Anabolic treatment is indicated for high and very-high risk patients with osteoporosis, but acceptance is limited because current anabolic medications require subcutaneous injections. The purpose of this study was to assess the effects of a novel orally administered PTH tablet on serum markers of bone formation (PINP and osteocalcin), bone resorption (crosslinked C-telopeptide [CTX]), BMD, and safety in postmenopausal women with low BMD or osteoporosis. In this 6-mo, double-blind, placebo-controlled study, 161 patients were randomized to oral PTH tablets containing 0.5, 1.0, 1.5, or 2.5 mg or placebo daily. Biochemical markers were assessed at 1, 2, 3, and 6 mo and BMD of LS, TH, and FN was measured at 6 mo. Biochemical marker changes were dose dependent with minimal or no effect at the 2 lowest doses. At the highest dose (2.5 mg once daily), serum PINP and OC levels increased 30% within 1 mo after oral PTH initiation (P < .0001), remained elevated through 3 mo, and were back to baseline at 6 mo. In contrast, serum CTX levels declined 16% and 21% below baseline at 3 and 6 mo, respectively (both P ≤ .02). At 6 mo, 2.5 mg tablets increased mean BMD vs placebo of the LS by 2.7%, TH by 1.8%, and FN by 2.8% (all P ≤ .01). There were no drug-related serious adverse events. The most common adverse events were headache, nausea, and dizziness. In contrast to subcutaneous PTH, the oral PTH tablet appears to increase BMD rapidly by the dual mechanism of stimulating formation and inhibiting bone resorption. This might be the first effective oral anabolic alternative to subcutaneous administration for the treatment of low BMD or osteoporosis.

To date, teduglutide, a peptide analog to the endogenous Glucagon-Like Peptide-2 (GLP-2), represents the most effective pharmacologic treatment to improve the absorption of nutrients in short bowel syndrome (SBS) patients. Currently, this peptide drug cannot be administered orally due to its negligible permeability and rapid degradation in the gastrointestinal tract; and thus, requires patients to take daily sub-cutaneous injections. In SBS patients, oral drug delivery has additional challenges because the site of absorption, the intestine, is short and less functional. Results of the reported herein study in rats, indicate that a novel, SNAC-based oral drug delivery platform designed to enable gastro-mucosal absorption of therapeutic peptides and proteins, may be utilized for the delivery of intestinotrophic peptides in the unique population of SBS patients, as a convenient alternative to daily injections.

ABSTRACT 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. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Oral delivery of peptides and proteins is hindered by their rapid proteolysis in the gastrointestinal tract and their inability to permeate biological membranes. Various drug delivery approaches are being investigated and implemented to overcome these obstacles. In the discussed study conducted in pigs, an investigation was undertaken to assess the effect of combination of a permeation enhancer - salcaprozate sodium, and a proteolysis inhibitor - soybean trypsin inhibitor, on the systemic exposure of the peptide teriparatide, following intraduodenal administration. Results demonstrate that this combination achieves significantly higher Cmax and AUC (~10- and ~20-fold respectively) compared to each of these methodologies on their own. It was thus concluded that an appropriate combination of different technological approaches may considerably contribute to an efficient oral delivery of biological macromolecules.

Background: Parathyroid hormone (PTH) plays a key role in calcium and phosphate homeostasis. Upon binding to its receptor, it signals via a second messenger, cyclic adenosine 3, 5’ monophosphate (cAMP). Lack of increase in plasma and urinary cAMP concentrations in response to PTH are used as diagnostic markers for pseudohypoparathyroidism (PHP), a condition primarily associated with resistance to PTH (Ellsworth-Howard Test). Aims: 1) Develop and validate a LC-MS/MS method for the quantification of cAMP in plasma and urine. 2) Investigate assay performance in a rat pharmacokinetic study investigating the response to an oral dose of PTH (1-34) and the response to subcutaneous (sc) PTH administration in a patient with suspected PHP. Method: cAMP and 13C5-cAMP internal standard were extracted from EDTA plasma using a weak anion exchange solid phase extraction. Chromatography was performed in positive electrospray ionisation mode, using a pentafluorophenyl column with a 10 mins 2% formic acid water:acetonitrile gradient. Transitions were m/z 330/136 for cAMP and 335/136 for 13C5-cAMP. Over concentrations ranging from 4.6 (lower limit of quantification) to 293.5 nmol/L, the calibration curve was linear (mean curve fits of >0.95, 5 repeats) and intra- and inter-assay precisions were <12% and <8%, respectively. Spiked recovery was 98±5%. Application: A single oral dose of 5 mg/kg PTH (1–34) or placebo was administered to Sprague-Dawley rats after an overnight fast. cAMP was analysed in EDTA samples obtained at baseline, prior to dosing and every 15 min for 1h and then hourly for another 3h after dosing. In the suspected PHP patient, urinary cAMP was measured after a standard 20µg sc injection of teriparatide (Forsteo). Results: In rats, plasma PTH (1-34) and cAMP increased significantly within 15min of dosing, reaching peak values between 15 and 30 mins. PTH (1–34) concentration increased significantly by up to 6770-fold, although response to PTH (1-34) varied between animals. Plasma cAMP typically tripled, from 36.5±3.7 nmol/L at baseline to 108.9±26.3 nmol/L. Placebo had no effect.Urine cAMP from the suspected PHP patient did not change significantly reflecting a lack of biological response to sc PTH (1-34) despite a significant increase in plasma PTH (1-34) (27.8 to 101.1 pmol/L). Conclusion: The present method was robust and selective. It also showed utility in determining cAMP in biological systems and the ability to study the effect of drugs such as Forsteo.

