1 Department of Pharmacology, Faculty of Health Sciences, Aarhus University, Aarhus University2 The Department of Endocrinology and Diabetes, Faculty of Health Sciences, Aarhus University, Aarhus University3 Department of Biomedicine - Forskning og uddannelse, Øst, Department of Biomedicine, Health, Aarhus University4 Novartis5 Department of Clinical Medicine - The Department of Endocrinology and Diabetes, Department of Clinical Medicine, Health, Aarhus University6 Department of Biomedicine - Forskning og uddannelse, Øst, Department of Biomedicine, Health, Aarhus University7 Department of Clinical Medicine - The Department of Endocrinology and Diabetes, Department of Clinical Medicine, Health, Aarhus University
Growth hormone deficient (GHD) patients are currently effectively treated with daily subcutaneous (sc) injections of hGH in the evening, but alternative routes would be attractive. An oral formulationulation of hGH, using an amino-caprilic acid derivative (5-CNAC, Emisphere's eligen® technology) as carrier has recently been developed. The aim of this study was to determine if this oral formulation of hGH could be absorbed and be bioactive. Eight GHD men (mean age 50 years) receiving sc hGH therapy were withdrawn from therapy for 7 days and then treated for 7 days orally with tablets of HGH191 (Novartis). Each tablet contained 100 mg of hGH and 200 mg 5-CNAC. One tablet was given at 08 h and 17 h, and two tablets at 22 h to match nocturnal GH secretion. The patients were studied thrice for 24 hours: at day 7 of washout, at days 1 and 7 of treatment. GH peaks were recorded in all patients, although minor endogenous GH secretion interfered. Following the last dose (22 h) after 7 days of treatment, median Tmax was 0.75 h (range 0.37-3.98 h), and the geometric mean Cmax was 1.08 µg/L (range 0.23-17.46 µg/L). Absorption was most pronounced after the morning and bedtime dose. Serum IGF-I levels only changed slightly from end of the washout period (mean 118.2 µg/L, 95% CI [96.0, 140.3]) to day 1 of treatment (mean 126.0 µg/L, 95% CI [111.0, 140.9]). However, at day 7 IGF-I levels (mean 153.2 µg/L, 95% CI [126.2, 180.2]) were significantly increased (p=0.025) vs. end of washout. GH and IGF-I levels revealed pronounced between- and within-subject variation. No significant adverse reactions were seen. In conclusion, this study shows, for the first time, absorption of an oral formulation of hGH. Bioactivity was demonstrated by increased serum IGF-I levels after 7 days treatment compared to the end of washout. Further studies should determine optimal formulation, dose and impact of meals, but the possibility of oral delivery of peptides opens new therapeutic perspectives.
Clinical - Physiology & Pharmacology of the Growth Hormone Axis: New Treatment Modalities & Indications, 2007