One major challenge in drug development is achieving the optimal residence time for a drug – often measured by its “half-life” in the body. The half-life of a drug is rarely too long, but often too short. When the half-life is short the drug must either be administered frequently or in very high doses so it lasts longer. Very frequent administration is inconvenient for the patient and leads to non-compliance; high doses lead to high drug level spikes – a high Cmax – and large excursions from high-to-low drug levels – peak/trough or Cmax/Cmin – that can cause toxicities. The ideal drug has an appropriately long half-life, low Cmax and low Cmax/Cmin.
Prolynx has a novel, proprietary technology for half-life extension of peptide, protein and small molecule drugs. It can achieve a long half-life and low Cmax for a drug that normally has a short half-life. First, we developed a library of “self-cleaving” β-eliminative linkers that are programmed to release a native, unmodified drug from a carrier over periods of hours to years. Each linker in the library contains a specific “modulator” that controls the drug release rate independent of enzymes or the species the system is used in. Second, we developed technology to use these linkers for releasable attachment of drugs to macromolecular carriers. In one format, the carrier is a circulating macromolecule, such as polyethylene glycol (PEG), that is administered by s.c. or i.v injection; with this format, we can usually extend the drug’s half-life to about one week – the limit dictated by the elimination of the circulating conjugate.
The second carrier format is a porous PEG-hydrogel fabricated as 40µm microspheres and injected as subcutaneous depots. Here, the drug is covalently tethered to the microspheres by a releasable linker, and is slowly released to give a half-life ranging from about a week to a month. Slower-cleaving linkers are also installed in the polymer crosslinks so gel degradation can be balanced with drug release.
ProLynx has numerous examples of half-life extension of short-lived therapeutics to periods of weeks to months. In addition to small molecules and peptides, we have recently shown the same technology can be applied to larger proteins – in one case increasing the half-life of a 25 kDa single chain antibody fragment to that typically seen with monoclonal antibodies. We are interested in applying our technology to extend half-lives of proprietary drugs of pharma companies, and also seeking collaborations on development of ProLynx’s long-lasting drug conjugates.
Please see our current Publications for more information.
Below is a calculator that estimates how the Prolynx hydrogel system will perform in half-life extension of a particular drug when administered subcutaneously. As inputs, the estimations require the MW of the drug, its pharmacokinetic parameters (t1/2,β, Vd, fractional bioavailability (F)) and the target minimum therapeutic concentration Cmin in plasma/serum of the species used. After choosing a desired dose interval of either one week or one month, the calculator estimates the steady-state dose required to maintain the target concentration Cmin and the Cmax and Cmax/Cmin that result. If the steady-state dose required is higher than the capacity of the hydrogel, an alert is given.
The calculator also provides the dose required to achieve a target drug concentration (entered as Cmin) at the end of the single dose interval entered above.
Desired Dosing Interval:
Drug Molecular Weight (g/mol):
Drug Fractional Bioavailability:
Drug Elimination t1/2,β (hours):
Volume of Distribution (L/kg):
Body Weight (kg):
|Steady State Calculated Parameters|
|Single Dose Calculated Parameters|
|Drug Molecular Weight||1019|
|Drug Fractional Bioavailability||1|
|Drug Elimination t1/2,β||0.5|
|Volume of Distribution||0.05|