Delving into the Latest Updates on Ronacaleret Hydrochloride with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Ronacaleret, Ronacaleret hydrochloride (USAN)

+ [2]

Target

CaSR

Mechanism

CaSR antagonists(Calcium sensing receptor antagonists)

Therapeutic Areas

Endocrinology and Metabolic DiseaseSkin and Musculoskeletal DiseasesOther Diseases+ [1]

Active Indication-

Inactive Indication

Bone marrow transplant rejectionFractures, BoneHematopoietic stem cell transplantation+ [4]

Originator Organization

Shire Development LLC

Active Organization-

Inactive Organization

GSK PlcShire Pharmaceuticals Services Ltd.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC25H32ClF2NO4

InChIKeyBQGSCEAKPBWIDI-VEIFNGETSA-N

CAS Registry702686-96-2

View All Structures (2)

The present study aims to evaluate the impact of 5 days oral administration of ronacaleret 100 miligram (mg) and 400 mg on changes in circulating CD34+ cells, when ronacaleret is followed by the administration of a single dose of plerixafor in healthy human volunteers.
This single centre adaptive design study will be carried out in 2 parts. The part A will evaluate the change in peripheral circulating CD34+ cells in response to two different 5 day regimens of ronacaleret (100 mg or 400 mg once daily), given in conjunction with a single dose of plerixafor (0.24 mg/kilogram [kg]) sub-cutaneously (SC) on the evening of the final days dosing approximately 12 hours before collection of CD34+ cells on day 6. Subjects (5 each) will be assigned to either one of the ronacaleret arms, in an open fashion. Comparisons will be made in the change from baseline to end of treatment peripheral CD34+ cell counts. Part A will be conducted in two cohorts with 5 subjects being enrolled into each of the 2 treatment arms making up the first cohort. Cohort 2 will involve up to 5 further subjects being enrolled into each treatment arm.
The structure of part B will be finalized following a review of data generated in part A.
The total study duration of Part A for each subject including the screening, treatment and follow-up periods will be approximately 7 weeks.

Start Date02 Nov 2012

Sponsor / Collaborator

GSK Plc

NCT01466335

/ CompletedPhase 1

A Randomized, Double Blind, Parallel Group, Single Center, Adaptive Phase I Study to Evaluate the Safety, Efficacy and Dose Responses of SB-751689 (Ronacaleret; a Calcium Sensing Receptor Antagonist) for Durations Not to Exceed 28 Days, Versusplacebo in Healthy Human Volunteers.

Ronacaleret is an orally administered CaSR antagonist which has previously been demonstrated to transiently increase PTH in both animals and humans. Additional studies in post-menopausal women and patients with distal radial fractures have demonstrated both anabolic and catabolic effects on bone biomarkers and scans of bone density. Based on ronacalerets ability to interact with the CaSR inducing PTH release and activating endogenous bone metabolism of both osteoblasts and osteoclasts, it is our intention to evaluate the impact activation of this pathway has on mobilization of Hematopoietic stem cell (HSCs) into the periphery.
This is an adaptive, phase I, randomized, single centre, double-blind dose finding, parallel-group, multi-cohort placebo controlled study of the efficacy and safety of ronacaleret in up to 45 healthy human volunteers. Cohorts of eligible subjects will be studied for periods up to 28 days. Total daily doses of ronacaleret will range from 100mg, up to 400mg and be administered for a maximum of 28days. The first part of this study will evaluate several doses and schedules of ronacaleret, run in parallel, with respect to their ability to affect mobilization of CD34+ cells into the peripheral circulation. In subsequent cohorts of the study we will utilize information obtained from previous cohorts to further refine and optimise those dosing paradigms which show efficacy. For the first cohort of study participants; the study will commence with 6 days of dosing in an inpatient setting followed by 21 days of continued dosing and evaluation as an outpatient, with a series of regularly scheduled visits, with the final visit on day 28. The study period will include evaluations of pharmacokinetic and pharmacodynamic parameters along with standard laboratory and safety evaluations. The second cohort may be treated with ronacaleret for periods ranging from 14 to 28 days in order to optimise the treatment paradigm with respect to pharmacodynamic efficacy. The PK/PD of each group in cohort one will be utilized to make adjustments in the total daily dose, dose frequency and or duration of dosing investigated in cohort 2. Decisions will be made as to dropping doses based on the PK/PD results and any safety considerations. An initial equal randomization amongst groups within the first cohort may be adjusted to allow for other randomization strategies as various doses and schedules are assessed.
The objective of this study is to characterise the dose-response curve for ronacaleret with respect to safety and efficacy based on changes in peripheral CD34+ cell counts. Results obtained from this study will inform us: of optimized doses, schedules, and durations of treatment for future studies. Additional cohorts may be added to further explore the dose schedule and duration if required. The exact number of cohorts studied will depend on the results obtain from the prior groups and the desire to explore a variety of doses and schedules. The aims of the present study (CR9115166) include an assessment of the pharmacodynamic effects (mobilization of CD34+ cells), safety, tolerability, and pharmacokinetics of ronacaleret in healthy human volunteers.

