Success in drugs-interaction projects depends on the effective application of these methods to datasets generated following optimal experimental conditions. We believe that design is critical. We count with a large experience in setting up combination experiments that are always a result of a collaborative work carried out together with our customers.
Drug interaction study phases
- Design and setup. Aligned with project goals this critical initial phase is aimed to determine the optimal condition of the study.
- Drug concentrations:
- Single Drug. If not available, single drugs are tested in advance to select the most suitable concentration for mixtures.
- Combination. Based on single drugs EC50s, a combination matrix of concentrations is defined to have the more informative and reliable data to fit the complex surface interaction model.
- Drug concentrations:
- Incubation times.
- Others: compound management, controls, plate design, etc.
- Experimental phase. According to the defined design and following quality control criteria.
- Analytical methods are applied, and results are shown in fully customized figures and visualizations.
- Deliverables: Pdf report, Excel data tables and Tibco Spotfire dynamic reports in customized applications running on a secure dedicated server.
Analytical procedures for drugs interaction measurement
Individual pre-fits of each drug at every tested concentration of the other are generated resulting in parallel dose-response curves.
Later, such fitting functions are used for feeding complex interaction 3D surface model with expected values coming out from the interpolation of tested dose of each drug in the corresponding fitting functions. Thus, we overcame variability due to high residual error and improved the results.
Calculation methods may use either the observed or the expected values described above as input data, and can be divided in 3 categories:
- Calculated indexes based on ratios of concentrations that provide the same effect with each drug alone or combined with the other (Combination Index and Loewe)
- Differences between observed and expected values from a reference additivity surface (Bliss and ZIP)
- Estimated parameters from a regression analysis to a complex surface model MuSyC (Multidimensional Synergy of Combinations ) that integrates and unifies benefits from previous methods.
- R. Greco, G. Bravo, and J. C. Parsons. The search for synergy: a critical review from a response surface perspective. Pharmacol Rev, vol. 47, no. 2, p. 331, (1995).
- Meyer, C. T. et al. Quantifying drug combination synergy along potency and efficacy axes. Cell Syst. 8, 97–108 (2019).
- Wooten, D. J., Meyer, C. T., Vito Quaranta, A. L. R. L. & Lope, C. F. Musyc is a consensus framework that unifies multi-drug synergy metrics for combinatorial drug discovery. Nat. Commun. 12, 1–16 (2021)