CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

Background: Cabotegravir (CAB) and rilpivirine (RPV) are two investigational long-acting (LA) agents and their interaction with rifampin (RIF) has not been fully elucidated. The aim of this study was to simulate and predict the influence of RIF on the pharmacokinetics (PK) of CAB and RPV four-weekly intramuscular (IM) administration using a physiologically-based pharmacokinetic (PBPK) model. Methods: The PBPK model was designed in Simbiology v. 4.3.1 (MATLAB 2013b) and 100 healthy adult individuals were used for simulations. PBPK models were qualified for the three drugs against available oral clinical data. Standard oral doses of 30 mg, 25 mg and 600 mg were used for CAB, RPV and RIF, respectively. Loading doses of 800 mg and 900 mg were used for CAB and RPV, respectively. 400/800 mg and 600/900 mg were used as q4/8-weekly IM maintenance doses for CAB and RPV. Models were also qualified against PK data in the LATTE-2 IM CAB and RPV study. Oral CAB-RIF, midazolam (CYP3A4 probe)- RIF and RPV-RIF drug-drug interaction (DDI) models were also qualified against PK data from clinical studies. The PBPK models were assumed to be qualified if the simulated values were ± 100 % from the mean reported clinical values. We evaluated the effect of 600 mg oral once-daily RIF on the PK of LA IM 4-weekly CAB and RPV loading and maintenance doses. Variation in PK parameters AUC, C max and C trough values are reported. Results: For the IM loading dose of CAB with 600 mg OD RIF, the PK parameters C max , AUC and C trough decreased by 57.6%, 43.8% and 44.0%, respectively, compared to CAB alone. For the maintenance doses there was an overall reduction between 39% and 46% in the PK parameters. A more marked reduction was observed for rilpivirine PK, with a decrease in C max , AUC and C trough of 90.9%, 83.9% and 83.6% for the loading dose, and a reduction in these parameters between 80.5% and 83% for maintenance doses. Conclusion: Models were qualified and PK data successfully predicted for CAB and RPV with RIF. This computational approach supports the prediction of potential DDIs for LA regimens, which cannot be readily investigated in vivo due to ethical and logistical barriers. This approach could rationally guide the design of alternative dosing strategies. The co-administration of RIF with CAB and RPV is predicted to substantially decrease ARV concentrations. 459 DOLUTEGRAVIR INTERACTIONS WITH ARTEMETHER-LUMEFANTRINE AND AMODIAQUINE-ARTESUNATE Stephen I. Walimbwa 1 , Mohammed Lamorde 1 , Catriona Waitt 2 , Julian P. Kaboggoza 1 , Laura Else 2 , Pauline Byakika-Kibwika 3 , Alieu Amara 2 , Joshua Gini 2 , Markus Winterberg 4 , Joel Tarning 4 , Saye Khoo 2 1 Infectious Disease Institute, Kampala, Uganda, 2 University of Liverpool, Liverpool, UK, 3 Makerere University College of Health Sciences, Kampala, Uganda, 4 Mahidol University, Bangkok, Thailand Background: We investigated potential drug-drug interactions between the most commonly used artemisinin-containing therapies artmether-lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) and dolutegravir (DTG). Methods: We undertook two pharmacokinetic (PK) studies in healthy Ugandan volunteers, using standard clinical treatment doses of AL and AS-AQ and 50mg of DTG once daily given with food. Rich PK sampling was performed after the final dose of AL or AS-AQ. Study A: DTG/AL interaction. Two-way cross-over study design (n=16) with 1:1 randomisation. Subjects received either 3 days of AL dosing or 6 days of DTG (to reach steady state) plus 3 days AL+DTG. Following washout (21 days), the opposite regimen was given. Study B: DTG/ AS-AQ interaction. Parallel study design (n=30) due to the long half-life of the active AQ metabolite, desethylamodiaquine (DEAQ). 1:1 randomisation to either 3 days of AS-AQ alone or 7 days of DTG alone followed by 3 days AS-AQ + DTG. Clinical and laboratory adverse events (AE) were reported using DAIDS criteria. Artemether (ARM), artesunate (ARS), dihydroartemisinin (DHA), lumefantrine (LF), desbutyl-lumefantrine (DLF), amodiaquine (AQ) and DEAQ were measured over 0-264 h (study A) and 0-624 h (study B) using LC-MS. Noncompartmental

