Comparison of drug combinations for a pair of antitumor agents in vitro, in vivo, and in clinics on the theoretical and practical perspectives
| In Vitro | In Vivo | ||
|---|---|---|---|
| In Animals | In Patients | ||
| Dose range | 0, 1/8, ¼, ½, 1, 2, and 4 of IC50 | 0, ¼, ½, 1, and 2 of ED50 | 0, 0.25, 0.5, and 0.75 of MTD |
| Dose density | 5–8 | 3–5 | 2–3 |
| Population size | 106 | 50–80 | 50–200 |
| Population variability | Uniform | Inbred | Vary |
| r value required | >0.95 | >0.90 | Not certain (>0.80?) |
| Prevalent m value | 0.8–1.5 | 0.8–3.0 | Not known (0.8–3.0?) |
| Conclusions available | Quantitative synergism or antagonism | Quantitative synergism or antagonism | Net therapeutic benefit for better or for worsea |
| Method of assessment | Combination index, isobologram, dose-reduction index | Combination index, isobologram, dose-reduction index | Comparing with each drug alone at or near MTD; balance between efficacy and toxicity; synergism cannot be determined |
| Length of time required | 1–2 weeks | 2–3 months | 1–2 yearsa |
| Flexibility of study | High | Low | Limiteda |
| Death as endpoint for toxicity | Always | Frequently | Not alloweda |
| Ethical and liability considerations | None | Low | Higha |
↵ a An open issue: Is it ethically acceptable or scientifically correct to conduct drug combination trials in humans without first doing drug combination studies in vitro or in animals