PMID- 20961422 OWN - NLM STAT- MEDLINE DCOM- 20110202 LR - 20211020 IS - 1472-6904 (Electronic) IS - 1472-6904 (Linking) VI - 10 DP - 2010 Oct 20 TI - Comparison of the pharmacokinetics, safety and tolerability of two concentrations of a new liquid recombinant human growth hormone formulation versus the freeze-dried formulation. PG - 14 LID - 10.1186/1472-6904-10-14 [doi] AB - 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 (AUC0-t) and maximum serum concentration (Cmax). 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 AUC0-t and Cmax 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 AUC0-t and 0.954 (0.875, 1.040) and 0.955 (0.876, 1.041) for Cmax for the 5.83 and 8.0 mg/mL formulations, respectively. No significant differences between the three treatments in half-lives, time to reach Cmax, 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. FAU - Liedert, Bernd AU - Liedert B AD - Merck KGaA, Darmstadt, Germany. FAU - Forssmann, Ulf AU - Forssmann U FAU - Wolna, Peter AU - Wolna P FAU - Golob, Michaela AU - Golob M FAU - Kovar, Andreas AU - Kovar A LA - eng SI - ClinicalTrials.gov/NCT01034735 PT - Clinical Trial PT - Comparative Study PT - Journal Article PT - Randomized Controlled Trial DEP - 20101020 PL - England TA - BMC Clin Pharmacol JT - BMC clinical pharmacology JID - 101088667 RN - 0 (Recombinant Proteins) RN - 12629-01-5 (Human Growth Hormone) SB - IM MH - Administration, Oral MH - Adolescent MH - Adult MH - Biological Availability MH - Chemistry, Pharmaceutical/*methods MH - Cross-Over Studies MH - Drug Tolerance MH - Drug-Related Side Effects and Adverse Reactions MH - Female MH - Freeze Drying/*methods MH - Human Growth Hormone/administration & dosage/adverse effects/blood/*pharmacokinetics MH - Humans MH - Male MH - Middle Aged MH - Recombinant Proteins/adverse effects/*pharmacokinetics MH - *Therapeutic Equivalency MH - Young Adult PMC - PMC2987775 EDAT- 2010/10/22 06:00 MHDA- 2011/02/03 06:00 PMCR- 2010/10/20 CRDT- 2010/10/22 06:00 PHST- 2009/10/13 00:00 [received] PHST- 2010/10/20 00:00 [accepted] PHST- 2010/10/22 06:00 [entrez] PHST- 2010/10/22 06:00 [pubmed] PHST- 2011/02/03 06:00 [medline] PHST- 2010/10/20 00:00 [pmc-release] AID - 1472-6904-10-14 [pii] AID - 10.1186/1472-6904-10-14 [doi] PST - epublish SO - BMC Clin Pharmacol. 2010 Oct 20;10:14. doi: 10.1186/1472-6904-10-14.