Indian J Pediatr(Suppl) 1991; 58 : 43-50

Growth HormoneTherapywith a New Delivery System Jan T. Jq~rgensen and S~ren Susgaard Medical Department~Growth Factors, Biopharmaceuticals Division, Novo Nordisk A/S, Denmark

Until recently the general regimenfor treatment of growth hormone deficient (GHD) children consisted of 2 to 3 intramuscular (i.m.) injections per week using conventional syringes and vials. However, studies within the last 5-10 year have shown that by dividing the same total weekly dosage into daily subcutaneous (s.c.) injections it is possible to achieve a significantly increasedgrowth rate. To make it more feasible for the patients and the parents to copewith this increased number of injections, an injection pen system (Nordiject) for administration of B-hGH has been developed. The No.rdiject pen has been investigated both with respect to patient acceptance and bioavailablity of the B-hGH (Norditropin) injected with the device. Twenty-seven children with growth retardation were included in a study. The patients had no problems with the handling of the pen and approximately 2/3 of them experienced less injection pain with the pe, compared to the syringe. Those patients who had previously been using conventional syringes strongly preferred the pen, and all wished to continue using the device. Fourteen adult GHD patients were included in a randomized cross-over study for investigation of bioavailability. Two separate s.c. injections of 4 IU of B-hGH (Norditropin) each were administered in random order by means of either syringe (4lU/ml) or injection pen (Nordiject) (12 IU/ml). On the basisof this study it was concluded that the bioavailabilityof B-hGH, measured as AUC, Cmax, and trnax, is equal following injection with the pen to that of injection by syringe. Key Words : Growth hormone; Injection pen; Patients" acceptance; Bioavailability

Human growth hormone (hGH) has been used for more than 30 years in replacem e n t therapy in children with growth hormone deficiency (GHD) 1, but until recently the only source of hGH was ex-

tracts derived from h u m a n pituitary glands. With the introduction of biosynthetic human growth hormone (B-hGH) in the mid 1980's produced by means of recombinant DNA technology, our knowledge of hGH physiology has inReprintrequests : Dr. J.T.Jqbrgensen,NovoNordisk AdS, Niels Steensensvej 1, DK-2820 Gentofte, creased considerably. This knowledge has been applied in proposing new dose Denmark. 43

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THE INDIAN JOURNAL OF PEDIATRICS

regimens and forms of administration. Until a few years ago, the standard regim e n for treatment of GHD children consisted of 2 to 3 intramuscular (i.m.) injections per w e e k using syringes and vials. With this treatment schedule, less than 50% of the patients reached a final height above the 3rd percentile. 2 However, recent studies have shown that by dividing the same total weeldy dosage into daily subcutaneous (s.c.) injections it is possible to achieve a significantly increased growth rate in GHD patients3-6as well as in Turner patients 7. In order to make this increased number of injections acceptable to the patients, a pen injection system for administration of B-hGH has been developed. 8 Similar pen injectors have been applied for several years in the treatment of diabetic patient. 9-10The injection pen system (Nordiject) developed by Novo Nordisk for administration of BhGH (Norditropin) has been extensively investigated with respect to both patient acceptance 11 and B-hGH bioavailability. 12

The Injection Pen The injection pen (Nordiject 24, Novo

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Nordisk A/S) is 145 m m long and weighs 35 g. It consists of a replaceable 27 G needle (0.4 x 12.5 ram) and a cartridge containing 2 ml of reconstituted B-hGH (12 IU/ml Norditropin, Novo Nordisk A/ S) (Figure 1). The needle length can be adjusted to 10, 8, or 6ram by the use of different replaceable collars, the lyophilized B-hGH is reconstituted in 0.9% benzyl alcohol (Novo Nordisk A/S). The dosaging device is operated by turning the scale on the grooved sleeve back to zero. The dosage scale can be present from 0.5 to 8.0 IU for a single injection. Another scale on the pen shows the residual amount of B-hGH in the cartridge. The reconstitution of the B-hGH is carried out in a special mixing device before the cartridge is mounted in the pen.

I. Patient Acceptance of Nordiject In order to evaluate the acceptability of the new growth hormone injection pen (Nordiject), a study was initiated in patients with growth retardation. Twentyseven children with growth retardation were included in the study :9 with GHD, 8 with partial GHD, and 10 were nonGHD. For the 18 patients with partial or

Fig. 1. The GH injection pen (Nordiject 24, Novo Nordisk A/S) which was evaluated in the study.

