Open-label extension of a randomized trial investigating safety and efficacy of rhPTH(1-84) in hypoparathyroidism.

Hypoparathyroidism (HypoPT) is a rare disease, often inadequately controlled by conventional treatment. PARALLAX was a mandatory post-marketing trial assessing pharmacokinetics and pharmacodynamics of different dosing regimens of recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) for treating HypoPT. The present study (NCT03364738) was a phase 4, 1-yr open-label extension of PARALLAX. Patients received only 2 doses of rhPTH(1-84) in PARALLAX and were considered treatment-naive at the start of the current study. rhPTH(1-84) was initiated at 50 µg once daily, with doses adjusted based on albumin-corrected serum calcium levels. Albumin-corrected serum calcium (primary outcome measure), health-related quality of life (HRQoL), adverse events, and healthcare resource utilization (HCRU) were assessed. The mean age of the 22 patients included was 50.0 yr; 81.8% were women, and 90.9% were White. By the end of treatment (EOT), 95.5% of patients had albumin-corrected serum calcium values in the protocol-defined range of 1.88 mmol/L to the upper limit of normal. Serum phosphorus was within the healthy range, and albumin-corrected serum calcium-phosphorus product was below the upper healthy limit throughout, while mean 24-h urine calcium excretion decreased from baseline to EOT. Mean supplemental doses of calcium and active vitamin D were reduced from baseline to EOT (2402-855 mg/d and 0.8-0.2 µg/d, respectively). Mean serum bone turnover markers, bone-specific alkaline phosphatase, osteocalcin, procollagen type I N-terminal propeptide, and type I collagen C-telopeptide increased 2-5 fold from baseline to EOT. The HCRU, disease-related symptoms and impact on HRQoL improved numerically between baseline and EOT. Nine patients (40.9%) experienced treatment-related adverse events; no deaths were reported. Treatment with rhPTH(1-84) once daily for 1 yr improved HRQoL, maintained eucalcemia in 95% of patients, normalized serum phosphorus, and decreased urine calcium excretion. The effects observed on urine calcium and the safety profile are consistent with previous findings. Clinical trial identifier: NCT03364738.

Extended Treatment With Recombinant Human Parathyroid Hormone (1-84) in Adult Patients With Chronic Hypoparathyroidism.

OBJECTIVE: Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is efficacious in patients with hypoparathyroidism but additional data supporting its prolonged use are needed. We evaluated whether efficacy, safety, and tolerability are maintained during long-term rhPTH(1-84) treatment of patients with chronic hypoparathyroidism. METHODS: This was a phase 4, single-center, open-label, single-arm, 3-year extension (NCT02910466) of the phase 3 Hypo Extended (HEXT) study (NCT01199614). Patients self-administered rhPTH(1-84) once daily by subcutaneous injection, with doses individualized based on clinical parameters. Albumin-adjusted serum calcium levels (primary outcome measure), other disease biomarkers, health-related quality of life, and safety of rhPTH(1-84) were assessed using descriptive statistics. RESULTS: All patients (n = 39) had been exposed to rhPTH(1-84) (mean exposure [SD] 8.5 [3.5] years) before the start of the study, resulting in a mean exposure of 10.8 years including the present study. Mean patient age was 51.9 years, 79.5% were female, and 97.4% were White. Mean albumin-adjusted serum calcium concentrations were within the target range, and mean serum phosphate, serum calcium-phosphate product, and 24-hour urinary calcium excretion levels were within reference ranges at end of treatment. Mean doses of supplemental calcium and active vitamin D were maintained throughout the study. Bone turnover marker levels were maintained from baseline to end of treatment. No clinically relevant changes in bone mineral density were observed. Patient-reported health-related quality-of-life scores were generally maintained throughout the study. Four adverse events were considered treatment related and no new safety signals were identified. CONCLUSION: The effects of rhPTH(1-84) on biochemical, skeletal, and health-related quality-of-life parameters did not wane with extended use.

A Phase I Randomized Trial of Once-Daily Versus Twice-Daily Recombinant Human Parathyroid Hormone (1-84) for Hypoparathyroidism.

