CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

430 EFFECT OF SEVERE RENAL IMPAIRMENT ON DORAVIRINE PHARMACOKINETICS Wendy Ankrom 1 , Kelly Yee 1 , Rosa Sanchez 1 , Adedayo Adedoyin 1 , Li Fan 1 , Thomas Marbury 2 , Richard A. Preston 3 , Sauzanne Khalilieh 1 , Marian Iwamoto 1 1 Merck & Co, Inc, Kenilworth, NJ, USA, 2 Orlando Clinical Rsr Cntr, Orlando, FL, USA, 3 Univ of Miami, Miami, FL, USA Background: Doravirine is a novel, potent, HIV-1 non-nucleoside reverse transcriptase inhibitor that is primarily metabolized by oxidation via CYP3A4 with limited renal excretion. As the HIV-infected population ages, the number of HIV-infected patients with chronic kidney disease will also increase. Even drugs with limited renal excretion have exhibited altered pharmacokinetics (PK) in patients with severe renal impairment. This study assessed the impact of severe renal impairment on the PK of doravirine. Methods: This was an open-label, single-dose study in subjects with severe renal impairment and healthy matched control subjects. The healthy control subjects were matched within +/-10 kg and +/-10 years of the mean weight and age, respectively, of the severe renal impairment cohort. A single dose of 100 mg doravirine was administered to subjects with severe renal impairment (eGFR < 30 mL/min/1.73 m^2) and to healthy matched controls (eGFR ≥ 80 mL/min/1.73 m^2). Blood samples to measure doravirine concentrations were collected through 96 and 72 hours postdose in renally impaired subjects and healthy controls, respectively. Results: Sixteen (16) adult subjects were enrolled; 8 (2 female, 6 male) with severe renal impairment and 8 (3 female, 5 male) healthy matched control subjects. In the subjects with severe renal impairment, AUC0-inf, and C24hr were modestly increased, while Cmax was minimally impacted. The geometric mean ratios (90% confidence intervals) [severe renal impairment/healthy] for doravirine Cmax, AUC0-inf, and C24hr were 0.83 (0.61, 1.15), 1.43 (1.00, 2.04), and 1.38 (0.99, 1.92), respectively. Terminal t1/2 was increased from 17 for healthy matched control subjects to 25 hrs for the subjects with severe renal impairment. There were no serious adverse experiences (AEs). Three (19%) subjects reported one AE each; only 1 of these (mild nausea) occurring in a subject with renal impairment was considered drug related. No subjects discontinued. Conclusion: Severe renal impairment had a modest, but not clinically meaningful, effect on the PK of doravirine. A single dose of 100 mg doravirine was generally well tolerated in subjects with severe renal impairment. 431 HIGHER PLASMA LEVELS AND MORE SIDE EFFECTS IN ELDERLY DARUNAVIR-TREATED PATIENTS Erika Ahlgren 1 , Arvid Edén 1 , Jaran Eriksen 2 , Staffan Nilsson 3 , Carl Johan Treutiger 2 , Anders Thalme 4 , Anders Blaxhult 5 , Åsa Mellgren 6 , Magnus Gisslén 1 , Lars-Magnus Andersson 1 1 Univ of Gothenburg, Gothenburg, Sweden, 2 Karolinska Inst, Stockholm, Sweden, 3 Chalmers Univ of Tech, Gothenburg, Sweden, 4 Karolinska Univ Hosp, Stockholm, Sweden, 5 Sodersjukhuset, Stockholm, Sweden, 6 South Älvsborgs Hosp, Borås, Sweden Background: An increasing proportion of people living with HIV-1 are 50 years or older. In older patients comorbidities and concomitant medications are more frequent, increasing the risk for potentially dangerous drug interactions (PDDIs). Data on the pharmacokinetics of PIs and NNRTIs in individuals 65 years and older are scarce. The aim of this study was to investigate differences in drug levels, PDDIs and side effects in people living with HIV-1 65 years or older, compared to individuals 49 years or younger in Sweden. Methods: From the Swedish HIV-cohort, we cross-sectionally included patients 65 years or older and controls 49 years or younger on stable treatment with atazanavir (ATV), darunavir (DRV) or efavirenz (EFV) since ≥6 months. Plasma drug levels were analyzed with high-performance liquid chromatography (HPLC). Comorbidities, concomitant medication, adherence and adverse effects were registered by a standardized questionnaire and structured medical record review. PDDIs were analyzed using drug interactions databases. Results: Between 2013 and 2015, we included 99 individuals 65 years or older (ATV n=19, DRV n=34, EFV n=46) and 97 younger controls (ATV n=18, DRV n=36, EFV n=43). Individuals with a two-dose DRV-regimen (n=10 in the study group and n=5 controls) were excluded from the drug level analysis. Steady state DRV concentrations were significantly higher in individuals 65 years or older compared to controls, (p=0.047) analyzed with ANCOVA adjusting for time, with log-transformed concentrations of DRV. The geometrical mean was 