Bioequivalence and Bioavailability Forum

Dear Chirag!

❝ For collection of ambulatory samples we have in-house limits of ± 2 hrs from the scheduled time.

Most CROs allow for flexible deviations based on the sampling interval; 5% of the shorter of the two time intervals surrounding the sample are suggested.^* Example:
scheduled interval shorter  5%   h:mm
   16        8                       
   24       12         8    0.4  0:24
   36       12        12    0.6  0:36
   48       24        12    0.6  0:36
   72       48        24    1.2  0:72
  120       48                       
For the last sample I would allow 5% of the last interval = 0:72. ±5% doesn’t make sense, IMHO. A subject may arrive late (positive deviation), but it should be pointed out in the ICF that if somebody shows up early he/she has to await the scheduled time point (see also the quote in this post). Generally I’m in favour of the lin-up/log-down trapezoidal rule for the calculation of AUC because the linear trapezoidal rule gives a positive bias in the elimination phase.

❝ The question is, how long the ambulatory sample can be collected beyond the allowed deviation of 2 hrs.

Tricky question. I would not send the subject home without taking a sample. State in the protocol what you would do in such a case. For AUC_∞ it shouldn’t be much of a problem. For AUC₇₂ you might consider using an estimated ₇₂ (given you have a reliable estimate of λ_z). With your current pro­ce­dure you might end up comparing AUC₇₀ to AUC₇₄; a case of apples-and-oranges statistics.
If you are concerned about the regulatory acceptance of the data due to a large deviation, you may exclude the subject from the assessment of AUC, but still keep the data of C_max (which is likely more variable and therefore more important).

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• G Pabst
  Deviations in sampling times (Chapter 5.5)
  in: W Cawello (ed), Parameters for Compartment-free Pharmacokinetics – Standardisation of Study Design, Data Analysis and Reporting
  Shaker Verlag, Aachen 2003, pp 78–79
  ISBN 3-8265-4767-5