J(~RGENSEN AND SUSGAARD : NEW DEI.IVERY SYSTEM FOR GROWTH HORMONE

non-Gift) the short stature was of idiopathic nature. The age of the children ranged from 5 to 20 years (mean 11.6 years). There were 13 girls and 14 boys, and of these children 17had been in treatment with hGH for between 2 months and 7 years before inclusion in the study. The patients received an average of 12.5 IU/week as daily s.c. injections by means of the injection pen. The trial was designed as an open study with a retrospective comparison for

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the patients that had been under GH treatment before inclusion. The patients were seen in the clinic at entry and after 3 and 6 months. The total s t u d y period was 6 months. At the start of the study both written and oral instructions were given to the patients and/or their parents in the use of the injection pen. The patients were instructed not to use the reconstituted B-hGH for more than 14 days, and to store the pen in a refrigerator after reconstitution. Forevaluation of acceptabil-

Less Pain

The Same

10

w .

~4

~~

~~

i

More Pain

~

O

1

2

T-

-I

7

4 6 No. of Patients

8

10

Fig. 2. Injectionpain with Nordiject24 comparedwith conventionalsyringes.

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Table 1. Evaluation of the Handling, Weight and Size of Nordiject 24 (n = 27) Easy

A bit difficult

Difficult

Dissolving procedure

18

9

0

Filling and changing of cartridge

17

9

1

Dosing the B-hGH

26

1

0

Changing the needle

27

0

0

Too high

Acceptable

Too low

2

25

0

Too large

Acceptable

Too small

0

27

0

Weight of the pen

Size of the pen

18 i

16 I

15

14 ,

!

12q

i

t

~

.. o]

o

o

< 8

8

-

12

_ ~

12

Age (Years) Parents

I-.: ]Child

Fig. 3. Relationship between age of the children and their ability to perform the injections with Nordiject 24.

ity, a questionnaire with 3 or4 item-categorized scales was used. Answers were given by either the patient or the parents, depending on the age of the child and the type of question posed. The local tolerability was assessed by inspection of the injection sites at each visit to the clinic. In

addition, the patients were instructed to collect a number of "'half-used" cartridges containing varying amounts of residual reconstituted B-hGH and return them to the clinic. The contents of the returned cartridges were analyzed for microbial contamination by means of mere-

J~RGENSEN AND SUSGAARD : NEW DELIVERY SYSTEM FOR GROWTH HORMONE

brane filtration. RESULTS Those 17 children already under treatment with growth hormone at the time of inclusion were asked to compare the injection pain of the pen to that of conventional syringes and needles. The results of this comparison are given in Figure 2. After 3 months in the study, the handling of the injection pen was evaluated, along with its weight and size. The results of this evaluation by all 27 patients are s h o w n in Table 1. The 17 patients w h o had previously been using syringes and vials were also asked to compare the overall use of the two modes of B-hGH administration, and all of them responded that the pen was more convenient to use than syringes and vials. All 27 patients participating in the study wished to continue with the injection pen. At each visit to the clinic the patients were questioned about their injection habits. All 27 patients preferred the thigh as the injection area, and both the right and left were used. After 6 months of treatment with the pen, 20 of the 27 patients were able to perform tl~e injections themselves. The remaining 7 patients needed assistance from their parents. There was a statistically significant relationship between the patients' age and their ability to perform the injections themselves (p~ 0.001) (Figure 3). At each visit the patients were examined for local reactions at the injection sites. NO reactions were observed in any of the patients at either 3 or 6 months of treatment with the injection pen, except in two patients who developed small hematomas, which in both cases had disappeared by the time of the next visit to

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the clinic. No other complications were observed during the studyperiod. Microbial testing was done on the residual reconstituted B-hGH in cartridges collected from the patients. Sixty-eight cartridges were tested, and in 67 no contamination was found (0 CFU/0.1 ml). In one cartridge 2 CFUs (colony forming units) were found, but upon repeating the test using twice the amount of reconstituted B-hGH no CFUs could be detected (0 CFU/0.2 ml). DISCUSSION In a surveyabout the psychosocial impact of long-term GH therapy, it was noted that among the major problems encountered were injection pain and difficulties with the treatment as such 13. In light of both these problems and the positive experiences from both insulin studies and this study, an injection pen for growth hormone administration would seem to be beneficial in the treatment of patients with growth retardation. The handling of injections was regarded as being less time consuming than before by both the patients and their families. Approximately 60% of the patients w h o before inclusion were using conventional syringes felt that the injections were less painful when using the injection pen. There are probably several factors involved in the explanation of this response. The psychological effect of using a pen instead of syringe and needle and also the fine, adjustable 27 G needle and the small injection volume m a y be important factors. Probably the most important factor is the n e w solvent used for reconstitution of the B-hGH : 0.9% benzyl alcohol. From a large study in more 300 GHD children it has been reported that using a 0.25% solution of