48% higher in the individuals ≥65 years. No significant difference was found in the ATV or EFV arms. The ≥65 group had a significantly higher median (IQR) number of concomitant medications, 3 (1-5) vs. 0 (0-2) (p <0,0001), and significantly more (median, IQR) PDDIs, 2 (0-3) vs. 0 (0-1) (p <0,0001) compared to controls. In individuals 65 years and older the DRV group had significantly more (median, IQR) PDDIs than the ATV and EFV study groups 3 (1-6) vs. 2 (0-3) and 1 (0-2) (p=0,002). The DRV group had a higher frequency of reported side effects than the ATV and EFV groups ≥65 years 37.9% vs. 0% and 23.8% (p=0.012). Conclusion: Higher steady state plasma levels of darunavir but not of atazanavir or efavirenz were found in people living with HIV-1 who are 65 years or older compared to matched younger controls. Consistent with this finding, the frequency of reported side effects were higher in the darunavir group than in the atazanavir and efavirenz groups. 432 PHARMACOKINETICS OF DOLUTEGRAVIR IN PEOPLE LIVING WITH HIV OVER THE AGE OF 60 Emilie Elliot 1 , Xinzhu Wang 2 , Nicole Pagani 1 , Alison Jenkin 1 , Jaime Vera-Rojas 3 , Isaac Day-Weber 2 , Graeme Moyle 4 , Myra McClure 2 , Marta Boffito 1 1 St. Stephen’s AIDS Trust–Chelsea and Westminster Hosp, London, UK, 2 Imperial Coll, London, UK, 3 Brighton and Sussex Med Sch, Brighton, UK, 4 Chelsea and Westminster Hosp, London, UK Background: Antiretroviral (ARV) pharmacokinetics (PK) and pharmacodynamics (safety and efficacy) may differ in older versus younger patients. The aim of this study was to evaluate dolutegravir (DTG) PK in people living with HIV (PLWH) ≥60  years following an ARV combination (cART) switch to abacavir (ABC)/lamivudine (3TC)/DTG fixed dose combination (FDC). Methods: The study protocol required the enrolment of PLWH aged ≥60 years (30%) and ≥65 years (70%), with HIV-RNA<50 copies/mL on any cART, HLAB5701 negative and no history of treatment failure. On day 1, all switched to ABC/3TC/DTG and, on day 28, intensive PK sampling was undertaken in a fasted state. DTG plasma concentrations were determined by UPLC and DTG steady-state PK parameters compared to those obtained from the PK sub-study of SPRING-1, where PLWH younger than 50 years underwent full DTG PK determination following ABC/3TC/DTG intake in a fasted state (control group). Non-parametric testing (Mann–Whitney U test) was used to compare DTG exposure in the two groups. Results: Full PK profiles were available from 28 PLWH over the age of 60 years (median/range age: 66/60-79 years; 1 female) and from 16 younger controls (median/range age: 37/22-50 years; 1 female). No differences in DTG PK parameters were observed between the two groups: geometric mean (95%CI) DTG Cmax, Ctrough and AUC0-24 were 4284 (3875-4951), 1104 (922-1286) ng/mL and 54386 (48051-60721) ng.h/mL in the over 60 years group and 3409 (2854-4184), 1130 (780-1480) ng/mL and 51124 (40461-61787) ng.h/ mL in the control group (p=0.66). The studied FDC was well tolerated, with no grade 3 or 4 side effects or laboratory abnormalities and no virological failures at week 4 post-switch. Conclusion: No significant changes in DTG exposure were observed, suggesting that advanced age does not affect DTG metabolism. ABC/3TC/DTG was well tolerated by PLWH over the age of 60 during the first month of treatment. 433 NOVEL HIV PI WITH HIGH RESISTANCE BARRIER AND POTENTIAL FOR UNBOOSTED QD ORAL DOSING John O. Link , Darryl Kato, Michael Moore, AndrewMulato, Bernard Murray, Judy Mwangi, Nathan D. Shapiro, George Stepan, Yujin Wang, Zheng-Yu Yang Gilead Scis, Inc, Foster City, CA, USA Background: Background: HIV protease inhibitors (PIs) represent an important antiretroviral class largely due to their low potential to select for clinical resistance. Despite extensive discovery and development efforts over the past 30 years, all marketed PIs suffer from high rates of hepatic oxidative metabolism, leaving none that are suitable for once-daily (QD) dosing without pharmacokinetic boosting. Here we describe a novel, potent HIV PI that exhibits a high resistance barrier, exceptional metabolic stability, and has the potential for use as an unboosted, QD oral agent for the treatment of HIV infection. Methods: Methods: Antiretroviral EC 50 and Hill-coefficient values were measured in a cytopathic MT4 T-cell assay. PI cross-resistance was assessed against a panel of atazanavir (ATV) and darunavir (DRV) resistance-associated HIV-1 mutants (RAMs). Predicted drug clearance (CL) was measured in human liver microsomes with added cofactors. Oral and intravenous pharmacokinetic studies were conducted in rat and dog.

Poster and Themed Discussion Abstracts

CROI 2017 180