Rational approach to the clinical protocol design for drug combinations: a review.
Based on the median-effect equation of Chou and the combination index (CI) equation of Chou-Talalay, a computer software for automated dose-effect analysis has been developed. This method provides quantitation of synergism (CI < 1) and antagonism (CI > 1) at different dose and effect levels. Therefore, it allows the selection of the best pair (or triplet) of combination, optimal combination ratio, and the best schedule of treatment. These analyses has been shown to be useful for the clinical protocol design. (Chang et al. Cancer Res. 45: 2434-2439, 1985). The user-friendly computer program also gives dose-reduction index (DRI) which determines how many fold of dose-reduction is allowed for each drug in synergistic combinations. Dose reduction leads to reduced toxicity while maintaining the desired efficacy (Chou et al. Encyclopedia of Human Biology 2:675-683, 1997; Encyclopedia of Cancer 1:368-379, 1997). The Chou-Talalay method distincts from all other methods by the fact that it not only takes into account the "potency" but also the "shape" of dose-effect curves of each drug and their combinations (Chou & Hayball, CalcuSyn for Windows, Biosoft, Cambridge UK, 1996). This method has been applied in combination of anticancer agents, anti-HIV agents, purging leukemic cells for autologous bone marrow transplantation (Chang et al. Cancer Res. 47:119-122, 1987) and combination of immunosuppressants for organs transplants. Specific examples of the theoretical equations, the median-effect plot, the CI plot, the isobologram, and the polygonogram are illustrated.
Chang
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Department of Pediatrics, Kaohsiung Medical University, Kaohsiung, Taiwan 807, R.O.C.
Chou
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D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002985:Clinical Protocols; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D008956:Models, Chemical