Improved Pharmacokinetic and Pharmacodynamic Profile of Rapid
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Emerging Treatments and Technologies ORIGINAL ARTICLE Improved Pharmacokinetic and Pharmacodynamic Profile of Rapid-Acting Insulin Using Needle-Free Jet Injection Technology E. (ELSEMIEK) E.C. ENGWERDA, BSC CEES J. TACK, PHD syringe. However, the glucose-lowering EVERTINE J. ABBINK, PHD BASTIAAN E. DE GALAN, PHD time-action profiles were not significantly different, the number of subjects exam- ined was low (n = 4), and the dose of in- OBJECTIVE—Insulin administered by jet injectors is dispensed over a larger subcutaneous sulin tested was relatively high (30 units area than insulin injected with a syringe, which may facilitate a more rapid absorption. This study fi for all) (9). compared the pharmacologic pro le of administration of insulin aspart by jet injection to that by Although rapid-acting insulin analogs conventional insulin pen. have clearly advanced glycemic treatment RESEARCH DESIGN AND METHODS—Euglycemic glucose clamp tests were per- of type 1 and insulin-requiring type 2 formed in 18 healthy volunteers after subcutaneous administration of 0.2 units/kg body wt of diabetes, their pharmacological profile is aspart, either administered by jet injection or by conventional pen, using a randomized, double- still far from mimicking the profile of blind, double-dummy, cross over study design. Pharmacodynamic and pharmacokinetic profiles endogenous insulin release. Indeed, the were derived from the glucose infusion rate (GIR) needed to maintain euglycemia and from time until insulin’s maximal glucose- plasma insulin levels, respectively. lowering effect generally amounts to .90 fi RESULTS—The time to maximal GIR was significantly shorter when insulin was injected with min, and the duration of signi cant hy- the jet injector compared with conventional pen administration (51 6 3 vs. 105 6 11 min, P , perinsulinemia often exceeds 3 hours 0.0001). The time to peak insulin concentration was similarly reduced (31 6 3vs.646 6min, (10–12). As a consequence, risks of (im- P , 0.0001) and peak insulin concentrations were increased (108 6 13 vs. 79 6 7mU/L,P = mediate) postprandial hyperglycemia and 0.01) when insulin was injected by jet injection compared with conventional pen injection. Jet (late) postprandial hypoglycemia remain injector insulin administration reduced the time to 50% glucose disposal by ;40 min (P , relatively high in many patients treated 0.0001). There were no differences in maximal GIR, total insulin absorption, or total insulin with rapid-acting insulin analogs. Faster action between the two devices. absorption of insulin may reduce these CONCLUSIONS—Administration of insulin aspart by jet injection enhances insulin absorp- risks and may provide a more physiolog- tion and reduces the duration of glucose-lowering action. This profile resembles more closely the ical meal-time substitution of insulin. The pattern of endogenous insulin secretion and may help to achieve better meal insulin coverage and aim of this study was therefore to compare correction of postprandial glucose excursions. the pharmacodynamic and pharmacoki- netic profile of subcutaneous administra- tion of the rapid-acting insulin analog aspart by jet injection to that of adminis- dministration of insulin by jet in- duration of (glucose-lowering) action re- tration by conventional insulin pen in jection is a needle-free alternative to duced. Studies on jet injection technology healthy individuals using the euglycemic A glucose clamp technique (13). We chose to conventional insulin administration for insulin administration date back to with syringes or insulin pens. Jet injectors the 1960s (2). Most have suggested faster use an insulin pen as comparator because deliver insulin at a high velocity (typically absorption of regular and NPH insulin insulin pens may be more accurate than .100 m/s) across the skin in the subcu- when injected with a jet injector rather syringes (14) and are currently used by taneous tissue and may dispense the in- than with a syringe (3–8). Data on the the vast majority of insulin-treated patients sulin over a larger area than insulin use of jet injectors for the administration with diabetes in western Europe (15). injected with a syringe (1). This may en- of rapid-acting insulin analogs are limited hance the efficiency with which insulin is to one open-label study. In that study, RESEARCH DESIGN AND absorbed from the subcutaneous com- peak insulin levels were reached in about METHODS—Writteninformedcon- partment into the circulation so that the half the time when lispro insulin was in- sent was obtained from 18 healthy, non- insulin peak can be advanced and the jected with a jet injector instead of a smoking subjects (men/women 5/13, mean 6 SD age 27.2 6 9.4 years, mean ccccccccccccccccccccccccccccccccccccccccccccccccc BMI 23.6 6 2.8 kg/m2, mean fasting 6 From the Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the plasma glucose level 5.09 0.35 mmol/L) Netherlands. who were