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Published online February 15, 2007
Diabetes Care 30:1261-1263, 2007
DOI: 10.2337/dc06-2208
© 2007 by the American Diabetes Association
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Clinical Care/Education/Nutrition
Brief Report

Pharmacokinetics and Pharmacodynamics of the Long-Acting Insulin Analog Glargine After 1 Week of Use Compared With Its First Administration in Subjects With Type 1 Diabetes

Francesca Porcellati, MD, Paolo Rossetti, MD, Natalia Busciantella Ricci, MD, Simone Pampanelli, MD, Elisabetta Torlone, MD, Susana Hernandez Campos, MD, Anna Marinelli Andreoli, MD, Geremia B. Bolli, MD and Carmine G. Fanelli, MD

Department of Internal Medicine, Section of Internal Medicine, Endocrinology, and Metabolism, University of Perugia, Perugia, Italy

Address correspondence and reprint requests to Prof. Geremia B. Bolli, University of Perugia, Department of Internal Medicine, Section of Internal Medicine, Endocrinology, and Metabolism, via E. Dal Pozzo, 06126 Perugia, Italy. E-mail: gbolli{at}unipg.it

Abbreviations: GIR, glucose infusion rate


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
Pharmacokinetics and pharmacodynamics of the long-acting insulin analog glargine (1) are superior to those of insulin NPH (2–9). In the clinical setting, this translates into lower risk of nocturnal hypoglycemia (10–13), lower A1C (provided that appropriate requirements of mealtime rapid-acting insulin are met) (11–13), and the convenience of once (12), compared with multiple, administration of NPH (14). However, no study has examined subjects after several days of its use versus the "first" subcutaneous injection.

The present studies were undertaken to establish the pharmacokinetics and pharmacodynamics of insulin glargine in type 1 diabetes after 1 week of its once-daily use and to compare it with those observed after the first injection.


   RESEARCH DESIGN AND METHODS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
After institutional review board approval, 20 type 1 diabetic subjects (12 male subjects, age 31 ± 2 years, type 1 diabetes duration 11 ± 1 years, BMI 23.3 ± 0.4 kg/m2, fasting plasma C-peptide <0.02 nmol/l, and A1C 7.1 ± 0.2%) using NPH as basal insulin and human regular insulin (n = 7) or lispro insulin (n = 13), in combination with NPH at each meal as previously described (14), were studied.

During a 2-week run-in period, subjects continued their previous model of insulin therapy, i.e., human regular insulin or the rapid-acting insulin analog lispro at breakfast, lunch, and dinner and NPH insulin at bedtime, or even at each meal in those patients (n = 13) who used lispro (14). Thereafter, subjects were studied with the glucose clamp technique after subcutaneous injection of 0.3 units/kg insulin glargine as previously described (6). Subjects were studied for 32 h in order to capture the expected longer duration of action of insulin glargine after 1 week of use versus first injection. Subjects were studied on two occasions according to a randomized, crossover, open, 3-week period study (Fig. 1). On one occasion, the clamp was performed on the day the subject received the first injection of glargine (day-1 study), at the end of 1 week of NPH treatment (sequence: NPHday-1/NPHday-2/NPHday-3/NPHday-4/NPHday-5/NPHday-6/clamp-Gday-1). The clamp was then followed by a washout period of 1 week during which patients resumed the treatment they were on in the run-in period and after which each patient was crossed over to the other sequence when the clamp was performed on the day they received the seventh injection of glargine at the end of a 1-week treatment with once-daily glargine injection at 1700 h (day-7 study) (sequence: Gday-1/Gday-2/Gday-3/Gday-4/Gday-5/Gday-6/clamp-Gday-7) (Fig. 1). A randomization list was constructed from random numbers generated by a computer.


Figure 1
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  		Figure 1— Study design. G, glargine; N, NPH.

 
Plasma glucose, C-peptide and insulin concentrations, and A1C were measured as previously described (6). Onset of action was the time after subcutaneous injection of insulin, at which the rate of intravenous insulin consistently decreased by 50% compared with the 20-min preinjection time period. End of action was the time at which plasma glucose consistently increased to >150 mg/dl (or 32 h in case plasma glucose did not increase >150 mg/dl by the end of study), and duration of action was the time period between the onset and end of action (6).

