Bioavailability of recombinant human growth hormone in different concentrations and formulations.

Whether the bioavailability of growth hormone depends on the concentration or formulation of the preparation was evaluated in 18 growth hormone-deficient patients. The design was a single-blinded, randomized cross-over study, where the patients were given a single, fixed dose subcutaneous injection of growth homrone (3 IU/m2) of 3 different preparations: (1) 4 IU/ml in a bicarbonate buffer dissolved in 0.9% benzyl alcohol (approximately 1.37 mg/ml), (2) 5.9 IU/ml in a phosphate buffer dissolved in 1.5% benzyl alcohol (approximately 2 mg/ml) and (3) 11 7 IU/ml in a phosphate buffer dissolved in 1.5% benzyl alcohol (approximately 4 mg/ml). Conventional growth hormone-therapy was withdrawn 2 days before each study period. Blood samples were drawn over a 24-hr period and assessed for growth hormone, serum insulin-like growth factor I (IGF-I), insulin and glucose. The geometric mean values (+/- geometric S.D) of the relative absorption fractions were F5.9 IU/4 IU = AUC5.9 IU/AUC4 IU = (+/- 1.139) (P = 0.66), F11.7 IU/AUC4 IU = AUC11.7 IU/AUC4 IU (1.14 +/- 1.21) (P = 0.009) AND F11.7 IU/5.9 IU = AUC11.7 IU/AUC5.9 IU = 1.12 (+/- 1.17) (P = 0.005), respectively. The 90% confidence intervals were contained within the limits of 0.80-1.25 accepted for bioequivalence. Geometric mean values (+/- geometric S.D.) of the relative observed maximum concentration, Cmax was for Cmax 5.9 IU/Cmax 4 IU = 1.04 (+/- 1.19) (P = 0.32), Cmax 11.7 IU/Cmax 4 IU = 1.24 (+/- 1.21) (P = 0.0002) and Cmax 11.7 IU/Cmax 5.9 IU = 1.19 (+/- 1.29) (P = 0.012). The median and the range values for the observed time to reach Cmax was tmax 5.9 IU/tmax 4 IU = 0.63 (0.04-1.00), tmax 11.7 IU/tmax 4 IU = 0.59 (0.06-1.0) and tmax 11.7 IU/tmax 5.9 IU = 0.90 (0.51-18.00). There were no significant differences in IGF-I, glucose and insulin profiles. Based on the upper limits of the 90% confidence intervals for relative AUC's the conclusion is that the three different preparations were bioequivalent.

Absorption kinetics of two highly concentrated preparations of growth hormone: 12 IU/ml compared to 56 IU/ml.

The purpose of this study was to compare the relative bioavailability of two highly concentrated (12 IU/ml versus 56 IU/ml) formulations of biosynthetic human growth hormone administered subcutaneously. After pretreatment with growth hormone for at least four weeks, nine growth hormone deficient patients with a mean age of 26.2 years (range 17-43) were studied two times in a randomized design, the two studies being separated by at least one week. At the start of each study period (7 p.m.), growth hormone was injected subcutaneously in a dosage of 3 IU/m2. The 12 IU/ml preparation of growth hormone was administered on one occasion, and the 56 IU/ml preparation on the other. Serum profiles of growth hormone were monitored by frequent measurements for 24 hr. Bioavailability and absorption dynamics were evaluated by the absorption fraction, F56 IU/12 IU, calculated from the mean integrated levels (AUC) of growth hormone, and the observed time, Tmax, to reach maximum concentration, Cmax. Levels of serum IGF-I, IGFBP-3, insulin and blood glucose were measured to study the short term metabolic effects of growth hormone. The absorption fraction, F (S.D.) was 1.034 (0.163). The 90% confidence interval was 0.934-1.144, which is included in the interval 0.8-1.25, implying that the two preparations are bioequivalent. Neither AUC (P = 0.90), Cmax (p = 0.47) or Tmax (P = 0.86) for the two formulations of growth hormone were significantly different. Similar levels of serum IGF-I, IGFBP-3, insulin and blood glucose were obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Subcutaneous absorption kinetics of two highly concentrated preparations of recombinant human growth hormone.

