Bioequivalence and Bioavailability Forum

Hi KVGR,

❝ For drugs demonstrating high intrasubject variability in distribution and/or clearance, AUC truncation should not be used.

❝ http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM238049.pdf

Personally I never understood why for the FDA truncated AUCs should not be used for HVDs/HVDPs.* Amiodarone is an example showing its applicability (all authors from the FDA).

Kharidia J, Jackson AJ, Ouderkirk LA. Use of Truncated Areas to Measure Extent of Drug Absorption in Bioequivalence Studies: Effects of Drug Absorption Rate and Elimination Rate Variability on this Metric. Pharm Res. 1999;16(1):130–4. doi 10.1023/A:1018839300168

In my studies on 200 mg amiodarone it was only borderline highly variable (CVs ~30% for AUC and C_max). I used AUC_0–72. I didn’t see high variability in clearance (CV of λ_z 23%). Given what is stated in the guidance, the paper given above, and my experiences I would say proceeding with AUC_0–72 is justi­fied.

❝ 2. In case of truncated study how can we handle the missing samples in statistical calculations.

Do you want a recipe? Please do your homework first – there are lot of posts covering this topic already. Which are your own thoughts?

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• Highly variable drug: CV_w ≥30% if administered as a solution. High variability is an intrinsic property of the drug (absorption/permeation, pre-systemic and/or first-pass metabolization, clearance).
  Highly variable drug product: Any of the above and high variability in formulation-related properties (liberation, influence of excipients).