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P194 Intracellular simeprevir concentrations are increased by the co-administration of darunavir/ritonavir (first clinical report from the Kinetic C study) Ariaudo A, Favata F, De Nicolò A, Marinaro L, Carcieri C, Gontero E, Cusato J, Bonora S, Di Perri G, D’Avolio A Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy Results Introduction Mean corpuscular volume of each PBMC sample was used to calculate the intracellular concentration of drug. We observed a significant correlation, p=0.016, between plasmatic and intracellular concentrations of SMV. We reported an increase in both plasmatic and intracellular concentration of SMV when co-administered with DRV/RTV: median of intracellular concentration was 25742 ng/ml (IQR 15975-25742) with DRV/RTV versus 7574 ng/ml (IQR 3785-9144) and median of plasmatic concentrations was 40014 ng/ml (IQR 7671;40014) versus 1395 ng/ml (IQR 544-2471) without co-administration. p. value= 0,048 Safety Box blot: difference between plasmatic an PBMC concentration of SMV at one month of therapy with (green box) or without (blu box) co-administration of DRV/RTV Material and Methods SPSS was used for statistical analysis. INTRACELLULAR CONCENTRATION The mean corpuscolar volume (MCV) for each PBMC sample was evaluated using a Beckman Coulter. The intracellular concentration of drugs is calculated using the number of cell in the sample and the MCV. RITONAVIR CONCENTRATION (ng/ml) We also observed a significant increased in DRV and a trend in RTV plasmatic concentrations in presence of SMV versus co-administration with other direct antiviral agents. DARUNAVIR CONCENTRATION (ng/ml) Plasma and PBMC samples from 9 patients from Amedeo di Savoia Hospital (Turin) at one month of therapy with SMV/sofosbuvir plus DRV/RTV, dolutegravir, rilpivirine, raltegravir or atazanavir, were collected and extracted. Analysis for PBMC concentration were conducted using a validate UHPLC/MS-MS method with a gradient of ammonium-acetate 5mM pH 9,5 and acetonitrile at a flow rate of 0.4 ml/min for the chromatographic separation. Detection was carry out with a triplequadrupole mass spectrometric coupled with electrospray ionization (ESI). For plasma DAA and ARV quantification, publicated methods were used [1,2]. 1 MONTH SMV PBMC CONCENTRANTION In the last few years, the development and introduction of the new direct antiviral agents (DAAs), have significantly improved the HCV treatment. Although the efficacy of new regimens is very high, adverse events and treatment failure are present and few data are available about the pharmacokinetic of these drugs in real patients. This is even more relevant in case of co-infected patients, because different therapies have to be combined. Interaction between simeprevir (SMV) and darunavir (DRV) has already been described at plasma level, but since it explicates its activity inside the cells, it could be useful to evaluate its concentration in the intracellular compartment. PBMC may represent a valid and easier available surrogate to hepatocyte cells. The aim of the study is to evaluate the intracellular concentrations and the pharmacokinetic of SMV and to relate it to DRV/ritonavir exposure. p. value= 0,024 Increase of DRV (right figure) and RTV (left administration with SMV is present. figure) plasma concentranion when co- Median PBMC/plasma ratio for SMV were 0.64 (IQR 0.49-3.45) and 5 (IQR 3.91-8.25) with or without co-administration respectively. Conclusions Data about intracellular concentrations could lead to a greater knowledge of SMV pharmacokinetic, toxicity and adverse events outcoming and could help in the management of the therapy, especially in case of multitreated patients. We confirm the plasmatic interaction between SMV and DRV/RTV. The high intracellular SMV concentrations, when coadministered with DRV, could be investigated as the real cause of skin reactions in some patients. For the future it will be useful to increment the number of patients analyzed to better evaluate drug-drug interactions, also with other concomitants drugs. Reference 1. 2. Ariaudo at all, J Pharm Biomed Anal. 2016 Jun 5;125:369-75. doi: 10.1016 Simiele at all, J Pharm Biomed Anal. 2017 May 10;138:223-230. doi: 10.1016 Author info: [email protected]
