A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate

Zdravković, Milan; Olsen, Anette Kristensen; Christiansen, Tina; Schulz, Rainer; Taub, Mitchell E.; Thomsen, Mikael S.; Rasmussen, Michael Højby; Ilondo, M M

doi:10.1007/s00228-002-0539-1

Cited by 14 publications

(8 citation statements)

References 12 publications

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“…The midazolam (generic midazolam supplied by Novartis Germany AG) dose was 5 mg given orally as solution, which is below the recommended sedative dose range of 7.5 to 15 mg but within the 2‐ to 8‐mg range of midazolam doses used to test CYP3A4/5 activity 12 – 14 . The solution was prepared from an intravenous dosing solution diluted in 30 mL of water.…”

Section: Methodsmentioning

confidence: 99%

Investigation of the Pharmacokinetic Interactions of Deferasirox, a Once‐Daily Oral Iron Chelator, With Midazolam, Rifampin, and Repaglinide in Healthy Volunteers

Skerjanec

Wang

Maren

et al. 2010

The Journal of Clinical Pharma

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Deferasirox, a newly developed iron chelator, was coadministered orally with either a known inducer of drug metabolism or with cosubstrates for cytochrome P450 (CYP) to characterize the potential for drug-drug interactions. In the induction assessment, single-dose deferasirox pharmacokinetics were obtained in the presence and absence of a repeated-dose regimen of rifampin. In the CYP3A interaction evaluation, midazolam and its active hydroxylated metabolite were assessed after single doses of midazolam in the presence and absence of steady-state concentrations of deferasirox. To test for interaction at the level of CPY2C8, single-dose repaglinide pharmacokinetics/pharmacodynamics were determined with and without repeated-dose administration of deferasirox. After rifampin, a significant reduction (44%) in plasma exposure (AUC) to deferasirox was observed. Upon coadministration of midazolam, there was a modest reduction of up to 22% in midazolam exposure (AUC, C(max)), suggesting a modest induction of CYP3A4/5 by deferasirox. Def erasirox caused increases in repaglinide plasma C(max) and AUC of 1.5-fold to over 2-fold, respectively, with little change in blood glucose measures. Specific patient prescribing recommendations were established when coadministering deferasirox with midazolam, repaglinide, and rifampin. These recommendations may also apply to other substrates of CYP3A4/5 and CYP2C8 or potent inducers of glucuronidation.

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Section: Methodsmentioning

confidence: 99%

Investigation of the Pharmacokinetic Interactions of Deferasirox, a Once‐Daily Oral Iron Chelator, With Midazolam, Rifampin, and Repaglinide in Healthy Volunteers

Skerjanec

Wang

Maren

et al. 2010

The Journal of Clinical Pharma

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“…Compared with other CYP3A probes, e.g. erythromycin, midazolam is not a substrate of P-glycoprotein (Takano et al, 1998), but a pure CYP3A substrate, neither an inhibitor or inducer of CYP3A, which makes it more suitable for evaluating in vivo drug-drug interaction or phenotyping (Lam et al, 2003;Ma et al, 2006;Streetman et al, 2000Streetman et al, , 2001Zdravkovic et al, 2003). The other advantages of using midazolam included a strong correlation between in vivo midazolam CL and in vitro hepatic CYP3A content (r = 0.93, p < 0.01) and the short elimination half-life after both i.v.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of midazolam and 1′‐hydroxymidazolam in human plasma by liquid chromatography with tandem mass spectrometry

Li¹,

Luo²,

Smith³

et al. 2007

Biomedical Chromatography

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A sensitive and simple liquid chromatography-tandem mass spectrometry method for the determination of midazolam and 1'-hydroxymidazolam in human plasma has been developed and validated with a dynamic range of 0.1-250 ng/mL. The analysis was based on semi-automated liquid-liquid extraction followed by evaporation of the extraction solvent, reconstitution and chromatography on a reversed-phase C(18) column. The mobile phase consists of 5 mm ammonium acetate and methanol and runs in gradient at a flow rate of 0.25 mL/min with column temperature of approximately 20 degrees C. The entire column effluent was transferred into the LC-MS/MS interface operated in positive electrospray ionization mode. The chromatographic run time was 4.3 min per injection, with retention times for midazolam, 1'-hydroxymidazolaml and the internal standard, triazolam, of 2.5, 2.3 and 2.1 min, respectively. The intra-day and inter-day precision (RSD %) and accuracy (bias %) of the quality control samples were <15.0% and within +/-13%, respectively. The current method has been applied to a clinical drug-drug interaction study in human.

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“…Tabimorelin failed to show beneficial effects on GH release in adult patients with GHD in a Phase II trial . Furthermore, tabimorelin was reported to inhibit CYP3A4, which may lead to unexpected side effects . To overcome this drawback, Novo Nordisk has developed some compounds derived from tabimorelin, such as NNC‐26‐1167, although these have not been evaluated in clinical trials so far.…”

Section: Results Of Major Clinical Trials and Current Statusmentioning

confidence: 99%

“…Tabimorelin increased GH release as well as production of insulin‐like growth factor‐1 (IGF‐1) and IGF binding protein 3 (IGFBP‐3) with subtle changes in adrenocorticotropic hormone, cortisol, and prolactin in healthy male subjects, while only 11% of patients with GHD responding to tabimorelin with a peak GH concentration >5 μg/L . Furthermore, tabimorelin was reported to inhibit CYP3A4, which may lead to unexpected side effects . To overcome this drawback, Novo Nordisk has developed some compounds derived from tabimorelin including NNC‐26‐1167, although these have never been tested in clinical studies.…”

Section: Pharmacologymentioning

confidence: 99%

Growth hormone secretagogues: history, mechanism of action, and clinical development

Ishida

Saitoh

Ebner

et al. 2020

JCSM Rapid Communications

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Growth hormone secretagogues (GHSs) are a generic term to describe compounds that increase growth hormone (GH) release. GHSs include agonists of the growth hormone secretagogue receptor (GHS‐R), whose natural ligand is ghrelin, and agonists of the growth hormone‐releasing hormone (GHRH) receptor, to which the GHRH binds as a native ligand. Several GHSs have been developed with a view to treating or diagnosing of GH deficiency, which causes growth retardation, gastrointestinal dysfunction, and altered body composition, in parallel with extensive research to identify GHRH, GHS‐R, and ghrelin. This review will focus on the research history and the pharmacology of each GHS, which reached randomized clinical trials. Furthermore, we will highlight the publicly disclosed clinical trials regarding GHSs.

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A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate

Abstract: This study shows that administration of NN703 and midazolam, a CYP3A4 substrate, leads to a significant increase in exposure of midazolam. This is consistent with NN703 inhibition of CYP3A4 activity.

Cited by 14 publications

References 12 publications

Investigation of the Pharmacokinetic Interactions of Deferasirox, a Once‐Daily Oral Iron Chelator, With Midazolam, Rifampin, and Repaglinide in Healthy Volunteers

Investigation of the Pharmacokinetic Interactions of Deferasirox, a Once‐Daily Oral Iron Chelator, With Midazolam, Rifampin, and Repaglinide in Healthy Volunteers

Simultaneous determination of midazolam and 1′‐hydroxymidazolam in human plasma by liquid chromatography with tandem mass spectrometry

Growth hormone secretagogues: history, mechanism of action, and clinical development

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