Recombinant human parathyroid hormone (1-84), rhPTH(1-84), is an approved adjunctive treatment to oral calcium and active vitamin D for adult patients with hypoparathyroidism; however, there is limited information on the effect of twice daily (BID) dosing of rhPTH(1-84). This was a phase I, open-label, randomized, crossover, multicenter study conducted in adult patients with chronic hypoparathyroidism. The primary objective was to assess the pharmacokinetic profile and pharmacodynamic effects of 1 day of treatment with rhPTH(1-84) administered subcutaneously at 25 µg BID, 50 µg BID, and 100 µg once daily (QD) with or without supplemental oral calcium. Safety and tolerability were evaluated as secondary objectives. In total, 33 patients with chronic hypoparathyroidism completed the study. Treatment with rhPTH(1-84), both BID and QD, over the short-term maintained serum calcium, lowered serum phosphorus, decreased urinary calcium excretion, and increased urinary phosphorus excretion. The decrease in urinary calcium excretion was numerically greater for BID than QD. Generally, baseline-adjusted pharmacokinetic parameters including area under the curve and maximum observed concentration increased with increasing rhPTH(1-84) dose, although this effect was not dose proportional. No new safety findings were observed. Our study revealed no differences thought to be clinically meaningful in pharmacokinetic or pharmacodynamic parameters with BID versus QD rhPTH(1-84) dosing. Future long-term studies are warranted to further elucidate the effects of alternative dosing strategies. © 2023 Takeda Development Center Americas, Inc and The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

A Pharmacokinetic Bridging Study to Compare Systemic Exposure to Budesonide between Budesonide Oral Suspension and ENTOCORT EC in Healthy Individuals.

BACKGROUND AND OBJECTIVES: Currently, there are no US FDA-approved therapies for eosinophilic esophagitis (EoE). Budesonide oral suspension (BOS; SHP621, TAK-721) is a viscous, muco-adherent, oral formulation of budesonide that is in phase III development for the treatment of EoE. BOS 2 mg twice daily was studied in 12- and 36-week phase III studies for the induction and maintenance of clinical remission in adults and adolescents with EoE (NCT02605837 and NCT02736409). ENTOCORT EC is a gelatin capsule formulation of budesonide that is FDA-approved for the treatment of mild-to-moderate active Crohn's disease (CD) in adults and children. This study compared the systemic exposure to budesonide from BOS with that from ENTOCORT EC, aiming to provide the pharmacokinetic (PK) bridge to the safety data of ENTOCORT EC. METHODS: Healthy adult volunteers (n = 22) were enrolled in an open-label, single-center, crossover study. Participants received a single oral dose of BOS 2 mg and a single oral dose of ENTOCORT EC 9 mg under fasting conditions in a randomized sequence, with a 48-h washout period between treatments. PK parameters were calculated by non-compartmental analysis and compared between treatments using a mixed-effects model with sequence and treatment as fixed effects and individuals within sequence as a random effect. RESULTS: Plasma budesonide concentrations showed that budesonide was absorbed significantly faster from BOS 2 mg than from ENTOCORT EC 9 mg, with peak concentrations reached at 1.5 and 4 h, respectively (p < 0.001). Systemic exposure to budesonide after a single oral dose of BOS 2 mg was lower than that observed after a single oral dose of ENTOCORT EC 9 mg; the least squares geometric mean maximum plasma concentration and the area under the concentration-time curve from the time of dosing to infinity and from the time of dosing to the last measurable concentration of budesonide after BOS 2 mg were 71.1%, 33.5%, and 33.6% of those after ENTOCORT EC 9 mg, respectively. No notable differences in treatment-emergent adverse events were observed between individuals treated with either drug; all events were mild and none resulted in discontinuation from the study. CONCLUSIONS: This study demonstrated that systemic exposure to budesonide after a single oral dose of BOS 2 mg was lower than that after a single oral dose of ENTOCORT EC 9 mg. These results provide PK bridging data to compare BOS with therapeutic doses of ENTOCORT EC with respect to safety information.

In vitro drug-drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes.

1. Budesonide is a glucocorticoid used in the treatment of several respiratory and gastrointestinal inflammatory diseases. Glucocorticoids have been demonstrated to induce cytochrome P450 (CYP) 3A and the efflux transporter P-glycoprotein (P-gp). This study aimed to evaluate the potential of budesonide to act as a perpetrator or a victim of transporter- or CYP-mediated drug-drug interactions (DDIs). 2. In vitro studies were conducted for P-gp, breast cancer resistance protein and organic anion and cation transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2) in transporter-transfected cells. Changes in mRNA expression in human hepatocytes and enzyme activity in human liver microsomes by budesonide were determined for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A. 3. The data indicated that budesonide is a substrate of P-gp but is not a substrate or an inhibitor of the other transporters investigated. Budesonide is neither an inducer nor an inhibitor of major CYP enzymes. The effect of P-gp on budesonide disposition is anticipated to be low owing to CYP3A-mediated clearance. 4. Collectively, our data indicate there is a low risk of budesonide perpetrating clinical DDIs mediated by the transporters or CYPs studied.

Neurokinin B Receptor Antagonism in Women With Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial.

