Unknown Dosing Histories

Another possibility for modeling unknown dosing intervals is to measure the trough level at the days that the patients undergo blood sampling for PK analyses, and use this trough level as starting point for the current dose. As an example, assume a drug that behaves according to a one-compartment model, and is given orally three times a day for 30 days. Then, the morning plasma concentration-time curve at any day that the patients are being sampled can be described as follows: C = C0*EXP(-Ke*T) + (D/V)*(Ka*(Ka-Ke))*(EXP(-Ke*T)-EXP(-Ka*T)) where C0 is the trough level measured before the morning dose at a particular sampling day. This equation assumes that the absorption phase from the previous dose died out by the time that the next dose is administered. An approach that I have used successfully is to consider C0 as another parameter to be estimated. This is helpful if you do not have a trough level measurement, or if you want to allow some flexibility by incorporating error on the through level, which is usually the case since that level may be low and difficult to measure. Besides, you can get estimates of population mean and variability on C0. Another advantage of this approach is that it allows for diurnal variations. In the case that I used this, the morning trough levels were higher in the morning than during the day (assuming equally spaced dosing intervals). However, since blood sampling during the night was difficult, we couldn't really find out what was going on during the night (change in CL or Ka?), and implement this in the model. By making C0 a fixed effect, we eliminated that problem.