Comparison of the Pharmacokinetics, Safety and Tolerability of Two Concentrations of a New Liquid Recombinant Human Growth Hormone Formulation versus the Freeze-dried Formulation

Bernd Liedert; Ulf Forssmann; Peter Wolna; Michaela Golob; Andreas Kovar

Disclosures

BMC Clin Pharmacol. 2010;10(14):1-7. 

In This Article

Discussion

This study has shown that both concentrations of a new liquid formulation were bioequivalent to the FD reference formulation in healthy volunteers with pituitary somatrope cell down-regulation. This conclusion is robust to adjustments to each subject's actual dose and to adjustments for active content. There were no apparent differences between the two liquid formulations of r-hGH and the FD formulation in the rate and extent of drug exposure, half-life, clearance or volume of distribution. In addition, variability in the PK parameters was low across the three treatments.

Demonstration of bioequivalence of different formulations is not assumed to be significantly influenced by characteristics of the study population. Because of this, data from healthy volunteers can be extrapolated to adult as well as child patients.

The r-hGH liquid multi-dose and the r-hGH FD formulations were administered at a dose of 4 mg. This dose level is far higher than the recommended therapeutic dose in adults (which is started at 0.15–0.3 mg/day and seldom exceeds 1.0 mg/day) or children (which does not exceed 0.05 mg/kg body weight/day),[12] but was chosen to allow accurate determination of GH PK parameters. Pituitary down-regulation was also necessary to suppress endogenous GH secretion in the healthy volunteers and to reliably calculate the PK parameters. The dose of 3 mg somatostatin in 25 hours was based on previous experience[13,14] and was also higher than therapeutic doses (which do not usually exceed 0.6 mg/day for adults[15,16]).

The high doses of drugs given led to higher rates of AEs than expected in clinical practice. Most of the AEs that were reported, including nausea, vomiting, headache and dizziness, can be related to the somatostatin infusion.[1,2,12–16] No serious AEs were reported. Both test preparations were well tolerated with regard to local site reactions, vital signs, ECG findings and laboratory findings, as was the reference FD preparation. Post-injection pain was mild and transient and any ISRs were similarly low in intensity.

The label for the liquid r-hGH is expected to be the same as for the FD r-hGH with the exception of the storage requirements. Although both the liquid and FD formulations (before reconstitution) have a shelf life of 2 years, the liquid must be stored at 2–8°C, whereas the FD formulation can be stored at < 25°C. The shelf-life and storage conditions after the cartridges have started to be used are the same across formulations: 21–28 days at 2–8°C (depending on the local label). Both liquid formulations will be available in 3 mL cartridges with stability for at least 18 months at 2–8°C, allowing inter-changeability between the electronic and needle-free delivery devices. It is hoped that the simplification of the injection or needle-free administration process provided by liquid r-hGH will make this treatment less of a burden for patients. Increasing the ease of injecting r-hGH may help to make treatment more convenient for patients, thereby improving adherence rates.

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