An orally administered PTH may have prodigious advantages in the treatment of hypoparathyroidism and osteoporosis. Unfortunately, the oral delivery of biologic macromolecules is characterized by a negligible bioavailability and a high dose-to-dose variability in absorption, resulting in difficulty in accurately titrating the drug effect. We present clinical study data of a novel oral peptide delivery technology demonstrating an enhanced bioavailability with reduced Cmax variability.
Methods: A Phase I, open label crossover pharmacokinetic (PK) study to assess the safety and PK of oral PTH (1-34) in ten healthy male adult volunteers was conducted. The PK profile of a fixed dose - 1.5mg PTH (1-34) of three different oral formulations was compared. PTH (1-34) levels in the plasma of subjects was analyzed at a number of time points post administration, utilizing a PTH (1-34) immunoassay (IDS; Bolden, UK). In parallel, to assess the pharmacodynamic (PD) effect, serum calcium of subjects receiving the different formulations of oral PTH (1-34) was analyzed.
Results: PK profiles of all oral PTH (1-34) formulations were characterized by a rapid absorption and elimination. The systemic exposure (AUC) of the basic oral formulation and two modified formulation versions were 3481 ±1843 pg*min/mL, 7976 ±2556 pg*min/mL and 11369 ±3719 pg*min/mL (mean ± SE). The maximal plasma concentration (Cmax) of these formulations were 145 ±56pg/mL, 375 ±108pg/mL, and 481 ±101pg/mL, respectively. Cmax coefficients of variation (CV%) of the same formulations were 123%, 91% and 67%, respectively. Similarly to the drug absorption, PD response of the modified formulations, presented as the maximal relative increase in albumin adjusted calcium, was improved from 0.07 ±0.29mg/dL to 0.32 ±0.24mg/dL.
Discussion: Inherent to oral drug delivery of biopharmaceuticals is the extremely low bioavailability and high absorption variability. The current results indicate that Entera’s delivery technology can overcome these two principal obstacles by achieving repeatable, clinically relevant systemic drug exposure. Entera’s proprietary delivery platform was optimized and achieved anenhancement in drug bioavailability in parallel with the significant decrease in its absorption variability. Similarly, its effect on blood calcium was enhanced by the novel oral formulation of PTH (1-34) pointing out the potential of the drug to be a first line treatment of hypoparathyroidism and osteoporosis.
|Publication status||Published - 11 Sep 2017|
|Event||ASBMR 2017 Annual Meeting - Colorado Convention Center, ASBMR Discovery Hall, United States|
Duration: 8 Sep 2017 → 11 Sep 2017
|Conference||ASBMR 2017 Annual Meeting|
|Period||8/09/17 → 11/09/17|