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THE INDIANJOURNALOF PEDIATRICS

metacresol for reconstitution of the growth hormone preparation caused local pain and discomfort at the injection site in 13% of the patients. After switching to a solution of 0.9% benzyl alcohol, me local discomfort was reported in only 4.6% of the patient. 14 The difference in the total number of episodes was even more pronounced : 69 with metacresol vs. 17 with benzyl alcohol. Local disconstituted with solvent containing metacresol have also been reported in other studies. 15-16 Due to the simplification of the injection procedure that the pen offers, the patients are able to play a more active part in the treatment. Seventy-five percent of the patients were able to administer the injections themselves. In a Canadian survey about the outcome of long-term growth hormone therapy, the self-injec-

]Serum GH

9

Vol. 58, No. 5 tion rate was reported to be only 6%, the remainder of the injections being performed by the parent, nurse, or physician. 17 The latter result may reflect the variation in treatment patterns in different areas of the world. The overall use of the injection pen was judged positively and it was preferred to syringes and vials by both the children and parents. These results are in accordance with experiences with similar devices for insulin administration 9"1~ and from treatment of children with growth retardation. 8,15 Whether the improved patient compliance during pen treatment may also result in a better growth response cannot be deduced from our data. But in this context it is noteworthy that Dean et a117 reported that 21% of GHD patients terminated treatment prematurely at their own request.

ng/ml

!

8

5- t

"i 3 2 1 0

V-

0

2

i

4

--i

l

6

8

--

--I

10

- - ~ - 4 IU/ml (Vial)

12 Hours ~-

14

16

18

20

22

24

12 IU/ml (Nordiject)

Fig. 4. Mean(X SEM)serum GH concentrationprofilesafter s.c. injectionof 4 IU GH. (X...X)administration by syringe,(O...O) administrationby injectionpen (Nordiject). Baselinevaluesare subtracted. (n = 14).

J(~RGENSENAND SUSGAARD: NEWDELIVERYSYSTEMFOR GROWTHHORMONE

II.

BioavailabilityofB-hGHInjected with Nordiject

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in Figure4. No statisticallysignificant difference could be detected between AUC-enand AUCs ringe The relative abp sorptlon fraction (~Y eWs rlnge) was calculated to 1.09 • 0.39P(m~an • SD). There was no statistically significant difference between syringe and injection pen with respect to either Cma • or tma x. The mean (+__SD) values for Cma • were 8.6 • 4.8 ng/ ml and 8.3 + 7.5 ng/ml foI syringe and injection pen, respectively. Corresponding tma• were 311 + 131 min for syringe and 309 _%104 rain for injection pen.

One feature of the injection pen is a higher B-hGH concentration in the cartridge (12 IU/ml) compared to the ordinary vial (4 IU/ml). The purpose of this is to minimize the injection volume as well as reduce the frequency of cartridge changes. For insulin it has been reported that an increase in concentration, corresponding to a decrease in injection volume, might lead to a decrease in bioavailability, in terms of the absorption rate. 18-20 DISCUSSION A study was initiated to investigate In this study the threefold difference in whether an increase in B-hGH concentraconcentration between syringe (4IU/ml) tion or a decrease in injection volume and injection pen (12 IU/ml) was investiwould influence the bioavailability, gated with respect to bioavailability. The evaluated as Cma x, tma• AUC (area two modes of administration, syringe under the curve). Fourteen adult GHD and injection pen (Nordiject), were patients were included in the study. All judged to be equal with respect to bipatients had been hypophysectomized in oavailability of B-hGH. Thus the decrease adult life due to pituitary tumours. The in bioavailability following increase in age of the patients ranged from 29 to 60 concentration reported from pharmacokiyears (mean 48 years). There were 5 fenetic studies with insulin preparations males and 9 males, all with a maximum could not be confirmed for B-hGH for the GH response to GHRH ~ 2.5 ng/ml. The concentration interval in question. study was designed as an open randomized cross-over trial, in which the paCONCLUSION tients, following an overnight fast, were From these studies it can be concluded injected with a fixed dose of 4 IU of Bthat the Nordiject pen is a safe and relih G H (Norditropin) either by convenable device for administration of growth tional syringes or Nordiject. Both types of hormone. The bioavailability of B-hGH injection were given s.c. in the thigh usfollowing pen injection is equal to that of ing a 27 G needle. Blood samples were injection by syringe. The overall accepdrawn over a period of 14 hours. At least 7 tance of the injection pen was high, and days separated injection with the alternaboth the children and their parents found five device. it convenient to use. The simplification of RESULTS the injection procedure offered by the pen is advantageous for the patients, and thus The mean serum GH profiles ( i SEM) afit may prove to be a useful device in the ter s.c. injections of 4 IU B-hGH using future optimization of GH therapy. both syringe and injection pen are shown

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THE INDIAN JOURNAL OF PEDIATRICS

Vol. 58, No. 5

ACKNOWLEDGEMENT We thank Mrs. Noelle Holten Pind for her advice and excellent secretarial assistance.

