Relationship between the Dose of Recombinant Human Growth Hormone (rhGH) and Insulin Growth Factor-1 (IGF-1) in Adult Patients with Growth Hormone Deficiency (AGHD)
Rujia Xie (1) and Jaap Mandema (2)
(1) Pfizer, Sandwich, UK; (2) Quantitative Solutions Inc. CA, USA
Objectives: The purpose of this meta-analysis was to characterise the relationship between rhGH dose, time, patient characteristics and IGF-1 in AGHD patients.
Methods: All uncontrolled and controlled trials that reported a change from baseline in IGF-1 in AGHD patients with at least one week of rhGH treatment were included in the database. Three trials with patient level data were included to obtain more information on the relationship between covariates and IGF-1 response. A nonlinear mixed effects regression method was utilized to analyse the data containing a total of 118 trials with 225 unique treatment arms representing 4298 patients. Additive trial and residual variability were estimated and the latter was weighted by sample size. A compound symmetry correlation was assumed between the IGF-1 observations within one arm of a trial to account for the repeated measurements over time. A log transformation was used to stabilize the variance across the response range.
Results: The dose response data for IGF-1 was well described by an Emax model. There was no significant effect of time on Emax indicating that the onset of effect is fast and stable after 1 week of treatment. The maximum response (Emax) was 365 ng/ml. The dose reaching half the Emax (ED50) was found to be significantly dependent on: baseline IGF-1, gender, body weight, and dose titration. Female subjects were less sensitive to treatment needing a 1.7-fold higher dose to get a certain IGF-1 response than males (typical male ED50=9.5mg/kg/day vs. female 16.5 mg/kg/day). For every 10 ng/ml increase in baseline IGF-1, the ED50 decreased by about 5%. This model was better than a model for the % change from baseline. The ED50 was significantly smaller in subjects with a higher baseline weight. The relationship indicated that across the weight range the patients required about the same total (non weight adjusted) dose to get a certain IGF-1 response. This suggests that body weight adjusted dosing is not necessary. The dose required to normalize IGF-1 (to 180 ng/ml) is 0.23 [0.21 to 0.27] mg/day in a typical male with adult onset GHD and 0.40 [0.35 to 0.45] mg/day in a typical female.
Conclusions: This meta-analysis provided a broad overview and understanding of the IGF-1 dose response relationship and the impact of key covariates.