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Background  Somatropin is recombinant human growth hormone (GH) used for the treatment of growth failure in children and GH deficiency in adults. Two concentrations of a liquid formulation have been developed: 5.83 and 8.0 mg/mL. This trial compared the pharmacokinetics (PK), safety and tolerability of these two liquid concentrations against the freeze-dried (FD) formulation in healthy volunteers.    Methods  In an open-label, single-centre, three-way crossover study, volunteers (aged 18-45 years) were given subcutaneous injections of the reconstituted FD and two liquid formulations in random sequential order, each at 4 mg/dose, with a 1-week wash-out period between doses. To suppress endogenous GH secretion, intravenous somatostatin was infused continuously 1 hour before to 24 hours after each dose, achieving a cumulative dose of 3 mg. Primary PK endpoints were area under the serum concentration-time curve (AUC 0-t ) and maximum serum concentration (C max ). For each of the two liquid formulations, bioequivalence with the FD formulation was concluded if the 95% confidence intervals (CIs) for the estimated test/reference ratios of geometric means of AUC 0-t  and C max  were within the standard pre-specified acceptance range (0.80-1.25).    Results  Fifteen men and 15 women enrolled (safety population, n = 30; PK population, n = 28). Bioequivalence with the FD formulation could be shown for both liquid formulations. The ratios of geometric means (95% CI) were 1.046 (0.980, 1.117) and 0.991 (0.929, 1.058) for AUC 0-t  and 0.954 (0.875, 1.040) and 0.955 (0.876, 1.041) for C max  for the 5.83 and 8.0 mg/mL formulations, respectively. No significant differences between the three treatments in half-lives, time to reach C max , clearance or volume of distribution were observed. After injection, the most common side-effects were pain or injection-site reactions (all of mild intensity). There were no clinically significant abnormal vital signs, ECG or laboratory findings. There were 56 treatment-related adverse events (AEs): 49 mild, 6 moderate and 1 severe (vomiting). No serious AEs occurred. The pattern of AEs was as expected and all resolved by study end.    Conclusion  Both concentrations of a new liquid multi-dose formulation are bioequivalent to the FD reference formulation and all are well tolerated.    Trial registration number  NCT01034735.

bmc clinical pharmacology

Comparison of the pharmacokinetics, safety and tolerability of two concentrations of a new liquid recombinant human growth hormone formulation versus the freeze-dried formulation