Statistical analysis
The linear trapezoidal rule was used to calculate the area under the time concentration curve. Cmax and Tmax were read directly from the plasma concentration time data for each subject. Data analysis was carried out by using ANOVA for crossover design (15). Data are means ± SD unless stated otherwise.


   RESULTS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
Mean daily blood glucose during the 2-week run-in, 3-week sequence day-1->day-7 study and 3-week sequence day-7->day-1 study were no different (P > 0.2).

The amount of insulin infused intravenously during the time period –2 to 0 h (preinjection period), to maintain target plasma glucose, was higher in the day-1 (3 ± 1.2 IU) than the day-7 (1.8 ± 1 IU, P < 0.02) study.

After time 0 h (Fig. 2), the amount of insulin infused intravenously was greater in the day-1 (0.9 ± 0.5 IU) than the day-7 (0.4 ± 0.25 IU, P = 0.01) study. The median time of end of intravenous insulin infusion was 80 min (95% CI 0–100) in the day-1 study and 40 min (0–70) in the day-7 study (P = 0.01). Plasma insulin concentrations were no different in day-7 versus day-1 studies either at baseline or over 0–32 h (P > 0.2), but insulin levels from 24 h to the end of study (32 h) were lower in day-1 versus day-7 studies (83 ± 11 vs. 111 ± 24 µU/ml per 8 h, respectively, P = 0.01).


Figure 2
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  		Figure 2— Insulin infusion rate (A), plasma glucose (B), GIR (C), and plasma insulin (D) after subcutaneous (s.c.) injection of insulin glargine in day-1 ({circ}) and day-7 (•) studies.

 
Plasma glucose concentration was greater on day-1 versus day-7 studies [PG(0–24h) 135 ± 5 vs. 132 ± 2 mg/dl, P = 0.023; PG(0–32h) 139 ± 9 vs. 133 ± 3 mg/dl, P = 0.01].

Baseline glucose infusion rate (GIR) was zero in the day-1 study but 0.19 ± 0.05 mg · kg–1 · min–1 in the day-7 study and subsequently increased slowly to similar plateau values on both occasions until 16 h, when GIR in day-7 studies was greater than in day-1 studies until the end of the study (P < 0.046).

The mean values of GIR (area under the curve: AUC0-end of GIR) were lower in day-1 than in day-7 studies (1,122 ± 449 vs. 1,353 ± 327 mg/kg, P = 0.046). GIR excursions (SD) were greater in day-1 than in day-7 studies (0.5 ± 0.2 vs. 0.3 ± 0.13 mg · kg–1 · min–1, P = 0.01). Onset of insulin action initiated earlier on day 7 compared with day 1, with a median estimated difference of 25 min (P = 0.002). End of action (median 25.6 h [95% CI 22.0–28.5] vs. 22 h [19.0–27.0]) and duration of action (24 h [22.0–28.5] vs. 20.2 h [17.0–25.0]) were longer on day 7 compared with day 1.


   CONCLUSIONS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
The results of this study indicate that pharmacokinetics and pharmacodynamics of insulin glargine are different after several days of subcutaneous injections compared with the first injection. Insulin glargine has an earlier onset and longer duration of action (median 24 h) after 1 week compared with the first day of its use. However, the duration of action is underestimated because in some subjects end of action was beyond 32 h (time at which studies were truncated). In addition, the intrasubject variability of insulin glargine is lower after 1 week of use.

Considering that the long-acting insulin analog glargine has a duration of action of 24 h or longer after repeated administration, in the clinical setting insulin glargine should be injected every 24 h in type 1 diabetic patients and dose adjustments should be made at intervals >24 h, possibly every few days.

For those patients who exhibit elevation of afternoon blood glucose ("afternoon phenomenon") (16), it is likely that factors other than the duration of action of glargine <24 h are involved. However, specific studies directed at understanding the mechanisms are needed.


   Acknowledgments
 
This is an investigator-initiated trial supported in part by a grant from Sanofi-Aventis.

