Long-Circulating Vasoactive 1,18-Octadecanedioic Acid-Terlipressin Conjugate

Area of Science:

• Pharmacology
• Hepatology
• Drug Development

Background:

• Hepatorenal syndrome (HRS) is a severe complication of end-stage liver disease with limited treatment options.
• Terlipressin (TP) is a vasopressin analogue used for HRS, but it has short circulation half-lives and potential side effects.
• Recent US approval of TP highlights the need for improved HRS therapies.

Purpose of the Study:

• To develop and evaluate a novel conjugate of terlipressin (TP) with 1,18-octadecanedioic acid (ODDA).
• To assess the noncovalent albumin-binding properties and therapeutic potential of ODDA-TP.
• To compare the efficacy, pharmacokinetics, and safety of ODDA-TP against TP alone.

Main Methods:

• Synthesis of the 1,18-octadecanedioic acid (ODDA) conjugate of terlipressin (ODDA-TP).
• In vitro studies assessing cellular receptor activation and plasma stability.
• In vivo pharmacokinetic and safety evaluations in rat models.

Main Results:

• ODDA-TP demonstrated enhanced stability in plasma and superior in vitro cellular receptor activation compared to TP.
• Pharmacokinetic studies revealed an elimination half-life 20 times longer for ODDA-TP than for TP.
• ODDA-TP exhibited a superior safety profile in preclinical evaluations.

Conclusions:

• The ODDA-TP conjugate offers a promising new therapeutic strategy for managing hepatorenal syndrome.
• Albumin binding via ODDA conjugation significantly improves TP's pharmacokinetic and safety profile.
• ODDA-TP represents a potential advancement in treating life-threatening liver disease complications.