Start Date27 Oct 2011

Sponsor / Collaborator

GSK Plc

EUCTR2007-001477-29-CZ

/ Not yet recruitingNot Applicable

A proof-of-concept study of SB-751689 in male and female subjects with a fractured distal radius.

Start Date17 Apr 2008

Sponsor / Collaborator-

100 Clinical Results associated with Ronacaleret Hydrochloride

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100 Translational Medicine associated with Ronacaleret Hydrochloride

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100 Patents (Medical) associated with Ronacaleret Hydrochloride

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14

Literatures (Medical) associated with Ronacaleret Hydrochloride

01 Sep 2017·Journal of Pharmaceutical SciencesQ3 · MEDICINE

Intestinal Drug Interactions Mediated by OATPs: A Systematic Review of Preclinical and Clinical Findings

Q3 · MEDICINE

Review

Author: Levy, René H ; Tay-Sontheimer, Jessica ; Zhou, Zhu ; Yu, Jingjing ; Ragueneau-Majlessi, Isabelle

In recent years, an increasing number of clinical drug-drug interactions (DDIs) have been attributed to inhibition of intestinal organic anion-transporting polypeptides (OATPs); however, only a few of these DDI results were reflected in drug labels. This review aims to provide a thorough analysis of intestinal OATP-mediated pharmacokinetic-based DDIs, using both in vitro and clinical investigations, highlighting the main mechanistic findings and discussing their clinical relevance. On the basis of pharmacogenetic and clinical DDI results, a total of 12 drugs were identified as possible clinical substrates of OATP2B1 and OATP1A2. Among them, 3 drugs, namely atenolol, celiprolol, and fexofenadine, have emerged as the most sensitive substrates to evaluate clinical OATP-mediated intestinal DDIs when interactions with P-glycoprotein by the test compound can be ruled out. With regard to perpetrators, 8 dietary or natural products and 1 investigational drug, ronacaleret (now terminated), showed clinical intestinal inhibition attributable to OATPs, producing ≥20% decreases in area under the plasma concentration-time curve of the co-administered drug. Common juices, such as apple juice, grapefruit juice, and orange juice, are considered potent inhibitors of intestinal OATP2B1 and OATP1A2 (decreasing exposure of the co-administered substrate by ∼85%) and may be adequate prototype inhibitors to investigate intestinal DDIs mediated by OATPs.

01 Jan 2017·Drug Metabolism and DispositionQ2 · MEDICINE

Inhibition of Intestinal OATP2B1 by the Calcium Receptor Antagonist Ronacaleret Results in a Significant Drug-Drug Interaction by Causing a 2-Fold Decrease in Exposure of Rosuvastatin

Q2 · MEDICINE

Article

Author: Matheny, Christopher ; Chen, Liangfu ; Patel, Dipal ; Ellens, Harma ; Ho, May ; Johnson, Marta

Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters [organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP1A2, OATP2B1, sodium-taurocholate cotransporting polypeptide, breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), MRP4, organic anion transporter 3]. It is therefore frequently used as a probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. Although each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo. Ronacaleret, a drug-development candidate for treatment of osteoporosis (now terminated), was shown to inhibit OATP1B1 in vitro (IC₅₀ = 11 µM), whereas it did not inhibit BCRP. Since a DDI risk through inhibition of OATP1B1 could not be discharged, a clinical DDI study was performed with rosuvastatin before initiation of phase II trials. Unexpectedly, coadministration with ronacaleret decreased rosuvastatin exposure by approximately 50%, whereas time of maximal plasma concentration and terminal half-life remained unchanged, suggesting decreased absorption and/or enhanced first-pass elimination of rosuvastatin. Of the potential in vivo rosuvastatin transporter pathways, two might explain the observed results: intestinal OATP2B1 and hepatic MRP4. Further investigations revealed that ronacaleret inhibited OATP2B1 (in vitro IC₅₀ = 12 µM), indicating a DDI risk through inhibition of absorption. Ronacaleret did not inhibit MRP4, discharging the possibility of enhanced first-pass elimination of rosuvastatin (reduced basolateral secretion from hepatocytes into blood). Therefore, a likely mechanism of the observed DDI is inhibition of intestinal OATP2B1, demonstrating the in vivo importance of this transporter in rosuvastatin absorption in humans.