This work is dedicated to the type 1 diabetic subjects of our diabetes center.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 15 February 2007. DOI: 10.2337/dc06-2208.

G.B.B. has received honoraria from Sanofi-Aventis.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication October 26, 2006. Accepted for publication February 3, 2007.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. Bolli GB, Di Marchi R, Park G, Pramming S, Koivisto VA: Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia 42:1151–1167, 1999[Medline]
  2. Dreyer M, Pein M, Schmidt C, Heidtmann B, Schlünzen M, Rosskamp D: Comparison of the pharmacokinetics/dynamics of Gly(A21)-Arg(B31,B32)-human-insulin (HOE71GT) with NPH-insulin following subcutaneous injection by using euglyacemic clamp technique (Abstract). Diabetologia 37(Suppl. 1):A78, 1994
  3. Heinemann L, Linkeschova R, Rave K, Hompesh B, Sedlak M, Heise T: Time.action profile of the long-acting insulin analog glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care 23:644–649, 2000[Abstract/Free Full Text]
  4. Owens DR, Coates PA, Luzio SD, Tinbergen J, Kurzhals R: Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men. Diabetes Care 23:813–819, 2000[Abstract/Free Full Text]
  5. Rave K, Nosek L, Heinemann L, Frick A, Becker R: Time-action profile of the long-acting insulin analogue insulin glargine in comparison to NPH insulin in Japanese volunteers. Diabetes Metab 29:430–431, 2003[Medline]
  6. Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, Cordoni C, Costa E, Brunetti P, Bolli GB: Pharmacokinetics and pharmacodynamics of the long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin injected subcutaneously and continuous subcutaneous infusion of insulin lispro. Diabetes 49:2142–2148, 2000[Abstract]
  7. Heise T, Nosek L, Ronn BB, Endahl L, Heinemann L, Kapitza C, Draeger E: Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 53:1614–1620, 2004[Abstract/Free Full Text]
  8. Scholtz HE, Pretorius SG, Wessels DH, Becker RH: Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique. Diabetologia 48:1988–1995, 2005[Medline]
  9. Gerich J, Becker RH, Zhu R, Bolli GB: Fluctuation of serum basal insulin levels following single and multiple dosing of insulin glargine. Diabetes Technol Ther 8:237–243, 2006[Medline]
  10. Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA: Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes: U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care 23:576–578, 2000[Free Full Text]
  11. Rossetti P, Pampanelli S, Fanelli C, Porcellati F, Costa E, Torlone E, Scionti L, Bolli GB: Intensive replacement of basal insulin in patients with type 1 diabetes given rapid-acting insulin analog at meal-time: a 3-month comparison between administration of NPH four times daily and glargine insulin at dinner or bedtime. Diabetes Care 26:1490–1496, 2003[Abstract/Free Full Text]
  12. Porcellati F, Rossetti P, Pampanelli S, Fanelli CG, Torlone E, Scionti L, Perriello G, Bolli GB: Better long.term glycaemic control with the basal insulin glargine as compared with NPH in patients with type 1 diabetes mellitus given meal-time lispro insulin. Diabet Med 21:1213–1220, 2004[Medline]
  13. Ashwell SG, Amiel SA, Bilous RW, Dashora U, Heller SR, Hepburn DA, Shutler SD, Stephens JW, Home PD: Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with type 1 diabetes. Diabet Med 23:285–292, 2006[Medline]
  14. Lalli C, Ciofetta M, Del Sindaco P, Torlone E, Pampanelli S, Compagnucci P, Cartechini MG, Bartocci L, Brunetti P, Bolli GB: Long-term intensive treatment of type 1 diabetes with the short-acting insulin analog lispro in variable combination with NPH insulin at mealtime. Diabetes Care 22:468–477, 1999[Medline]
  15. Senn S: Cross-Over Trials in Clinical Research. 2nd ed. New York, John Wiley & Sons, 2002, p. 98–125
  16. Porcellati F, Rossetti P, Fanelli CG, Bolli GB: Optimized use of glargine in intensive treatment of type 1 diabetes: benefits and a new question (Abstract). Diabetes 54(Suppl. 1):A129, 2005

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