457 PHARMACOKINETICS OF EFAVIRENZ 400MG WITH ISONIAZID/ RIFAMPICIN IN PEOPLE WITH HIV Maddalena Cerrone 1 , Xinzhu Wang 2 , Megan Neary 3 , Christine Weaver 1 , Serge Fedele 1 , Isaac Day-Weber 2 , Andrew Owen 3 , Andrew Hill 3 , Myra McClure 2 , Marta Boffito 1 1 Chelsea and Westminster Hospital, London, UK, 2 Imperial College London, London, UK, 3 University of Liverpool, Liverpool, UK Background: Antiretroviral (ARV) dose reductions compensate for finite global manufacturing capacity and allow access programmes to reach larger numbers of people living with HIV (PLWH). The ENCORE-1 study showed that efavirenz 400mg (EFV400) is as effective as the standard adult dose of 600mg. WHO recommend EFV400 as an alternative first-line ARV, with a disclaimer that no data on EFV400 with anti-tuberculosis (TB) treatment exist. Many PLWH need TB treatment with isoniazid (INH) and rifampicin (RIF) that affect cytochrome P450 and ARV exposure. Methods: This open-label study investigated the pharmacokinetics (PK), efficacy, CYP2B6 pharmacogenetics of EFV400 + INH/RIF in PLWH without TB (TB-), receiving tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and EFV 600mg with a viral load (VL)< 50 copies/mL. They were switched to TDF/FTC/ EFV400. Weekly therapeutic drug monitoring (TDM), steady-state PK profiles of EFV400 without (PK1) and with INH/RIF following 4 (PK2) and 12 (PK3) weeks of co-administration, safety, virologic efficacy, polymorphisms in CYP2B6 (516C>T; 938T>C) were evaluated. Subjects who completed PK2 were included in the full PK analysis. Results: 34 PLWH were screened and 26 baselined, 22 completed PK2 (3 withdrew for EFV400 TDM results <800ng/mL in >3 consecutive visits, as per protocol stopping rule, and 1 because of non-drug related liver toxicity), and 17 completed PK3 (2 withdrew for liver toxicity, 1 for low EFV levels, 1 was pregnant, 1 is ongoing). Baseline median (range) age and CD4 count (n=22) were 47 (22-60)years and 591 (223-1159)cells/mm 3 . 10 were Black Africans, 8 White, 4 other. All had VL<50 at baseline, which was maintained throughout the study. Geometric mean ratios (GMR) PK2/PK1, n=22 (90%CI) of EFV400 C max , AUC, and C24h were 0.91 (0.83-0.99), 0.91 (0.86-1.13), 0.85 (0.72-0.99). GMR (90%CI) of PK3/PK2 and PK3/PK1 (n=17) C max , AUC, and C24h were 0.97 (0.88- 1.06), 0.94 (0.88-1.06), 0.91 (0.78-1.05) and 0.85 (0.78-0.94), 0.86 (0.80-1.09), 0.77 (0.64-0.94). 11/22 subjects were carriers of 516T (10) and/or 938C (3) slow metabolisers alleles. Conclusion: INH/RIF co-administration in TB-PLWH with a VL<50 was associated with limited changes in EFV400 exposure (<23%) and EFV400 concentrations were maintained within ranges of those measured in PLWH in ENCORE-1 (Dickinson et al. 2015). Results from this cohort conclude that EFV400 can be co-administered with anti-TB treatment. This should be confirmed in TB+ PLWH. 458 IN SILICO DRUG INTERACTION OF LONG-ACTING RILPIVIRINE AND CABOTEGRAVIR WITH RIFAMPIN Rajith Kumar Reddy Rajoli 1 , Paul Curley 1 , David Back 1 , Charles W. Flexner 2 , Andrew Owen 1 , Marco Siccardi 1 1 University of Liverpool, Liverpool, UK, 2 Johns Hopkins Hospital, Baltimore, MD, USA

Poster Abstracts

CROI 2018 163