The Benefits and Challenges of PEGylating Small Molecules - Pharmaceutical Technology

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The Benefits and Challenges of PEGylating Small Molecules
Polyethylene glycol (PEG) conjugation is a highly effective technical and commercial strategy to develop macromolecules. The authors explain the benefits and process of PEGylation and how it may be applied to small molecules.

Pharmaceutical Technology

Examples of PEGylated small molecules in development

Small-molecule drugs in development can be coupled to large-molecular-weight PEGs as prodrugs. The potential benefits of using large-molecular-weight PEGs as prodrugs are:

  • Increased circulating half life
  • Modified biodistribution
  • Improved safety
  • Enhanced water solubility.

A molecule that would particularly benefit from this approach is irinotecan. Irinotecan is a $1-billion oncolytic drug with suboptimal pharmacokinetics that treats colorectal cancer and other solid tumors. Irinotecan is cleared from the body within a few hours, and its short half life necessitates high doses to achieve therapeutic drug levels. The drug consequently causes many side effects, including neutropenia and severe diarrhea. Dose reductions for patients who cannot tolerate the side effects compromise the drug's therapeutic efficacy.

The goal of PEGylation is to increase the half life and exposure profiles of irinotecan to improve its efficacy and increase the maximum tolerated dose (MTD). These changes ultimately could improve care, outcomes, and patients' quality of life. The strategy to achieve these benefits uses a large-molecular-weight PEG with a linkage to irinotecan that is gradually cleaved to release the parent compound.

Figure 1: The effects of irinotecan and PEG-irinotecan on the growth of irinotecan-resistant human colon tumor (HT29) in a mouse xenograft model. (FIGURES ARE COURTESY OF THE AUTHORS.)
Preclinical comparisons of PEG–irinotecan with irinotecan demonstrated the former's superior efficacy in three mouse xenograft models (irinotecan-resistant colon cancer, breast cancer, and lung cancer). PEG–irinotecan produced a 2–3-log increase in exposure to irinotecan's active metabolite (SN-38) in colorectal tumors in mice, and reduced neutroepenia and diarrhea and achieved a higher MTD in rats and dogs (see Figures 1–3). Animal data also show a more sustained level of SN-38 than that achieved with native irinotecan as a consequence of PEG–irinotecan's slower release and longer half life.

Figure 2: Concentration of tumor SN38 in mice with HT29 tumors. (FIGURES ARE COURTESY OF THE AUTHORS.)
A similar effect was seen in humans. In Phase I clinical trials, PEG–irinotecan demonstrated reduced neutropenia in the active-dose range in addition to some preliminary antitumor activity. PEG–irinotecan is currently in Phase II clinical trials.

Figure 3: The effect of irinotecan and PEG-irinotecan on neutropenia in animals. (FIGURES ARE COURTESY OF THE AUTHORS.)
In addition to irinotecan, the large molecular weight PEG prodrug approach is being applied to docetaxel, a $2.2 billion drug used to treat solid tumors. This drug produces dose-limiting neutropenia. Preclinical studies show antitumor activity in xenograft models of prostate, breast, and lung cancers as well as superior efficacy in taxane-resistant cell lines. PEG–docetaxel is currently in development.

Small-molecule drugs can also be coupled to small-molecular-weight PEGs for CNS exclusion. The potential benefits of small molecular weight PEG technology are:

  • Modified biodistribution
  • Decreased transport
  • Improved oral bioavailability
  • Modified metabolism.


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