Enhanced bioavailability and reduced pharmacokinetic variability of Oral PTH (1-34) in man

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

Safety and efficacy of oral human parathyroid hormone (1-34) in hypoparathyroidism: An open-label study

The standard treatment of primary hypoparathyroidism (hypoPT) with oral calcium supplementation and calcitriol (or an analog), intended to control hypocalcemia and hyperphosphatemia and avoid hypercalciuria, remains challenging for both patients and clinicians. In 2015, human parathyroid hormone (hPTH) (1-84) administered as a daily subcutaneous injection was approved as an adjunctive treatment in patients who cannot be well controlled on the standard treatments alone. This open-label study aimed to assess the safety and efficacy of an oral hPTH(1-34) formulation as an adjunct to standard treatment in adult subjects with hypoparathyroidism. Oral hPTH(1-34) tablets (0.75 mg human hPTH(1-34) acetate) were administered four times daily for 16 consecutive weeks, and changes in calcium supplementation and alfacalcidol use, albumin-adjusted serum calcium (ACa), serum phosphate, urinary calcium excretion, and quality of life throughout the study were monitored. Of the 19 enrolled subjects, 15 completed the trial per protocol. A median 42% reduction from baseline in exogenous calcium dose was recorded (p =.001), whereas median serum ACa levels remained above the lower target ACa levels for hypoPT patients (>7.5 mg/dL) throughout the study. Median serum phosphate levels rapidly decreased (23%, p =.0003) 2 hours after the first dose and were maintained within the normal range for the duration of the study. A notable, but not statistically significant, median decrease (21%, p =.07) in 24-hour urine calcium excretion was observed between the first and last treatment days. Only four possible drug-related, non-serious adverse events were reported over the 16-week study, all by the same patient. A small but statistically significant increase from baseline quality of life (5%, p =.03) was reported by the end of the treatment period. Oral hPTH(1-34) treatment was generally safe and well tolerated and allowed for a reduction in exogenous calcium supplementation, while maintaining normocalcemia in adult patients with hypoparathyroidism

Systemic Changes in Endocannabinoids and Endocannabinoid-like Molecules in Response to Partial Nephrectomy-Induced Ischemia in Humans

Renal ischemia–reperfusion (IR), a routine feature of partial nephrectomy (PN), can contribute to the development of acute kidney injury (AKI). Rodent studies show that the endocannabinoid system (ECS) is a major regulator of renal hemodynamics and IR injury; however, its clinical relevance remains to be established. Here, we assessed the clinical changes in systemic endocannabinoid (eCB) levels induced by surgical renal IR. Sixteen patients undergoing on-clamp PN were included, with blood samples taken before renal ischemia, after 10 min of ischemia time, and 10 min following blood reperfusion. Kidney function parameters (serum creatinine (sCr), blood urea nitrogen (BUN), and serum glucose) and eCB levels were measured. Baseline levels and individual changes in response to IR were analyzed and correlation analyses were performed. The baseline levels of eCB 2-arachidonoylglycerol (2-AG) were positively correlated with kidney dysfunction biomarkers. Unilateral renal ischemia increased BUN, sCr, and glucose, which remained elevated following renal reperfusion. Renal ischemia did not induce changes in eCB levels for all patients pooled together. Nevertheless, stratifying patients according to their body mass index (BMI) revealed a significant increase in N-acylethanolamines (anandamide, AEA; N-oleoylethanolamine, OEA; and N-palmitoylethanolamine, PEA) in the non-obese patients. No significant changes were found in obese patients who had higher N-acylethanolamines baseline levels, positively correlated with BMI, and more cases of post-surgery AKI. With the inefficiency of ‘traditional’ IR-injury ‘preventive drugs’, our data support future research on the role of the ECS and its manipulation in renal IR