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A Phase I Study of the Biomarker Response and Pharmacokinetic Profile of Thyrotropin-Releasing Hormone (TRH) Administered as a Sublingual Tablet
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16-220-1
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A Phase I Study of the Biomarker Response and Pharmacokinetic Profile of Thyrotropin-Releasing Hormone (TRH) Administered as a Sublingual Tablet
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Dr. Jonathan Covault
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This present study will compare effects (both good and bad) of two doses of sublingual Thyrotropin releasing hormone (TRH) tablets, to the standard i.v. dose of TRH and, for comparison, to a tablet of TRH that is meant to be swallowed rather than dissolved under the tongue. The two primary measures that will be evaluated in healthy volunteers are:
1. The classic response to TRH, which is measured as the increase in the hormone thyrotropin (TSH) from baseline levels to the peak level achieved following administration of TRH.
2. The pharmacokinetic (the way the body absorbs, distributes and gets rid of a drug) profile of TRH in blood plasma after sublingual tablet administration.
Additional goals of the present study include assessment of selected behavioral measures after TRH administration by the sublingual, i.v. and regular oral tablet routes, determination of changes in selected measures of immune system function, and evaluation of physiological (pulse, blood pressure and EKG) measures and reports of any side effects observed following administration of the different TRH formulations. Objectives:
1. To compare the biomarker response (i.e., the TSH response) after administration of TRH by intravenous injection (0.5 mg), after two doses of a sublingual TRH tablet formulation (0.5 mg and 5 mg), and after administration of a standard oral tablet formulation of TRH (5 mg).
2. To determine the pharmacokinetic profile of TRH administered by intravenous, sublingual tablet and oral tablet formulations, as assessed by determination of plasma TRH concentration at specified times over a 180 minute period of evaluation.
3. To evaluate the tolerability of TRH administered by intravenous, sublingual and standard oral tablet formulations as determined by assessment of vital signs, laboratory measures and subject reports of adverse effects.
4. To collect samples to carry out assessments of effects of TRH administered by intravenous, sublingual tablet and oral tablet formulations on selected indices of immune system function and behavioral responses for which future funding is being sought.
Study Hypothesis:
The central hypothesis of the present study is that a unique sublingual tablet formulation of TRH, developed by Dr. Bogner at the UConn School of Pharmacy and demonstrated to show promising enhancement of lipophilicity based on in vitro laboratory assessments, will provide suitable bioavailability when administered to normal human subjects. For appropriately selected compounds, sublingual administration can avoid problems related to poor absorption in the GI tract, metabolism by enzymes at the level of the intestinal membrane wall, and the hepatic first-pass effect (Goswami et al., 2008). Compounds with suitable lipophilicity can permeate the sublingual epithelial cell layer and reach the underlying connective tissue layer, which is highly vascularized. Via this route, appropriately selected compounds can gain efficient access to the general circulation and demonstrate good bioavailability in plasma, thus supporting therapeutic application after sublingual tablet administration. Previous in vitro studies in Dr. Bogner's laboratory documented a greater than 100-fold increase in lipophilicity for the novel TRH formulation, thus predicting the likelihood of suitable bioavailability associated with sublingual tablet administration in human subjects. The proposed Phase I study will document that administration of the optimized sublingual TRH tablet formulation produces the classic biomarker response to TRH and will also delineate the pharmacokinetic profile of TRH in plasma following sublingual tablet administration.
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Brain, Spinal Cord and Nervous System
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Rare Diseases
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Check with study contact
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Patricia Keltonic. Telephone: (860) 679-4116. Email: keltonic@uchc.edu or Galina Prpich. Telephone: 860-679-7539 Email: prpich@uchc.edu or Mariola Borla-smialek. Telephone: (860) 679-2996. Email: smialek@uchc.edu
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Enrolling/recruiting. For current recruitment status, please check with study contact.
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