CONTEXT: Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is characterized by high secretion levels of LH and T. Currently, there is no treatment licensed specifically for PCOS. OBJECTIVE: The objective of this study was to investigate whether a targeted therapy would decrease LH pulse frequency in women with PCOS, subsequently reducing serum LH and T concentrations and thereby presenting a novel therapeutic approach to the management of PCOS. DESIGN: This study is a double-blind, double-dummy, placebo-controlled, phase 2 trial. SETTINGS: University hospitals and private clinical research centers were included. PARTICIPANTS: Women with PCOS aged 18-45 years participated. INTERVENTION: Intervention included AZD4901 (a specific neurokinin-3 [NK3] receptor antagonist) at a dose of 20, 40, or 80 mg/day or matching placebo for 28 days. MAIN OUTCOME MEASURE: Change from baseline in the area under the LH serum concentration-time curve over 8 hours (area under the curve) on day 7 relative to placebo was measured. RESULTS: Of a total 67 randomized patients, 65 were evaluable. On day 7, the following baseline-adjusted changes relative to placebo were observed in patients receiving AZD4901 80 mg/day: 1) a reduction of 52.0% (95% confidence interval [CI], 29.6-67.3%) in LH area under the curve; 2) a reduction of 28.7% (95% CI, 13.9-40.9%) in total T concentration; and 3) a reduction of 3.55 LH pulses/8 hours (95% CI, 2.0-5.1) (all nominal P < .05). CONCLUSIONS: The NK3 receptor antagonist AZD4901 specifically reduced LH pulse frequency and subsequently serum LH and T concentrations, thus presenting NK3 receptor antagonism as a potential approach to treating the central neuroendocrine pathophysiology of PCOS.

Effect of CYP2C19 polymorphism on the pharmacokinetics of rosuvastatin in healthy Taiwanese subjects.

CYP2C19 contributes to N-desmethyl rosuvastatin formation in "in vitro" models. Approximately 80% of Taiwanese are CYP2C19 extensive metabolizers (EMs, CYP2C19*1/*1, *1/*2, or *1/*3). We studied the potential effect of CYP2C19 genotypes on rosuvastatin pharmacokinetics in healthy Taiwanese subjects following single and multiple daily oral doses of rosuvastatin calcium (20 mg). Geometric mean ratios for poor metabolizers (PMs): EMs for rosuvastatin were 0.974 and 0.872 for area under the curve and maximum plasma concentration on day 1 (1.01 and 0.965 on day 17) and for N-desmethyl rosuvastatin, 1.21 and 1.07 on day 1 (1.14 and 1.09 on day 17), respectively. Changes of lipid profiles from baseline to day 18 for PMs and EMs were -52.4% and -53.3% (low-density lipoprotein cholesterol), and -34.2% and -30.0% (total cholesterol), respectively. Rosuvastatin was generally well-tolerated by both PMs and EMs. These results suggest that CYP2C19 polymorphism does not affect rosuvastatin pharmacokinetics in healthy Taiwanese in a clinically meaningful way.

Evidence-based considerations for the clinical use of locally delivered, controlled-release antimicrobials in periodontal therapy.

PURPOSE: Locally delivered, controlled-release antimicrobials have long been available in dentistry. Their utilization in routine clinical practice, however, has been slow, perhaps because of concerns about clinical benefits or costs or possibly due to a lack of understanding of their efficacy or proper use. In this paper the evidence regarding locally delivered, controlled-released antimicrobials is considered, and some of the controversies surrounding these agents are discussed. Evidence-based considerations regarding their use are also summarized. Scaling and root planing (SRP) procedures are the backbone of non-surgical periodontal therapy. Since a number of well designed clinical trials have demonstrated that adjunctive, locally delivered, controlled-release antimicrobials make SRP significantly more effective to reduce clinical signs of chronic periodontitis with a known safety profile, and since SRP procedures have previously been considered the standard of care for non-surgical periodontal therapy, a case is made that SRP in combination with adjunctive therapy, administered in a manner consistent with the approved full prescribing information, could be considered a new standard.

Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a Phase I study.

Saracatinib (AZD0530) is an orally active once-daily Src kinase inhibitor which modulates key signaling pathways in cancer cells. In a Phase I study in patients with advanced solid malignancies resistant to standard treatment we assessed the effect of saracatinib on bone turnover. Fifty-one patients were randomized into three parallel groups to receive saracatinib 50, 125 or 175 mg/day. After a single dose followed by a 7-day washout, patients received once-daily doses for 21 days. Bone turnover markers were measured in serum and urine samples collected before dosing on days 1, 2, 3, 17 and 28. Samples were available at baseline and more than one other time point for 44 patients. Bone resorption markers were significantly decreased by saracatinib. Serum cross-linked C-terminal telopeptide of type I collagen (sCTX) changed in the 50, 125 and 175 mg/day groups by -36% (95% CI -58, -4), -64% (95% CI -75, -48) and -75% (95% CI -83, -61), respectively, at day 28. Urinary cross-linked N-terminal telopeptide of type I collagen/creatinine ratio (uNTX/Cr) changed in the 50, 125 and 175 mg/day groups by; -13% (95% CI -33, 13), -48% (95% CI -59, -34) and -50% (95% CI -62, -35), respectively, at day 28. The significant decreases in bone resorption markers indicate that suppression of Src kinase inhibits osteoclast activity in patients with advanced cancer. This result suggests that saracatinib may have therapeutic benefit in metastatic bone disease.

Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial.

Src is a nonreceptor tyrosine kinase thought to be essential for osteoclast function and bone resorption. We investigated the effect of the orally available Src inhibitor saracatinib (AZD0530) on bone turnover in healthy men. The study was part of a randomized, double-blind, placebo-controlled multiple-ascending-dose phase I trial of saracatinib. Fifty-nine healthy men (mean age 34.6 years) were divided into five cohorts; four with 12 subjects and one with 11 subjects, and randomized within each cohort in the ratio 3:1 to receive a single dose of saracatinib or placebo, respectively, followed 7 to 10 days later with daily doses for a further 10 to 14 days. Dosing levels of saracatinib ascended by cohort (60 to 250 mg). Markers of bone turnover were measured predose and 24 and 48 hours after the initial single dose and immediately before and 24 and 48 hours and 10 to 14 days after the final dose. Data from 44 subjects were included in the analysis. There was a dose-dependent decrease in bone resorption markers [serum cross-linked C-telopeptide of type I collagen (sCTX) and urinary cross-linked N-telopeptide of type I collagen normalized to creatinine (uNTX/Cr)]. At a dose of 250 mg (maximum tolerated dose), sCTX decreased by 88% [95% confidence interval (CI) 84-91%] and uNTX/Cr decreased by 67% (95% CI 53-77%) from baseline 24 hours after the final dose. There was no significant effect on bone formation markers. There were no significant adverse events. We conclude that inhibition of Src reduces osteoclastic bone resorption in humans. Saracatinib is a potentially useful treatment for diseases characterized by increased bone resorption, such as metastatic bone disease and osteoporosis.

Effects of third generation aromatase inhibitors on bone health and other safety parameters: results of an open, randomised, multi-centre study of letrozole, exemestane and anastrozole in healthy postmenopausal women.

Given potential differences between the skeletal and other effects of the third generation aromatase inhibitors (AIs), we conducted an open, randomised Phase I study, comparing the effects of three licensed AIs on bone turnover markers, lipid profiles and adrenal function. Treatment comparisons were undertaken in 90 healthy postmenopausal women with normal bone mineral density who received once daily oral anastrozole (1mg, n=29), letrozole (2.5mg, n=29) or exemestane (25mg, n=32) for 24weeks with a subsequent 12week washout period. All three AIs induced increases in bone resorption markers, but no significant differences were observed in their effects on bone turnover markers. Greater differences were observed in lipid metabolism. Notably, exemestane, but not anastrozole or letrozole, significantly increased the LDL:HDL cholesterol ratio by 12weeks, largely mediated by a decrease in HDL-cholesterol. Further, long-term clinical studies are required to determine the impact, if any, of the differences observed between the AIs

Efficacy of controlled-release subgingival chlorhexidine to enhance periodontal regeneration.

BACKGROUND: Periodontal regeneration success may be limited by placing bone grafts and membranes in infected sites. The objective of this study was to test the hypothesis that adjunctive subgingival administration of chlorhexidine gelatin bioresorbable chips enhances bone gain when used in conjunction with guided tissue regeneration. METHODS: This was a single center, blinded, 2-arm parallel design study of 44 subjects with one or more sites with probing depth and clinical attachment loss > or = 5 mm following initial therapy and radiographic evidence of bone loss. The patients were randomly assigned to receive either chlorhexidine (CHX) chip or sham chip placement one week prior to regenerative therapy that included graft placement and site coverage with guided tissue membranes. Patients also received CHX or sham chip placement, per their randomization, adjunctively to scaling and root planing or maintenance procedures. Periodontal examinations were completed at baseline (8 weeks prior to surgery); 1 week prior to surgery; and at 3, 6, and 9 months postsurgery. The major outcomes for the study were changes in bone height and bone mass as measured from standardized radiographs used for quantitative digital subtraction radiography over the 11-month study period. RESULTS: Subjects receiving sham chip placement gained a mean bone height of 1.49 +/- 0.22 mm, while patients receiving the CHX chips gained significantly more bone height (3.54 +/- 0.45 mm; P<0.001). Similarly, subjects receiving CHX chips as an adjunct gained significantly more bone mass (5.57 +/- 0.69 mg; P<0.001) than the standard therapy (2.59 +/- 0.34 mg). CONCLUSIONS: These pilot results indicate that locally delivered, controlled-release antimicrobial treatment may improve the amount of bone gain during guided tissue regeneration procedures. These data support the evidence that infection control is an important variable in successful regeneration.