Bioavailability of Recombinant Human Growth Hormone in Different Concentrations and Formulations

Abstract: 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 (～1.37 mg/ml), (2) 5.9 IU/ml in a phosphate buffer dissolved in 1.5% benzyl alcohol (～2 mg/ml) and (3) 11.7 IU/ml in a phosphate buffer dissolved in 1.5% benzyl alcohol (～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 Conventional growth hormone-therapy was withdrawn 2 days before each study period.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 F_{5.9 IU/4 IU}= AUC_{5.9 IU}/AUC_{4 IU}=(～1.139) (P=0.66), F_{11.7 IU}/AUC_{4 IU}=AUC_{11.7 IU}/AUC_{4 IU} (1.14±1.21) (P=0.009) and F_{11.7 IU/5.9 IU}=AUC_{11.7 IU}/AUC_{5.9 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, C_max was for C_{max 5.9 IU}/C_{max 4 IU} = 1.04 (～1.19) (P=0.32), C_{max 11.7 IU}/C_{max 4 IU}=1.24 (～1.21) (P=0.0002) and C_{max 11.7 IU}/C_{max 5.9 IU}=1.19 (～1.29) (P=0.012). The median and the range values for the observed time to reach C_max was t_{max 5.9 IU}/t_{max 4 IU}=0.63 (0.04-1.00), t_{max 11.7 IU}/t_{max 4 IU}=0.59 (0.06-1.0) and t_{max 11.7 IU}/t_{max 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.