Broad variability in pharmacokinetics of GH following rhGH injections in children

Abstract

Objective: Daily subcutaneous self-injection of GH is used worldwide to treat short stature in childhood; longitudinal data on the impact of this regimen on GH-uptake are lacking. Design: Children with/without GH-deficiency participating in clinical trials were followed prospectively ( s 8 times). Blood was sampled pre-GH-injection (dose GH(33)/GH(67) mu g/kg) and either every 30 min thereafter for 24 h (Experimental-setting; 59 GH-curves/15 children); or every 2 h thereafter for 16 h (Clinical-setting; 429 GHcurves/117 children). Pharmacokinetics were estimated by time T-max (h) of maximal GH-concentration (C-max , mU/L) and area under the curve for 16 h (AUC, mU/L * h). Results: In the Clinical-setting, median C-max was 71 mU/L and AUC was 534 mU/L * h, with coefficients of variation for intra-individual variation of 39% and 36%, respectively, and inter-individual variation of 44% and 42%, respectively. 43% of C-max and AUC variability was explained by GH-dose and proxies for injection depth (baseline GH-level, GH(peak) width, BMISDS). In the Experimental- versus Clinical-setting, 85% and 40% of GH-curves, respectively, reached zero-levels within 24 h. A longer duration was found following a more superficial GH-injection. Spontaneous GH-peaks were identified already 6 h after the GH-injection in about half of the curves of both GHD and non-GHD patients. Conclusion: Very broad intra-individual and inter-individual variability was found. A high GH-peak will optimize growth effects; the highest C-max was found after a deep injection of GH at the higher dose and concentration. In as many as 60% of the children, GH remained detectable in serum after 24 h; a constant GH-level will promote IGF-I and metabolic effects.