Bioequivalence and Bioavailability Forum

❝ The researcher wants me to estimate the PK parameters of the single dose from the blood concentrations of multiple dosing.

❝ is this possible?

1) Do you know the half-life of this drug?
2) Was there drug accumulation?
3) Is the elimination kinetic complicated (i.e, biphasic elimination)

J

Hi Jeewaka,

❝ […] a PK study where multiple doses are given […] to estimate the PK parameters of the single dose from the blood concentrations of multiple dosing.

❝ is this possible?

Not easy. You could only perform modeling assuming (!) linear PK (clearance will not change over time). Given your sampling schedule I guess it will be very difficult to model anything beyond a simple one compartment model (e.g., ≥2, Michaelis-Menten elimination, circadian rhythms influencing the PK after the morning/evening doses, saturation of metabolising enzymes after accumulation, auto-induction or inhibition …). Even then you get only PK parameters describing the overall behaviour of the drug – not “of the single dose”. See this example of auto-induction (slides 21–22). With your sampling schedule I guess it would be impossible.* Next time I strongly suggest to sample at the pre-doses to get an idea. Much better to sample after the first dose as well.

   The combination of some data and an aching desire
for an answer does not ensure that a reasonable answer
can be extracted from a given body of data.    John W. Tukey

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• You can come up with a couple of models assuming something (i.e., to avoid over-parameterisation). Very difficult to decide which one describes the PK “best”.

Assuming you are in steady-state on day 15 (and linear PK/no induction, of course), the AUC over the dosing interval on Day 15 should equal the AUC0-oo of a single dose.

To estimate the Cmax following single-dose you would need to sample on Day 1 imho...