01 Aug 2015·American Journal of Physiology-Renal PhysiologyQ3 · MEDICINE

Antialbuminuric actions of calcilytics in the remnant kidney

Q3 · MEDICINE

Article

Author: Miyazaki, Takashi ; Suzuki, Hiromichi ; Ishii, Naohito ; Takenaka, Tsuneo ; Nishiyama, Akira ; Hayashi, Matsuhiko ; Inoue, Tsutomu

Hyperphosphatemia accelerates the progression of chronic kidney diseases. In the present study, the effects of ronacaleret, a calcilytic agent, on renal injury were assessed in the following four groups of rats: 5/6-nephrectomized Wistar rats as a control (C group), rats treated with ronacaleret (3 mg·kg−1·day−1; R group), rats treated with calcitriol (30 ng·kg−1·day−1; V group), and rats treated with both ronacaleret and calcitriol (R + V group). Three months later, rats were euthanized under anesthesia, and the remnant kidneys were harvested for analysis. Albuminuria was lower in the R and V groups than in the C group ( P < 0.05). Creatinine clearance was elevated in the R and V groups compared with the C group ( P < 0.05). Serum Ca2+ and renal ANG II were higher in the R + V group than in the C group ( P < 0.05 for each), and serum phosphate was reduced in the R group compared with the C group ( P < 0.05). Fibroblast growth factor-23 was lower in the R group and higher in the V and R + V groups than in the C group. However, parathyroid hormone did not differ significantly among the four groups. Renal klotho expression was elevated in the R and V groups compared with the C group ( P < 0.05). The present data indicate that ronacaleret preserves klotho expression and renal function with reductions in serum phosphate and albuminuria in 5/6-nephrectomized rats. Our findings demonstrate that vitamin D prevents declines in klotho expression and renal function, suppressing albuminuria.

100 Deals associated with Ronacaleret Hydrochloride

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External Link

KEGG	Wiki	ATC	Drug Bank
D08991	-	-	DB05255

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Osteoporosis	Phase 2	HK	GSK Plc	14 May 2007
Osteoporosis	Phase 2	DK	GSK Plc	14 May 2007
Osteoporosis	Phase 2	MX	GSK Plc	14 May 2007
Fractures, Bone	Phase 2	-	Shire Pharmaceuticals Services Ltd.	-
Hematopoietic stem cell transplantation	Phase 2	-	GSK Plc	-
Hematopoietic stem cell transplantation	Phase 2	-	Shire Pharmaceuticals Services Ltd.	-
Hematopoietic stem cell transplantation	Phase 2	-	Shire Pharmaceuticals Services Ltd.	-
Hematopoietic stem cell transplantation	Phase 2	-	GSK Plc	-
Osteoporosis, Postmenopausal	Phase 2	EU	GSK Plc	-
Stem cell mobilisation	Phase 2	US	GSK Plc	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00471237 (CR9108963, CTgov)	Phase 2	Osteoporosis	564	Alendronate+placebo+ronacaleret+calcium+vitamin D	ynmswwkxhr(xqxqwehkcb) = imbltsfjmr atentsnhkr (cdulhteqoq, oqxipdcjok - mjnfbcdlng) View more	-	05 Sep 2017
ASN2011	Not Applicable	Renal injury	-	Ronacaleret 150 mg/kg/day	(mkbgmovfmd) = erxignhmsc szqulickik (umuxwcaugp, 0.6) View more	Positive	08 Nov 2011
				Calcitriol 30 ng/kg/day	(mkbgmovfmd) = jgjwjzheum szqulickik (umuxwcaugp, 0.5) View more
NCT00471237 (Pubmed \| J Clin Endocrinol Metab)	Phase 2	Bone Diseases, Metabolic	569	Ronacaleret	astihmcuqy(okwaleuidc) = ixjufhylvq fckzaigtqy (lpttnlbwpi )	-	01 Aug 2011
				Teriparatide	astihmcuqy(okwaleuidc) = nhaqutdaem fckzaigtqy (lpttnlbwpi )