Dear all,
I set up workflows to calculate partial AUCs by different methods.
- Cut at the individual tmax.
Might be awful! - Cut at a pre-specified time.
Recommended by the FDA (‘old’ methlylphenidate guidance, zolpidem) and the EMA (biphasic products). - Cut at the reference treatment’s median tmax.
The FDA’s “early exposure” for IR products. The 2nd pAUC is not required. - Cut at the individual reference treatment’s tmax.
Health Canada’s “early exposure”. The 2nd pAUC is not required. - Cut at half of the intended dosing interval tau.
EMA MR guideline (if both pAUCs pass BE, the otherwise mandatory MD study can be waived).
Note that the end-time of the 2nd partial AUC is tau – and not tlast as in the other methods. If you don’t have samples at exactly tau in all cases (e.g., missing samples, BQLs, deviations from the sampling scheduled at tau) you need a reliable estimate of λz in order to perform the required inter- or extrapolation.
Example with three subjects: tmax of T (2, 3, 2) and tmax of R (3, 2, 3).
#1: Cut-off times for T (2, 3, 2) and for R (3, 2, 3).
#3: Cut-off-time 3 for all subjects irrespective of treatment.
#4: Cut-off times (3, 2, 3) for all subjects irrespective of treatment.
The attached project is a test case:
Bimodal formulations, unbalanced sequences, and a lot of deviations from scheduled sampling times. Since PHX/WNL interpolates lin/log between decreasing concentrations (regardless which trapezoidal method was selected) I suggest to use the lin-up/log-down trapezoidal method for consistency. BTW, in the study we used #2 (4 hours).
Limitations:
- 2×2×2 crossover.
- Treatments have to be coded T and R.
- Only one cut-off time (hence, not suitable for the current FDA guidance for methylphendidate).
Enjoy!
Attached Files
Edited by Helmut Schütz, 12 November 2016 - 02:30 PM.