OBJECTIVE: The relative bioavailability of two highly concentrated (12 IU/ml) formulations of biosynthetic human growth hormone (GH) administered subcutaneously was compared. DESIGN: A randomized, crossover study. Conventional GH therapy was withdrawn 72 hours before each study period. There was a washout period of at least four weeks between the study periods. SETTING: Participants were recruited from an outpatient clinic and were hospitalized during the two study periods. PATIENTS: Fourteen GH-deficient patients (mean age 25.2 y, range 14-54). One patient was excluded from data analysis because of signs of endogenous GH secretion. INTERVENTIONS: At the start of each study period, GH 3 IU/m2 was injected subcutaneously. The two formulations, PenFill and PenSet, differ in the buffers used and in the relative content of mannitol and glycine. Serum profiles of GH were monitored frequently for 24 hours. Samples were taken every 30 minutes for 6 hours and then hourly. MAIN OUTCOME MEASURES: Bioavailability (F) and absorption dynamics of human GH were measured. The relative absorption fractions estimated from the areas under the individual serum concentration curves from 0 to 24 hours, and the observed time (Tmax) to reach the maximum concentration (Cmax) were determined. Short-term metabolic effects of GH on insulin-like growth factor (IGF-I), glucose, and insulin were determined. RESULTS: The geometric mean (SD) of F was 0.910 (1,236). The 90 percent confidence interval was 0.819-1.010. Mean (+/- SD) of Cmax was 12.65 +/- 5.89 and 12.58 +/- 4.40 ng/mL for PenFill and PenSet, respectively. Corresponding values for Tmax were 5.49 +/- 1.55 and 5.89 +/- 1.79 hours for PenFill and PenSet, respectively. There was a considerable interindividual variation, but the relative absorption fraction did not significantly differ from 1 (p = 0.13). Neither Cmax (p = 0.74) nor Tmax (p = 0.58) of the two formulations was significantly different. Injection of the two formulations induced similar increments in serum IFG-I (p = 0.48). Serum insulin and blood glucose concentrations were not significantly different. CONCLUSIONS: There is no significant difference between the absorption kinetics and short-term metabolic effects of these two highly concentrated formulations of biosynthetic GH. The two formulations are bioequivalent.

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 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 increased growth rate. To make it more feasible for the patients and the parents to cope with this increased number of injections, an injection pen system (Nordiject) for administration of B-hGH has been developed. The Nordiject pen has been investigated both with respect to patient acceptance and bioavailability 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 pen 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 (4IU/ml) or injection pen (Nordiject) (12 IU/ml). On the basis of this study it was concluded that the bioavailability of B-hGH, measured as AUC, Cmax, and tmax, is equal following injection with the pen to that of injection by syringe.

Influence of concentration and injection volume on the bioavailability of subcutaneous growth hormone: comparison of administration by ordinary syringe and by injection pen.

In order to study whether the bioavailability of subcutaneously injected growth hormone (GH) is dependent on the concentration/volume injected, the relative GH bioavailability was evaluated in 14 GH-deficient patients. In a cross-over study the patients received, in random order two separate subcutaneous GH injections (Norditropin) 4 IU administered by means of an ordinary syringe (4 IU ml) and an injection pen with cartridge (Nordiject 24) (12 IU/ml). Blood samples were drawn over a 14 hr period and assayed for serum concentrations of GH and IGF-I. The mean value (+/- S.D.) of the relative absorption fraction (Fpen/sy) was 1.09 +/- 0.39. Mean values of Cmax were 8.6 ng/ml +/- 4.8 and 8.3 ng/ml +/- 7.5 for syringe and pen respectively. Corresponding values for Tmax were 311 min. +/- 131 for syringe and 309 min. +/- 104 for pen. Although a considerable interindividual variation was seen, the relative absorption fraction did not differ significantly from 1 (2 P = 0.78). Further there was no significant difference in neither Cmax (2 P = 0.39) nor Tmax (2 P = 0.55). IGF-I serum profiles tended to be higher following syringe compared to pen injection (2 P = 0.054). On the basis of this study we conclude that in this dosage regimen. GH bioavailability following pen injection equals that of injection by syringe (i.e. no effect of a three fold increase/decrease in GH concentration/volume respectively).