L., R.H., and H.R.M. interpreted the data. R.J.B.G. and H.R.M. drafted the manuscript. R.J.B.G., D.L., R.H., and H.R.M. reviewed and edited the manuscript. All authors approved final version. H.R.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
1. Heller S, Damm P, Mersebach H, et al. Hypoglycemia in type 1 diabetic pregnancy: role of preconception insulin aspart treatment in a randomized study. Diabetes Care 2010;33:473–477 2. Mathiesen ER, Kinsley B, Amiel SA, et al.; Insulin Aspart Pregnancy Study Group. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care 2007;30:771–776 3. Murphy HR, Elleri D, Allen JM, et al. Closed-loop insulin delivery during pregnancy complicated by type 1 diabetes. Diabetes Care 2011;34:406–411 4. Murphy HR, Kumareswaran K, Elleri D, et al. Safety and efficacy of 24-h closed-loop insulin delivery in well-controlled pregnant women with type 1 diabetes: a randomized crossover case series. Diabetes Care 2011;34:2527–2529 5. Haidar A, Elleri D, Kumareswaran K, et al. Pharmacokinetics of insulin aspart in pump-treated subjects with type 1 diabetes: reproducibility and effect of age, weight, and duration of diabetes. Diabetes Care 2013;36:E173–E174
Copyright of Diabetes Care is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