11.

12.

REFERENCES

1. Raben MS. Treatment of a pituitary dwarf with human growth hormone [Letter to the Editor]. J Clin Endocrinol Metab 1958; 18 : 901903. 2. Burns EC, Thomas JM, Preece MA, Cameron N. Final height and pubertal development in 55 children with idiopathic growth hormone deficiency, treated for between 2 and 15 years with human growth hormone. Eur J Pediatr 1981; 137 : 155-164. 3. Kastrup KW, Christiansen JS, Andersen JK, 9 rskov H. Increased growth rate following transfer to daily s.c. administration from three weekly i.m. injections of hGH in growth hormone deficient children. Acta Endocrinol (Copenh) 1983; 104 : 148-152. 4. H e r m a n u s s e n M, Geiger-Benoit K, Sippel WG. Catch-up growth following transfer from three weekly i.m. to daily s.c. administration of hGH in GH deficient patients, monitored by knemometry. Acta Endocrinol (Copenh) 1985; 109 : 163-168. 5. Albertsson-Wikland K, Westphal O, Wungren U. Daily subcutaneous administration of human growth hormone in growth hormone deficient children. Acta Paediatr Scand 1986; 75 : 89-97. 6. Kikuchi K, Sudo M, Miyamoto A et al. Growth response to daily subcutaneous administration of growth hormone. Acta Paediatr Jpn 1988; 30 : 557-563. 7. Rosenfeld RG. Non-conventional growth hormone therapy in Turner syndrome: the United States experience. Horm Res 1990; 33 : 137-143. 8. Jqbrgensen JOL, Mdpller J, Jensen FS et al. Growth hormone administration by means of a n injection pen. Pharm Toxica11989; 65 : 96-99. 9. Berger AS, Saurbrey N, Kuhl C, Villumsen J. Clinical experience with a new device that will simplify insulin injections. Diabetes Care 1985; 8 : 73-76. 10. J~rgensen JOL, Flyvbjerg A, J~rgensen JT et

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al. NPH insulin administration by means of a pen injector. Diabetic Med 1988; 5 : 574-576. Jt~rgensen JT. Mortensen HB, ]'dprgensen JOL. Patient acceptance of Nordiject - A new drug delivery system for growth hormone. DICP Ann Pharmacother 1991 (in press). Blok GJ, Van der veen EA, Susgaard S, Larsen F. Influence of concentration and injection volume on the bioavailability of subcutaneous growth hormone. Comparison of administration by ordinary syringe and by injection pen. Pharmacol Toxicol 1991 (in press). Blizzard RM. Psychosocial impact of longterm growth hormone therapy. In: Raiti S., Tolman RA, eds. Human Growth ttormone. New York: Plenum Medical Book Company, 1986 : 93-106. Jqbrgensen JT, Mortensen HB, Jt~rgensen JOG Jakobsen G. Acceptability of Nordiject. A new drug delivery system for growth hormone (Abstract). Presented at the 19th European Symposium on Clinical Pharmacy, Barcelona, October 24-26, 1990. Pharmaceutisch Weekblad Scientificed. 1990; 12 : G9. Albertsson-Wikland K. Simplified growth hormone therapy - first clinical experience with the Kabi pen. Acta Paediatr Scand 1988; 343 (Supp]): 103-106. Danielson K, Neumeyer L, Ritzen M. Genotropin 16 IU Kabivial is more convenient than conventional administration systems for children on growth hormone therapy. Acta Paediatr Scand 1990; 370 (suppl): 208-211. Dean HJ, Mctaggart TL, Fish DG, Friesen G. The educational, vocational and marital status of growth hormone deficient adults treated with growth hormone during childhood. AJDC 1985; 139 : 1105-1110. Binder C, Lauritzen T, Faber O, Pramming S. Insulin pharmacokinetics. Diabetes Care 1984; 7 : 188-199. Hildebrandt P, Sestoft L, Nielsen SL. The absorption of subcutaneously injected shortacting soluble insulin : Influence of injection technique and concentration. Diabetes Care 1983; 6 : 459-462. De Meijer Phem, Russel FGM, Van Lier HJJ, Van Ginneken CAM. A comparison of three mathematical models to describe the d i s a p pearance curves of subcutaneously injected 125 I labelled insulin. Br J Clin Pharmaco11989; 27 : 461-467.

Growth hormone therapy with a new delivery system.

Until recently the general regimen for treatment of growth hormone deficient (GHD) children consisted of 2 to 3 intramuscular (i.m.) injections per we...
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