Improved Pharmacokinetic and Pharmacodynamic Profile of Rapid

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 examined 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 pharmacokinetic profile of subcutaneous administration 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. Mean plasma glucose levels dur- 6 glucose and plasma insulin. Subsequently, sulin concentration (C-INSmax), the area ing the clamps were 5.0 0.1 mmol/L all participants received both insulin (as- under the insulin concentration curve with both devices. The corresponding co- fi 6 part, Novo Nordisk, Bagsvaerd, Denmark) (INSAUC), and the time until 50% of in- ef cients of variation were 8.0 0.8% in a dose of 0.2 units/kg body wt and a sulin absorption, calculated as 50% of the and 7.3 6 0.5% for the jet injector and comparable volume of placebo solution area under the insulin concentration curve conventional insulin pen, respectively. fi (Test Medium Pen ll, Novo Nordisk, (T-INSAUC50%). Bagsvaerd, Denmark) simultaneously in- Pharmacodynamic end points jected subcutaneously in the abdomen. Analytical procedures All results of pharmacodynamic end On one occasion, insulin was adminis- Plasma glucose levels were determined in points are shown in Fig. 1 and listed in tered by jet injection (Insujet, European duplicate, immediately after blood sam- Table 1. The time to maximal glucose- Pharma Group bv, Schiphol-Rijk, the pling by the glucose oxidase method lowering effect, as represented by T-GIRmax, Netherlands) and placebo by conventional (Beckman Glucose Analyzer II, Beckman was reduced by .50% when insulin pen (NovoPen III, Novo Nordisk); on the Instruments, Fullerton, CA). Blood sam- was administered with the jet injector other occasion, insulin was injected by the pled for plasma insulin measurements as compared with conventional insulin conventional pen and placebo by the jet was collected in lithium-heparin tubes administration. There were no differen- injector. Two-by-two block randomiza- and placed on ice. After centrifugation, ces in maximal glucose-lowering effect 2 tion was used to randomize the sequence the supernatant was stored at 20°C. (C-GIRmax) or the total amount of glucose by which the two devices were used for Plasma insulin was measured by radioim- administered (GIRtot) between the two de- insulin and placebo injections. The jet munoassay (19) after all experiments vices. However, the time to 50% of glu- injector device used in this study was were performed. cose disposal (T-GIR50%), representing equipped with a loaded spring mecha- the total duration of insulin action, was nism, kept in place by a counterpressure Statistical analyses approximately 40 min shorter for insulin lock/release system. After pressing the Assuming a T-GIRmax of 94 min with a SD administration by jet injector than that by nozzle perpendicular to the skin, the jet of 46 min for aspart insulin administered conventional insulin pen.

2 DIABETES CARE care.diabetesjournals.org Engwerda and Associates

time to reach maximal glucose-lowering effect in comparison with conventional insulin administration. In addition, insulin administration by jet injection reduced the total duration of hyperinsulinemia and insulin action by 30–40 min when compared with conventional insulin administration. There were no indications that these benefits of the jet injector over the conventional pen differed between women and men. Our data are in line with previous studies that have shown a more rapid increase in insulin levels and shorter duration of hyperinsulinemia after administration of regular insulin by jet injection compared with administration by needle syringe (3–8). The results of the current study also extend those of a recent study performed by Sarno et al. (9), who compared administration of various Figure 1—Mean plasma insulin levels after administration of rapid-acting insulin by the jet insulins (including lispro insulin) with jet injector (closed symbols, black line) or the conventional insulin pen (open symbols, dashed line) injection to that with needle syringes. In during the euglycemic glucose clamp. that study, time to peak insulin levels after lispro insulin administration was shorter for the jet injector than for needle syringe Pharmacokinetic end points There was no indication that sex injection, but a statistically significant The results of pharmacokinetic end modified the pharmacodynamic or phar- pharmacodynamic effect could not be es- points are also listed in Table 1. In analogy macokinetic differences between the jet tablished. Also, the number of volunteers with the pharmacodynamic results, the injector and conventional pen for insulin examined was small (n = 4) and the dose time to reach peak insulin levels was re- administration. In fact, the jet injector of insulin used was fixed at a relatively duced by more than 50% after jet injector performed significantly better than the high level (30 units for all). Our study con- insulin administration as compared with conventional pen in both groups, when vincingly shows the pharmacokinetic insulin administration with the conven- analyzed separately (data not shown but and pharmacodynamic superiority of jet tional pen. Insulin administered with available upon request). injection over conventional needle pens the jet injector also resulted in higher for administration of rapid-acting insulin — peak insulin levels (C-INSmax) than in- CONCLUSIONS In this study, the at a dose that is realistic for many people sulin administered with the conven- pharmacodynamic and pharmacokinetic with type 1 or type 2 diabetes. It is also the fi tional insulin pen (Fig. 2). The INSAUC pro les of the rapid-acting insulin analog first time that jet injection technology was did not differ between the jet injector aspart, injected by either jet injection tech- compared with an insulin pen, which and the conventional insulin pen, but nique or by conventional insulin pen, were most patients prefer over syringes for their fi T-INSAUC50% was signi cantly shorter compared. We found that the jet injector ease of use and high level of accuracy (20). for the jet injector, indicating faster in- greatly enhanced the rate of insulin absorp- Insulin injected by jet injection dis- sulin absorption from the subcutaneous tion, resulting in a truly immediate onset plays a specific cone-like dispersion pat- tissue into the circulation. of action and approximately halving of the tern in the subcutaneous tissue with a relatively large surface area (1,2). It seems plausible that this dispersion pattern en- Table 1—Pharmacokinetic and pharmacodynamic parameters for insulin administration hances absorption of insulin into the with the jet injector and the conventional insulin pen circulation, thus explaining a more immediate glucose-lowering effect. The current Jet injector Conventional insulin pen P value jet injector uses a high-velocity jet that ensures .90% delivery of injected insulin Pharmacokinetic parameters into the subcutaneous tissue, without risk- 6 6 , T-INSmax (min) 31 3646 0.0001 ing penetration of the underlying muscle, 6 6 C-INSmax (mU/L) 108 13 79 7 0.012 at a jet stream diameter of ;0.15 mm. z 21 z 21 6 6 INSAUC (unit min mL )14.61.6 15.2 1.4 0.53 These device characteristics compare fa- 6 6 , T-INSAUC50% (min) 111 5 147 5 0.0001 vorably to the length and diameter of Pharmacodynamic parameters pen needles that typically measure 6–8 6 6 T-GIRmax (min) 51 3 105 11 0.0001 mm and 0.5 mm, respectively. A limita- z 21 z 21 6 6 C-GIRmax (mg kg min )6.490.58 6.09 0.56 0.50 tion to the use of jet injectors in compar- 6 6 GIRtot (g) 70.0 6.9 83.3 9.8 0.19 ison with insulin pens is that sufficient 6 6 , T-GIR50% (min) 123 7 166 6 0.0001 training is required with both air-free care.diabetesjournals.org DIABETES CARE 3 Insulin administration by jet injection

