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