Significant discrepancy in cyclosporin A post-dose concentrations when analyzed with specific RIA and HPLC method

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Clinical Chemistry
• Transplantation Medicine

Background:

• Therapeutic drug monitoring (TDM) of cyclosporin A (CsA) often utilizes C(2) or AUC sparse sampling.
• C(2) sampling is favored over C(0) for potentially more accurate parent drug measurement by immunoassays due to lower metabolite formation.

Purpose of the Study:

• To compare whole blood CsA and metabolite concentrations using HPLC and RIA methods.
• To evaluate the accuracy of C(2) and AUC sampling for CsA TDM.

Main Methods:

• 40 stable renal transplant male patients on CsA were studied.
• Whole blood CsA and metabolites (AM1, AM9, AM4N) were measured by RIA and HPLC over 12 hours post-dose.
• AUC(0-12), C(max), t(max), and C(avg) were calculated and compared.

Main Results:

• RIA significantly overestimated CsA levels compared to HPLC between 0.5-5 hours post-dose (43-56% difference at 1-3 hours).
• AUC(0-12), C(max), and C(avg) were significantly higher with RIA.
• The ratio of metabolites to parent drug decreased, but absolute metabolite concentrations increased.

Conclusions:

• Alternating RIA and HPLC methods for CsA TDM, especially with C(2) or AUC sampling, can lead to misleading interpretations.
• Assay method consistency is crucial for accurate CsA therapeutic drug monitoring.