secretion more closely and could therefore be useful in providing a more phys- iologic postprandial insulin proﬁle. Future research will need to investigate whether these results can be replicated in patients with diabetes and what the clinical impli- cations are.

Acknowledgments—This study was funded by European Pharma Group (EPG). No potential conflicts of interest relevant to this article were reported. E.E.C.E. performed the experiments, analyzed and interpreted data, wrote the manuscript, and reviewed and edited the manuscript. E.J.A. wrote the study protocol, performed the experiments, analyzed and interpreted data, and reviewed and edited the manuscript. C.J.T. designed the study, interpreted data, and reviewed and edited the manuscript. B.E.d.G. designed the study, wrote the study protocol, Figure 2—Mean GIR after administration of rapid-acting insulin by the jet injector (closed performed the experiments, analyzed and in- symbols, black line) or the conventional insulin pen (open symbols, dashed line) during the terpreteddata,andreviewedandeditedthe euglycemic glucose clamp. manuscript. The authors are indebted to Karin Saini, Anja Rasing, and Marielle Verstegen (Radboud filling of the injection chamber and the what extent the favorable pharmacologi- University Nijmegen Medical Centre) for their injection procedure itself. We had to re- cal properties of insulin administration assistance during the clamps; to Petra van de schedule the first experiment, probably by jet injection found in this study trans- Ven and Sandra Hendriks (Radboud Univer- fi sity Nijmegen Medical Centre) for preparing because of an air bubble in the system, late into clinical bene t in the longer term the insulin pens; and to the volunteers for their and another experiment because of early for patients with diabetes. participation in this study. The authors also discharge of the spring system, possibly A strength of our study is the use of a thank Marc Entius, Gerard Akkerhuis, and related to failure of the lock/release sys- double-dummy cross over study design, Marleen Driesen from EPG (Schiphol-Rijk, the tem. However, after proper training, ad- ensuring that both participants and in- Netherlands) for monitoring the study. ministration of the entire dose of insulin vestigators were truly blinded during the can be achieved in almost all instances execution of the experiments. This con- (21). trasts with previous studies on jet injec- References The pharmacokinetic and pharmaco- tors. Moreover, because we used a placebo fi 1. Mitragotri S. Current status and future dynamic pro le of rapid-acting insulin solution that contained the same ingre- prospects of needle-free liquid jet in- administered by the jet injector ap- dients as the insulin solution (except for jectors. Nat Rev Drug Discov 2006;5:543– proached the physiological pattern of insulin), the smell and viscosity of the 548 endogenous insulin secretion and sub- two liquids were indistinguishable. A 2. Weller C, Linder M. Jet injection of insulin sequent glucose-lowering response more limitation of this study is that the eugly- vs the syringe-and-needle method. JAMA closely than insulin administered by a cemic clamps were performed in healthy 1966;195:844–847 conventional insulin pen. Consequently, individuals rather than in patients with 3. Taylor R, Home PD, Alberti KG. Plasma fi a more physiological meal insulin sub- diabetes, the target population for such free insulin pro les after administration stitution may decrease immediate post- a device. In addition, only one insulin of insulin by jet and conventional syringe injection. Diabetes Care 1981;4:377–379 prandial hyperglycemia, whereas the more dose was investigated; it cannot be de- 4. Pehling GB, Gerich JE. 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