CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

by immediate centrifugation, washing with ice cold PBS and freeze thaw for cell lysis. GZR concentrations were quantified using LC-MS/MS and IC 50 were calculated. The abundance of OATP1B1 in pooled human cryopreserved hepatocytes aged 18-60 years old and three individual elderly donors aged 74-80 years old were quantified using a sandwich ELISA. Statistical significance was assessed using an unpaired t-test. Results: DRV reduced OATP1B1-mediated uptake of GZR by 35% (maximal inhibition at 0.01µM; IC 50 of 4.4×10 -8 µM) whilst RTV decreased uptake by 40% (maximal inhibition at 10µM; IC 50 of 9.4µM) (see figure). When compared to pooled hepatocytes from donors aged 18-60 years old, abundance of OATP1B1 in three individual elderly donors aged 74-80 years old were between 35% and 56% lower with P values between 0.005 and 0.032. Conclusion: The in vitro model identified that RTV does not inhibit OATP1B1- mediated transport in the range of physiologically relevant concentrations, unlike DRV which produced a moderate inhibition of OATP1B1. Our experimental approach represents an effective strategy to characterize the role of transporters in DDIs and may be useful to identify clinically relevant DDIs. Furthermore, the lower expression of OATP1B1 in hepatocytes from elderly donors provides a plausible mechanistic basis for the increased GZR AUC reported in this sub-population and justifies further investigation.

43% lower 007-TP concentrations in PBMCs ([95% CI -60%, -19%]; p=0.0017). SR showed a trend towards 25% lower 007-TP in PBMCs ([95% CI -47%, 7%]; p=0.11) and UTox-positive revealed 46% lower 007-TP PBMC concentrations ([95% CI -63%, -23%]; p=0.0009). 007-TP in DBS did not significantly differ by cocaine use (p>0.3). Conclusion: Intracellular 007-TP concentrations in PBMCs, but not DBS, were lower in cocaine users. This difference was stronger by UTox, suggesting a temporal or frequency effect of cocaine use on 007-TP in PBMCs. Differences in findings between cell types may be due to differences in cell-specific expression of DAA-converting enzymes or transporters, or immune activation of PBMCs by cocaine. Further research is needed to elucidate a possible mechanism consistent with this interaction and whether these differences impact SVR.

Poster Abstracts

469 INTRACELLULAR SOFOSBUVIR (SOF) CONCENTRATIONS IN PERSONS WITH HCV AND COCAINE USE Kristina M. Brooks 1 , Jose R. Castillo-Mancilla 1 , Mary Morrow 2 , Samantha MaWhinney 2 , Ryan T. Huntley 1 , Joshua Blum 3 , David L. Wyles 3 , Lane R. Bushman 1 , Peter L. Anderson 1 , Jennifer J. Kiser 1 1 University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 2 Colorado School of Public Health, Aurora, CO, USA, 3 Denver Health and Hospital Authority, Denver, CO, USA Background: There are limited data on the effects of drug use on direct acting antiviral (DAA) pharmacokinetics (PK). Certain drugs, such as cocaine, may affect DAA PK through enzyme or transporter modulation or immune activation. We examined the influence of cocaine on GS-331007 triphosphate (007-TP; also known as GS-461203) concentrations, the active anabolite of SOF, in PBMCs and dried blood spots (DBS) in persons who use drugs receiving ledipasvir (LDV)/SOF for HCV treatment. Methods: Persons with HIV/HCV or HCV mono-infection and self-reported drug use within 30 days of screening were eligible for the study. Adherence to LDV/ SOF was monitored through directly (video-based) or wirelessly (Wisepill®) observed therapy. A self-reported (SR) drug use questionnaire documenting yes/no use of cocaine, a urine toxicology screen (UTox), and convenience PK samples were collected bi-weekly over 12 weeks of LDV/SOF. 007-TP concentrations in PBMCs and DBS were quantified using LC/MS-MS. A mixed- effects model was used to analyze the influence of average adherence over the previous 2 weeks (adh2wk) and cocaine use (yes/no) on log-transformed 007-TP in PBMCs and DBS. Cocaine use was examined by SR, UTox, and both combined. Results: Samples and questionnaires were available from 46 participants (43 HIV/HCV, 3 HCV only; 235 person-visits). Fifteen participants (33%) used cocaine by SR or UTox at 39 person-visits. Median (IQR) adh2wk in cocaine users was 86% (64%, 100%) vs. 100% (91%, 100%) in non-users. Adh2wk was a significant predictor of 007-TP concentrations in PBMCs and DBS (p<0.0001 for both). After controlling for adherence, overall cocaine use was associated with

470 PREDICTION OF RENAL OAT1 AND OAT3 INHIBITION BY CABOTEGRAVIR USING PBPK MODELLING Kunal S. Taskar 1 , Aarti Patel 1 , Simon J. Cozens 1 , Susan Ford 2 , William Spreen 3 , MArk Baker 4 , Parul Patel 3 1 GlaxoSmithKline, Ware, UK, 2 GlaxoSmithKline, Research Triangle Park, NC, USA, 3 ViiV Healthcare, Research Triangle Park, NC, USA, 4 ViiV Healthcare, Nyon, Switzerland Background: Cabotegravir (CAB) is an integrase strand transfer inhibitor being investigated for the treatment and prevention of HIV-infection. It is being developed as a long acting (LA) intra-muscular injection to facilitate every 1 or 2-month dosing. It is necessary to evaluate the impact of CAB on the exposure and clearance of co-medications. In vitro studies indicated that CAB inhibits renal transporters OAT1 and OAT3 with half maximal inhibitory concentrations of 0.81 and 0.41 µM, respectively. The objective of the present analysis was to build a physiologically based pharmacokinetic (PBPK) model of CAB to predict the clinical implications of renal OAT1/OAT3 inhibition on co-medications. Methods: A mechanistic PBPK model of CAB in the adult population was built using the Simcyp® v17.1 simulator by incorporating physico-chemical properties, in vitro clearance mechanisms, and in vivo data and validated as per regulatory specifications. The CAB PBPK model was validated through comparison with available clinical PK data following oral CAB 30mg administration in healthy volunteers. The simulator was qualified for predicting observed OAT1 and/ or OAT3 inhibition based DDIs. DDI simulations were performed to evaluate the effect of CAB oral doses on the exposure of OAT1/OAT3 substrates (methotrexate, tenofovir, ciprofloxacin, cidofovir, cefuroxime, oseltamivir carboxylate, baricitinib, and S44121). Results: Simulated DDIs for above mentioned OAT1/OAT3 substrates and inhibitors (probenecid, diclofenac) were within two-fold of the observed clinical DDIs. This qualified the Simcyp® v17.1 simulator and related files as appropriately sensitive for predicting OAT1/OAT3 inhibition-mediated clinical

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