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Raising LLOQ in authentic plasma can mask elimination data, Yang Liu warns
Summary
Using a mock case, Yang Liu showed how setting a high lower limit of quantitation (LLOQ) in authentic plasma (2 ng/mL in the example) can render many pre‑dose and elimination samples BQL, prevent baseline correction and reduce confidence in BE conclusions.
Yang Liu described a mock case ("endogenous drug a" in human plasma) where an applicant increased the LLOQ to 2 ng/mL to declare the matrix interference‑free. The speaker said the elevated LLOQ led to most pre‑dose samples and late elimination samples being reported as below the limit (BQL), preventing baseline correction and removing measurable data needed for PK calculations.
"Only after 2.5 half‑lives the concentration theoretically will drop to about 1.75," Yang Liu said, adding that with the elevated 2 ng/mL LLOQ "this 1.75 cannot be detected," illustrating how data loss can occur and why sensitivity matters when assessing BE for endogenous drugs.
The presenter showed a sensitivity comparison where surrogate‑matrix analysis preserved area under the curve that the elevated‑LLOQ authentic method missed. He concluded that choosing an LLOQ that inadvertently censors expected elimination concentrations can undermine the ability to demonstrate bioequivalence.
Recommendation: validate methods such that the LLOQ brackets expected elimination concentrations, or use validated surrogate matrices with documented sensitivity and parallelism to recover low‑level data without bias.
