Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques.

Venuto CS, Markatou M, Woolwine-Cunningham Y et al.

Department of Neurology; Center for Human Experimental Therapeutics, University of Rochester, Rochester, NY, USA.

Antimicrobial agents and chemotherapy. Mar 2017.

Background: The liver is crucial to pharmacology, yet substantial knowledge gaps exist in understanding of its basic pharmacologic processes. Improved understanding in humans requires reliable and reproducible liver sampling methods. We compared liver concentrations of paritaprevir and ritonavir in rats using samples collected by fine needle aspiration (FNA), core needle biopsy (CNB), and surgical resection.Methods: Thirteen Sprague Dawley rats were evaluated, nine who received paritaprevir/ritonavir 30/20-mg/kg by oral gavage daily for 4 to 5 days. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry on samples collected via FNA (21G needle) with 1, 3 or 5 passes (FNA1, FNA3, FNA5); CNB (16G needle); and surgical resection. Drug concentrations were also assessed in plasma. Analyses included non-compartmental pharmacokinetic analysis and use of Bland-Altman techniques.Results: All liver tissue samples had higher paritaprevir and ritonavir concentrations compared to plasma. Resected samples, considered the benchmark measure, resulted in estimating the highest values for the pharmacokinetic parameters of exposure (Cmax, AUC0-24) for paritaprevir and ritonavir. Bland-Altman analyses showed that the best agreement occurred between (tissue resection, CNB) with 15% bias; followed by (FNA3, FNA5) with 18% bias; and (FNA1, FNA3) with 22% bias for paritaprevir.Conclusions: Paritaprevir and ritonavir are highly concentrated in rat liver. The best agreement was observed between tissue resections and CNB followed by FNA with 3 and 5 passes and FNA with 1 or 3 passes. Further research is needed to validate FNA sampling in humans with the possible derivation and application of correction factors for drug concentration measurements.

Pubmed

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