Is it more important to match post-treatment activity profiles rather than crude drug half-lives? (A) Two drugs in a CT have broadly similar half-lives. (B) The two drugs in the CT have very different PD profiles. (C) Multiplying concentration profiles post-treatment (shown in (A)) by the dose-effect relationships (shown in (B)) gives a drug activity profile post-treatment; as can be seen these profiles are very different leading one drug to persist as a vulnerable monotherapy. (D) A practical example of this effect: the drugs appear to be perfectly ‘matched’ with similar half-lives (as in (A)) and identical kill rates (both assumed to have the ‘blue’ profile shown in (B)), but toxicity concerns means the ‘blue’ drug must be given at 2.5-fold lower dosages, leading to a severe mismatch in drug activity profiles. Note the similarities between the results shown in (C) and (D). [Figure 2 was constructed using simple PK/PD models and their corresponding equations[26, 29]. Parameter values for the two drugs are as follows: Dose is 11 mg/kg for both in (A), (B) and (C) and 11 mg/kg for ‘blue’ and 27.5 mg/kg for ‘red’ in (D); volume of distribution is 150 L/kg; elimination rate per day is 0.03 for ‘blue’ and 0.032 for ‘red’ (equivalent to half-lives of 23.1 and 21.7 days, respectively); maximal drug-killing rate per day (Vmax) is 3.45; IC50 is 0.044 mg/L for ‘blue’ and 0.0176 mg/L for ‘red’ in (A),(B) and (C) and 0.044 mg/L for both in (D); slope of dose-response curve (n) is 6].