PEG-Calcimimetic Conjugates for Extended Half-Life
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Solution Overview
Problem
Current calcimimetics, such as cinacalcet, have drawbacks including drug-drug interactions due to CYP2D6 inhibition, require daily administration, and can cause hypocalcemia and other risks associated with a short half-life, limiting their therapeutic convenience and safety.
Innovation Solution
Development of calcimimetic compounds covalently attached to a poly(alkylene oxide) oligomer via a releasable linkage, which includes amino acids, allowing for a stable or bioavailable form with a longer half-life and reduced side effects, enabling less frequent dosing and improved bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If cinacalcet is administered daily, then therapeutic effect is maintained, but patient convenience is reduced and compliance is challenging
Solution Approach 1:
The patent modifies the molecular parameters of cinacalcet by conjugating it to polyethylene glycol (PEG) chains of different lengths. This changes the pharmacokinetic parameters including half-life, clearance, and bioavailability, enabling once-weekly dosing while maintaining therapeutic effect. The PEG conjugation alters the drug's physical-chemical properties to achieve prolonged duration of action.
2Reliability
If cinacalcet is used to treat hyperparathyroidism, then parathyroid hormone secretion is reduced, but drug-drug interactions occur due to CYP2D6 inhibition
Solution Approach 1:
The PEG chain acts as an intermediary that separates the calcimimetic activity from the CYP2D6 inhibition. The conjugated PEG-cinacalcet maintains the therapeutic effect at the calcium-sensing receptor while the PEG moiety modifies the drug's interaction with CYP2D6, reducing harmful drug-drug interactions. The intermediary PEG structure allows selective retention of beneficial effects while mitigating adverse interactions.
3Reliability
If cinacalcet is administered at standard doses, then parathyroid hormone levels are lowered, but hypocalcemia and other risks occur
Solution Approach 1:
The PEG conjugation changes the pharmacokinetic parameters of cinacalcet, resulting in prolonged half-life and altered concentration-time profile. This allows for reduced dosing frequency and adjusted dosing magnitude that maintains therapeutic efficacy while reducing peak concentrations that cause hypocalcemia. The parameter modification enables safer dosing regimens with lower risk of adverse effects.
Data Source
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AI summary
The invention relates to (among other things) oligomer-calcimimetic conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over previously administered compounds.