Doravirine and Rilpivirine Intra Cellular Accumulation in the Clinical Setting

Abstract

Background: Doravirine (DOR) and Rilpivirine (RPV) are the NNRTIs currently most used in the clinical setting, in dual and triple drug regimens (2DR and 3DR). Intracellular (IC) Pharmacokinetics (PK) of these drugs has not been fully elucidated. Our aim was to compare plasma PK and IC accumulation in real-life experienced patients (pts). Methods: Pts on DOR- and RPV-including Antiretroviral (ARV) regimen were considered. DOR and RPV plasma and IC (PBMCs) concentrations were measured at 12 (37%) (T12) and 24 ± 4 hours (63%) (T24) after last drug intake by means of UHPLC-MSMS validated methods. Results: 90 pts (65% on 3DR and 35% on 2DR) were included: 52% on DOR- and 48% on RPV-containing ARV. RPV IC/plasma ratio was significantly higher than DOR IC/plasma ratio: 6.034 (4.878-7.186) vs. 1.479 (1.256-1.702) (p=0.001) independently from timing T12 (p=0.003) and T24 (p<0.001). RPV in 3DR resulted to have higher plasma and IC accumulation compared to 2DR. Linear and significative correlations between DOR and RPV plasma and IC concentrations were found (+0.749, p<0.001 and +0.733, p<0.001). No significative correlation between overall DOR and RPV PK and creatinine, BMI or age or difference by gender was found. Conclusion: RPV proved to accumulate in PBMCs at a higher degree as compared to DOR: RPV and DOR IC levels were 498% and 50% higher than in plasma. RPV showed an IC PBMC/plasma ratio 3-fold higher than DOR. Potential explanation could rely on the higher lipophilicity of RPV. Clinical significance of these data needs to be investigated in further studies.