Elena Lundberg1, Björn Andersson2, Berit Kriström3, Sten Rosberg4, Kerstin Albertsson-Wikland5. 1. Institute of Clinical Science/Pediatrics, Umeå University, SE-90185 Umeå, Sweden. Electronic address: Elena.lundberg@umu.se. 2. Institute of Clinical Science/Pediatrics, Umeå University, SE-90185 Umeå, Sweden. Electronic address: Bjorn.andersson@medic.gu.se. 3. Institute of Clinical Science/Pediatrics, Umeå University, SE-90185 Umeå, Sweden. Electronic address: Berit.kristrom@umu.se. 4. Department of Physiology/Endocrinology, Institute of Neurosciences and Physiology, The Sahlgrenska Academy at University of Gothenburg, SE-40530 Gothenburg, Sweden. Electronic address: Sten.rosberg@gu.se. 5. Department of Physiology/Endocrinology, Institute of Neurosciences and Physiology, The Sahlgrenska Academy at University of Gothenburg, SE-40530 Gothenburg, Sweden. Electronic address: Kerstin.albertsson.wikland@gu.se.
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 (≤8 times). Blood was sampled pre-GH-injection (dose GH33/GH67 μg/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 GH-curves/117 children). Pharmacokinetics were estimated by time Tmax (h) of maximal GH-concentration (Cmax, mU/L) and area under the curve for 16 h (AUC, mU/L ∗ h). RESULTS: In the Clinical-setting, median Cmax 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 Cmax and AUC variability was explained by GH-dose and proxies for injection depth (baseline GH-level, GHpeakwidth, 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 Cmax 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.
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 (≤8 times). Blood was sampled pre-GH-injection (dose GH33/GH67 μg/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 GH-curves/117 children). Pharmacokinetics were estimated by time Tmax (h) of maximal GH-concentration (Cmax, mU/L) and area under the curve for 16 h (AUC, mU/L ∗ h). RESULTS: In the Clinical-setting, median Cmax 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 Cmax and AUC variability was explained by GH-dose and proxies for injection depth (baseline GH-level, GHpeakwidth, 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 Cmax 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.