Quality Assurance in Drug Assaying and Pharmacokinetics-Blood Protein Evaluation in Calibration Curves
In bioanalytical drug assays, plasma protein/albumin content can challenge the biomatrix and reduce drug recovery through the albumin-binding affinity (ABA) of drug molecules. Global quality assurance in sample preparation for analyte quantification during bioavailability assessments has evolved extensively, and the quality standards of the strictly regulated current global quality controlled drug manufacturing processes (cGQMP) now apply in pharmacokinetics (PK) studies. Previous analyses in large clinical trials had found that laboratory-prepared calibrator plasma/serum protein levels differed significantly from those of patients with occasional hyperproteinemia/hypoproteinemia and disease-related hyperalbuminemia/hypoalbuminemia. We, therefore, investigated improving assay accuracy by including adjustments for patient plasma/serum protein levels in protein evaluation calibrations curves (PROTEC). Using a combined PROTEC of two calibrators (with 1.6 ± 0.5 g/dL and 4.3g/dL albumin, respectively) to test rifampicin recovery from patients with hypoalbuminemia (1.6 ± 0.5 g/dL), we found that relative accuracy of drug recovery differed by minimum 0.1% for low ABA drugs and maximum >20% for moderate ABA drugs. Assay accuracy improved after accommodating for varying patient plasma/serum protein levels. We, therefore, propose using patient-calibrator PROTEC-PK in validation assay development/therapeutic drug monitoring to ensure that patient albumin levels are within acceptable validation accuracy ranges.