Celator’s proprietary technology platform, CombiPlex, is positioned to introduce an entirely new medical standard for combining chemotherapies. Incorporating high throughput screening, mathematical algorithms for synergy analysis and advanced drug delivery technologies, CombiPlex makes it possible to identify, deliver and maintain pre-specified synergistic drug ratios with the goal of improving clinical outcomes.
About Combination Chemotherapy
For most patients with cancer, standard of care usually involves the use of combinations of individual drugs. This strategy is based on the proven premise that cancer cells can be destroyed more effectively by combining drugs with different and complementary mechanisms of action. While the range of drugs used in combination has expanded, the process used to develop these drug regimens has not changed substantially since this strategy was first introduced in the mid-1900s.
Because many cancer drugs are toxic at certain dosing levels, clinicians typically select individual drugs that do not have overlapping toxicities. Drugs are combined at their “maximum tolerated dose” (MTD), the dose at which a drug has been shown to deliver maximum benefit balanced by an acceptable level of toxicity.
This approach assumes that drugs combined at their individual MTD will result in therapies with maximum clinical benefit in patients. We now know that in many cases this is likely incorrectly for two important reasons:
- Preclinical research has shown that dosing individual drugs at MTD does not always produce combination drug regimens that deliver maximum efficacy. A different ratio of the drugs may be synergistic, additive or antagonistic.
- Combining drugs at their synergistic ratio is not enough. Without a technology to maintain that ratio in patients, the individual drugs will be metabolized independently and at different rates. As a result, the ratio of drugs will change over time and may negatively impact their effectiveness.
Understanding the Impact of Drug Ratios
Researchers at Celator were among the first to recognize the critical role that drug ratios can play when combining drugs. The results of multiple in vitro and preclinical studies have demonstrated that the molar ratios of drugs used can have a significant impact on the overall efficacy and safety of combination chemotherapy.
Drugs used to treat cancer typically work by triggering cellular “death pathways” that target and destroy cancer cells. Researchers now recognize that the same drugs combined at different ratios can result in distinctly varied efficacy and safety profiles. Depending on the ratio of the combined drugs, the outcome can be:
- Additive – the anti-cancer effect of the drugs is equal to the sum of the individual drugs.
- Synergistic – the anti-cancer effect of the drugs is greater than the sum of the individual drugs.
- Antagonistic – the anti-cancer effect of the drugs is less than the sum of the individual drugs.
Based on the concept of synergistic ratios, Celator has identified a number of ratio-dependent chemotherapy drug combinations. In this process, CombiPlex technology screens and measures the synergistic benefit of drug ratios in panels of tumor cells. In the example below, CombiPlex was used to screen combinations of the drugs cytarabine and daunorubicin. The results of this screening show the ratios of cytarabine and daunorubicin that are synergistic (green), additive (yellow) or antagonistic (red) in targeting different cell lines and tumor types.
The next graph shows the effectiveness of combining the drugs irinotecan HCI and floxuridine at different ratios in in vitro tumor models. The combination of irinotecan HCI and floxuridine shows significant synergy when the drugs are combined at a 1:1 molar ratio. When the molar ratio is changed to 5:1, efficacy is sharply reduced, with one cell line showing reduced synergy and the other two showing antagonism. When the ratio is changed to 10:1, the antagonism is even greater.
Celator’s research suggests that many drug combinations that are known to be effective in treating cancer could have improved clinical benefit based on the concept of synergistic drug ratios. CombiPlex makes it possible for the first time to identify the ratio of drugs that will deliver synergistic benefit, lock this drug ratio in a drug delivery vehicle and maintain the synergistic ratio in patients. The company’s lead product candidates are based on approved and widely used chemotherapeutic drugs and the goal is to improve the clinical benefit of these drugs.
The CombiPlex Advantage: Locking in a Synergistic Drug Ratio
A key advantage of the CombiPlex technology platform is the ability to overcome the inherently dissimilar pharmacokinetics of individual drugs. This makes it possible to maintain synergistic ratios after administration to patients. The technology’s advanced particulate delivery system uses liposomes, polymers, and nanotechnologies specially formulated to control the distinct pharmacokinetics of individual drugs.
Through extensive research, Celator has identified a range of drug delivery carriers able to encapsulate drugs at synergistic ratios. After infusion, the pharmacokinetics of the drugs are controlled by the carrier, making it possible to sustain a synergistic ratio over an extended period of time.
Creating a New Generation of Products
Based on the broad potential applications of the CombiPlex technology platform, Celator could evaluate an expansive range of product candidates. The company currently has two products in clinical development:
Other product candidates are at various stages of preclinical development.
Initially, Celator’s development programs involved the use of approved drugs with proven anti-cancer activity. However, the CombiPlex technology platform has the potential to be applied to both proven drugs or new compounds in development. Celator is actively pursuing broad patent protection. Issued patents and pending patent applications include CombiPlex, lipid-based carrier formulations, novel peptide, polymer and lipid-polymer hybrid technologies and product-specific clinical use as well as composition and method. This could result in a potentially expansive range of product opportunities for the company and its collaborators.
Ratiometric Dosing: A Promising New Approach to Developing Drug Combinations
This approach identifies a synergistic ratio of two or more drugs and locks the ratio in a drug delivery vehicle, to deliver and maintain the synergistic ratio through pharmacokinetic control.
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