Background: PTH(1-34) (Teriparatide) is an anabolic agent used in treatment of osteoporosis. It promotes bone formation and reduces the risk of vertebral and some non-vertebral fractures. The route of administration by daily subcutaneous (sc) injection can cause problems in certain patients. A new oral delivery system for human PTH(1-34) has been developed as a possible treatment option. Galitzer et al. presented pre-clinical data (ASBMR 2012, MO0402) and first-in-human results (ASBMR 2013, FR0378) on safety, tolerability and absorption dynamics of oral PTH(1-34) in various dosages. We now describe the pharmacokinetics (PK) of oral PTH(1-34) compared to sc and placebo in healthy subjects. Objective: A single-center, double blinded, triple crossover study was designed to compare the 1.8 mg optimal dose of oral PTH(1-34) against standard dosage of teriparatide injection and oral placebo. Method: The study was conducted following and in accordance with the Hadassah Medical Center ethical approval committee. 12 healthy volunteers (6m/6f), 18-50y, received three treatments: single sc injection of 20µg FORTEO®, 1.8 mg oral PTH(1-34), or placebo. Blood samples were collected at time 0, 10, 15, 20, 30, 45, 60, 75, 90, 120, 180, 240, 300 minute post dose. Plasma concentration of PTH(1-34) (IDS, Tyne and Wear, UK) and cyclic adenosine 3’,5’monophosphate (cAMP) were measured on all samples. Results: All 12 subjects on oral PTH(1-34) showed rapid, post dose increase then decrease of PTH(1-34), from baseline mean (±SD) of 5.9 (1.8) pg/mL to peak mean of 185.3 (±128.8) pg/mL. PK profiles of oral PTH(1-34) showed Cmax (pg/mL), Tmax (mins), AUC0-last of 238.3 (110.8), 17.5 (5.4) and 6161.7 (2726.7), respectively; whereas sc showed mean Cmax (pg/mL), Tmax (mins), AUC0-last of 172.3 (55.7), 20.8 (8.7) and 13965.9 (2984.8), respectively. Plasma cAMP increased in all subjects in response to oral PTH(1-34) and sc treatment. Serum adjusted calcium in all subjects remained within normal limits throughout the studies. Conclusion: PK profiles showed a single oral dose of 1.8 mg PTH(1-34) is rapidly absorbed, and no significant difference in Cmax and Tmax when compared with 20µg of sc teriparatide. A significant difference in the rate of plasma clearance and AUC0-last value was observed (fig.1). These differing profiles and modality of administration of PTH(1-34) could offer unique advantages in the treatment of calcium and metabolic bone disorders.

During recent years there has been increasing interest in the Lycopodium alkaloid huperzine A as a potential therapeutic agent for neurodegenerative diseases. This study aimed to characterize huperzine A's permeability across the enterocyte barrier along the gastrointestinal tract with an emphasis on the effect of ionization on the drug absorption. Intestinal permeability of huperzine A was evaluated by in vitro Caco-2 and parallel artificial membrane permeation assay models and by the ex vivo Ussing chamber model. The permeability rate was strongly dependent on the degree of ionization and increased with elevation of the donor medium pH in all studied models. The transport of the unionized fraction was similar to the permeability of the markers for passive transcellular diffusion. Addition of the paracellular permeability modulator palmitoylcarnitine in the Caco-2 model led to significant enhancement in the permeability of the ionized huperzine A fraction. No evidence of active transport of huperzine A was detected in this study. The Ussing chamber model experiments showed similar drug permeability along the entire rat intestine. In conclusion, huperzine A permeates the intestinal border mainly by passive transcellular diffusion whereas some fraction, dependent on the degree of huperzine A ionization, is absorbed by the paracellular route. Huperzine A's permeability characteristics pave the way to the development of its oral extended release dosage form. The specific population of the potential users of huperzine A and the high potency of this molecule support the rationale for such a delivery.