recruited by advertisement. Corresponding author: Bastiaan E. de Galan, [email protected]. None of the participants were on chronic Received 28 January 2011 and accepted 17 May 2011. medication (with the exception of oral DOI: 10.2337/dc11-0182. Clinical trial reg. no. NCT00983775, clinicaltrials.gov. © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly contraceptives), reported type 2 diabetes cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ among first-degree relatives, or had a his- licenses/by-nc-nd/3.0/ for details. tory of cardiovascular events. A pregnancy care.diabetesjournals.org DIABETES CARE 1 Diabetes Care Publish Ahead of Print, published online June 29, 2011 Insulin administration by jet injection test was performed in female subjects at injector releases insulin with sufficient subcutaneously in the abdomen by con- the screening visit to exclude pregnancy. force to enter the subcutaneous tissue to a ventional pen injection (10), we calcu- The study was approved by the institu- depth equivalent to standard needle sy- lated that a total of 18 subjects would be tional review board of the Radboud Uni- ringe. To avoid premature insulin release, needed to find a 20% reduction in the versity Nijmegen Medical Centre. the system unlocks only when sufficient primary end point with 80% statistical pressure has been applied to the nozzle. power at the conventional P value of Experimental study design Both the jet injector and the conventional 0.05, after correction for small sample All participants underwent two euglyce- pen were operated by trained personnel sizes. mic glucose clamp experiments (13,16) to only and were prepared by a nurse who All data are expressed as means 6 investigate the pharmacokinetics and was not involved in the trial. After admin- SEM, unless otherwise indicated. Mean pharmacodynamics of rapid-acting insu- istration of insulin and placebo solution, outcomes for all study end points were lin delivered by jet injection or conven- plasma glucose was maintained at eugly- tested by paired t tests. The GIR and in- tional pen injection, using a double-blind, cemic levels (;5.0 mmol/L) for 8 h by a sulin concentration profiles were com- double-dummy, randomized cross over variable infusion of 20% dextrose, the pared by ANOVA. All statistical analyses study design. There was a washout period rate of which was determined by plasma were performed by SPSS 16.0 (Statistical of at least 1 week between the two clamps, glucose measurements at 5-min intervals Package for Social Sciences, Chicago, IL). whereas female subjects were tested at during the first 4 h and at 10-min inter- A P value of , 0.05 was considered sta- 4- or 8-week intervals to ensure that ex- vals thereafter. Blood for plasma insulin tistically significant. periments took place during correspond- levels was sampled every 10 min during ing periods of the menstrual cycle. the 1st hour and every 30 min for the re- RESULTS—All 18 subjects completed Participants were admitted to the re- mainder of the study. the study. In two subjects, one of the search unit at 0830 h after an overnight All pharmacodynamic and pharma- clamp experiments had to be rescheduled fast and having abstained from smoking, cokinetic study end points were derived because insulin levels failed to increase, alcohol use, and caffeine use for at least from the exogenous glucose infusion rate with both incidents occurring when the 24 h. The experiments were performed (GIR) and insulin concentration profiles. jet injector contained insulin. In one in- in supine position in a temperature con- The primary study end point was the stance, the jet injector was incompletely – trolled room (22 24°C). Two catheters time to maximal GIR (T-GIRmax), corre- checked for air bubbles in the system. In were inserted intravenously. One catheter sponding to the time until the maximal the other instance, the spring was released was inserted in retrograde fashion in a glucose-lowering effect of insulin was before proper contact could be made with dorsal hand vein for blood sampling. obtained. Secondary pharmacodynamic the skin, after which the jet injector was This hand was placed in a heated box, end points were the maximal GIR (C- returned to the manufacturer and re- kept at 55°C to arterialize venous blood GIRmax),thetimeto50%ofglucosedis- placed. Injections were well tolerated by (17,18). The other catheter was placed in posal (T-GIR50%), and the total amount the participants, although some partici- an antecubital vein of the contralateral of glucose administered calculated from pants regarded the firm pressure required arm for administration of 20% dextrose. theareaunderthecurve(AUC)(GIRtot). for injection with the jet injector as un- After instrumentation, a 30-min equil- Secondary pharmacokinetic end points pleasant. Neither injection mode resulted ibration period was included before blood included the time to maximal insulin in skin reactions such as hematomas or was sampled for baseline values of plasma concentration (T-INSmax), the maximal in- redness.