CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

differences in hydrolysis pathways between TDF and TAF, and reassures on the safety of TAF + b/PI + LDV/SOF in HIV/HCV-coinfected patients.

451 TOTAL DOLUTEGRAVIR LEVELS DECREASED BUT FREE FRACTION INCREASED BY VALPROIC ACID Henrieke A. Prins 1 , Pauline Bollen 2 , Kirsten Velthoven 3 , Bart Rijnders 1 , Theodora de Vries-Sluijs 1 , Els van Nood 1 , Jan Nouwen 1 , Hannelore Bax 1 , Mariana de Mendonca Melo 1 , Annelies Verbon 1 , David M. Burger 2 , Casper Rokx 1 1 Erasmus University Medical Center, Rotterdam, Netherlands, 2 Radboud University Medical Center, Nijmegen, Netherlands, 3 Radboud University, Nijmegen, Netherlands Background: Dolutegravir-containing regimens are used worldwide to treat people living with HIV-1. A previous report on two patients suggested a drug-drug interaction (DDI) between dolutegravir (DTG) and valproic acid (VPA) causing >80% decreased DTG plasma concentrations. The underlying mechanism is unclear. In this pharmacokinetic (PK) sub study, we evaluated the DTG-VPA DDI in HIV-1 patients on DTG-containing regimens and identified a potential mechanism. Methods: HIV-1 patients participating in a RCT investigating VPA as a latency reversing agent (LUNA: clinicaltrials.gov NCT: 03525730) were recruited in a pre- defined PK sub study if they were on DTG-containing regimens for >6 months with a plasma HIV-RNA of <50 c/mL. Patients all received 50 mg DTG QD and were randomized to receive either VPA 30 mg/kg BID from day 0 to 14 or not. Total DTG, unbound DTG, and DTG-glucuronide trough plasma concentrations were measured on day 0 (pre-dose and 6 hours post-dose VPA and DTG), and on day 1, 7, 14, and 42. Intra subject DTG concentrations were evaluated and compared to DTG controls without VPA. Results: Nine HIV-1 patients on DTG were included in total. Of the six who were randomized to receive VPA, total DTG trough levels (geometric mean (GM)) were 1.35 mg/L on day 0 (before VPA) and 1.11 mg/L on day 42. During 14 days of VPA treatment, total GM DTG concentrations decreased sharply to 0.85, 0.31 and 0.14 mg/L on Day 1, 7 and 14, respectively, while total DTG concentration in the controls remained comparable: 1.49, 1.74 and 1.51 mg/L on days 1, 7, and 14 respectively. We observed a parallel increase in the unbound fraction of DTG: 0.28-0.26%without VPA compared to 0.46-0.58% during VPA administration (figure 1) without relevant alterations in the controls (median 0.25%). Unbound DTG concentrations were above the established in vitro EC 90 value for unbound DTG of 0.9 µg/L in >90% of the participants. Conclusion: This study shows that total DTG plasma concentrations decrease sharply after the addition of VPA, thus confirming the DDI. The decrease can be explained, at least partly, by displacement of DTG by VPA via competitive protein binding. Since unbound DTG levels remained sufficient this DDI should not be a reason to withhold DTG treatment to people living with HIV-1 who are also receiving VPA.

450 HIGH-DOSE RIFAMPICIN FOR THE TREATMENT OF LEPROSY IN HIV PATIENTS TAKING DOLUTEGRAVIR Hannah Kinvig 1 , Felix Stader 2 , Fazila S. Bunglawala 1 , Rajith Kumar Reddy Rajoli 1 , Nicolas Cottura 1 , Alice E. Howarth 1 , Andrew Owen 1 , Catia Marzolini 2 , Marco Siccardi 1 1 University of Liverpool, Liverpool, UK, 2 University Hospital Basel, Basel, Switzerland Background: High dose rifampicin is being investigated for shortening TB therapy as well as in other indications such as leprosy. Strategies to manage the risk of drug-drug interactions (DDIs) with co-administered antiretroviral drugs may therefore be needed. The current study used physiologically-based pharmacokinetic (PBPK) modelling to predict the magnitude of DDI between once monthly (QMT) high dose rifampicin (RIF) and multiple dolutegravir (DTG) regimens for the treatment of leprosy in HIV coinfected patients. Methods: A whole-body PBPK model was designed in Simbiology v. 9.4.0 (MATLAB R2018a) and used to simulate 100 adult individuals. The DTG model was qualified against reported clinical data for DTG 50mg once daily (QD) and twice daily (BID). The RIF model describing the induction of DTG’s major metabolic pathways, UGT1A1 and CYP3A4, was qualified using in vitro and oral clinical data for midazolam, nifedipine, raltegravir, DTG and RIF. As per convention, PBPK models were assumed to be qualified if the simulated values were within 2-fold of the mean reported clinical values and if the absolute average-fold error (AAFE) was below 2. The verified DTG and RIF models were used to simulate the magnitude of DDI between RIF 600mg QMT co- administered with DTG 50mg BID as well as RIF 1200mg QMT co-administered with DTG 50mg BID, DTG 50mg three times daily (TID) and DTG 100mg BID. Results: The PBPK models were successfully qualified according to the criteria. There was a tendency to overpredict the magnitude of RIF induction for DTG 50mg BID, with simulated versus observed area under the curve (AUC), maximum plasma concentration (C max ) and minimum plasma concentration (C min ) ratios of 0.63, 0.58 and 0.74, respectively. The simulated C min of DTG after the administration of RIF are summarised in the table. For DTG 50mg BID co-administered with RIF 1200mg QMT, the C min minus one standard deviation (SD) fell below DTG’s protein adjusted (PA)-IC 90 1 day post RIF dose and recovered within 24 hours. Conclusion: The PBPK model predicted marked reductions in the C min of several DTG dosing regimens when co-administered with 600mg and 1200mg RIF QMT. Importantly, the return of DTG plasma concentrations to steady state C min was predicted to be considerably delayed after coadministration of both 600mg and 1200mg RIF QMT. These simulations could inform development of effective high-dose RIF strategies for special HIV populations with comorbidities such as Leprosy.

Poster Abstracts

CROI 2020 158