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

Results

Participants

Fifteen men and 15 women were enrolled. Two subjects dropped out at the time of check-in for the third period due to non-adherence to protocol requirements. The mean age of the volunteers was 31.8 years (range 18–45 years). At the pre-study examination, the mean weight was 70.4 kg (54.9–91.8 kg), BMI was 23.7 (20.1–28.7) and height was 1.72 m (1.54–1.89 m). The characteristics of subjects were similar across the treatment sequences: the mean age range was 24.2–38.0 years, mean weight 65.0–76.5 kg and mean BMI 23.0–24.8 kg/m2, and the number of subjects per sequence ranged between 1 and 4. In total, 21 volunteers were non-smokers and nine were smokers.

The PK population comprised 28 subjects, and all 30 subjects received at least one dose of trial medication, so were included in the safety evaluation.

Pharmacokinetics

Bioequivalence to the FD formulation could be demonstrated for both concentrations of the liquid-formulation treatment as the 95% CI for the ratios of geometric means for AUC0-t and Cmax fell within the acceptance criteria of 0.80–1.25. The actual dose of the treatments administered varied slightly between the FD formulation and the two concentrations of the liquid formulation (Table 1). However, adjustments for actual dose administered, active content, or both, further supported the conclusion of bioequivalence (Table 2).

All pre-dose serum samples had concentrations of GH below the LLOQ. Overall, the PK parameters of the two strengths of liquid formulation and the FD formulation of r-hGH showed low variability. There were no significant differences between the three treatments in half-lives (t1/2), time to reach Cmax (tmax), clearance (CL/f) or volume of distribution (Vz/f) (Table 3). The least squares geometric means in Table 2 are derived from the mixed model. They deviate very slightly from the ordinary geometric means in Table 3, therefore. The mean concentration-time profiles showed low and similar intra-subject variability and were close to superimposable for the three treatments (Figure 1).

Figure 1.

Mean concentration-time profile of r-hGH in serum (n = 28). Administered dose of 4 mg.

Tolerability and Safety

Twenty-six subjects (87%) reported pain after drug administration. Most of the episodes were very mild, with a mean intensity of only 3.52 mm on the 100 mm VAS and a maximum of 29 mm. The pain typically resolved within 5 minutes of injection.

A total of 31 ISRs occurred in 19 subjects (Table 4). Reactions comprised redness, bruising and itching. Fourteen, eight and nine ISRs occurred after treatment with the 5.83 mg/mL liquid, 8.0 mg/mL liquid and FD formulations, respectively. Twenty-six of the reactions were recorded 5 minutes post-dose. All reactions were mild, with no local reactions considered moderate or severe.

AEs were experienced by 26/30 (87%) subjects. There were 95 AEs overall (four pre-dose) with 56 considered as treatment-related (Table 5). Of the treatment-related AEs, 49 were mild in intensity, with only six instances of moderate AEs and one case of severe vomiting. There were no serious or life-threatening AEs and all events resolved by the end of the study.

There were no clinically significant abnormal vital signs or ECG results. All laboratory values were within the reference range or were judged by the investigator not to be clinically relevant.

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