CROI 2020 Abstract eBook
Results: Among the 12 children enrolled, the median age was 38 months (range 26 to 50 months), 75%were female, the median CD4 cell count was 1211 cells/mm 3 and CD4%was 34%. All children were receiving lopinavir/ritonavir, zidovudine, lamivudine (and one was also on abacavir). All but one infusion occurred on schedule and to completion, and infusions were well tolerated. No infusion reactions occurred, and no grade 3 or 4 events were related to either bNAb. For VRC01LS, median (range) first dose peak concentrations (C max ) and Day 84 trough concentrations (C84D) were 726 (559-799) mcg/mL and 157 (126-201) mcg/mL respectively, both about half of predicted values based on PK in uninfected adults (Figure 1A). For 10-1074, median (range) first dose C max and C84D concentrations were 1633 (1174-1999) mcg/mL and 258 (122-467) mcg/mL respectively, both somewhat greater than predicted values from HIV-infected adults on suppressive ART (Figure 1B). Conclusion: Intravenous VRC01LS and 10-1074 were safe and well tolerated among HIV+ children receiving ART.Pediatric PK of these two bNAbs differed from PK in adults. For VRC01LS, an increased maintenance dose of at least 15mg/kg may be needed to achieve concentrations similar to adults when dosed monthly. For 10-1074, predicted adult concentrations were slightly exceeded with 30mg/kg monthly.
CAB was > 0.166μg/mL (protein adjusted (PA)-IC 90 ) in 30/30 subjects at the 1-month LTFU visit, and ranged between 0.034 to 0.152μg/mL (< PA-IC 90 ) in 8 subjects and was nonquantifiable (
467 WITHDRAWN 468 MK-8504 AND MK-8583 (TENOFOVIR PRODRUGS) SINGLE-DOSE PK AND ANTIVIRAL ACTIVITY IN HIV Randolph P. Matthews 1 , Sarah J. Hsieh 1 , Jesse C. Nussbaum 1 , Guido H. Jajamovich 1 , Tian Zhao 1 , Diana Selverian 1 , Michaelanne Wasenius 1 , Liesbeth Haspeslagh 2 , Caroline Cilissen 2 , Dirk Schuermann 3 , Sylvie Rottey 4 , Marta Boffito 5 , Deanne J. Rudd 1 , S. Aubrey Stoch 1 , Marian Iwamoto 1 1 Merck & Co, Inc, Kenilworth, NJ, USA, 2 MSD Belgium, Brussels, Belgium, 3 Charité Universitätsmedizin, Berlin, Germany, 4 Ghent University, Ghent, Belgium, 5 Chelsea and Westminster Hospital, London, UK Background: There is a need for Human Immunodeficiency Virus (HIV-1) treatments with improved safety profiles and increased ease of administration. MK-8504 and MK-8583 are nucleoside reverse transcriptase inhibitors (NRTIs) that are novel tenofovir (TFV) prodrugs, with a potential for weekly dosing due to the long t 1/2 of the active diphosphate (TFV-DP). Single-dose pharmacokinetics (PK) and antivirologic activity of these compounds were assessed in two Phase 1 programs. Methods: Single doses of 2-240 mg MK-8504 were tested in healthy adults, and single doses up to 240 mg were tested in ART-naïve persons living with HIV (PLWH). Single doses of MK-8583 2-150 mg were tested in healthy adults, and a single dose of 100 mg was tested in ART-naïve PLWH. Plasma and peripheral blood mononuclear cells (PBMCs) were collected up to 10 days after dosing for PK and viral load (VL). Results: Oral MK-8504 and MK-8583 were rapidly absorbed (T max ~ 0.5 hour); MK-8583 was rapidly eliminated from plasma (t 1/2 0.2-0.4 hours), while MK-8504 had slower elimination (t 1/2 6-8 hours). As expected, plasma TFV concentrations were generally similar, with a median T max of 1-4 hours after both MK-8504 and MK-8583 administration, and a t 1/2 of 20-38 hours for MK-8504 and 19-30 hours for MK-8583. The levels of TFV-DP in PBMCs exhibited a median T max of 4-24 hr for both compounds, with a t 1/2 of 48-115 hours for MK-8504 and 65-192 hours for MK-8504. The PK in PLWH and healthy participants were similar. Despite PBMC TFV-DP concentrations consistently above the efficacious trough concentration for marketed TFV prodrugs (100 nM), HIV-1 VL reduction was suboptimal for both compounds. The mean VL reduction at 7 days was 0.6 log 10 copies/mL for MK-8583 and 0.9 log 10 copies/mL at the top dose of MK-8504, and several participants failed to achieve consistent VL reduction. There was
466 CABOTEGRAVIR AND RILPIVIRINE PK FOLLOWING LONG-ACTING HIV TREATMENT DISCONTINUATION Susan Ford 1 , Herta Crauwels 2 , Kelong Han 3 , Stefaan Rossenu 2 , Feifan Zhang 3 , Jenny O. Huang 4 , David A. Margolis 5 , Kenneth Sutton 5 , Krischan J. Hudson 5 , Peter E. Williams 2 , William Spreen 5 , Parul Patel 5 1 GlaxoSmithKline, Research Triangle Park, NC, USA, 2 Janssen, Beerse, Belgium, 3 GlaxoSmithKline, Collegeville, PA, USA, 4 GlaxoSmithKline, Mississauga, Canada, 5 ViiV Healthcare, Research Triangle Park, NC, USA Background: Long-acting (LA) regimens of cabotegravir (CAB) + rilpivirine (RPV) given monthly and every 2-months are in development for maintenance of HIV suppression. Both products exhibit absorption-rate limited PK following intramuscular (IM) administration, with apparent half-life (t 1/2 ) estimates of 5.6 -11 weeks (CAB) and 28 weeks (RPV). Following LA treatment discontinua- tion, CAB and RPV may remain measurable in plasma for a year or longer. Available long-term follow up (LTFU) pharmacokinetic (PK) data from discontinued subjects in Phase 2b/3 studies (LATTE-2/ATLAS) are presented. Methods: HIV-infected subjects who received CAB LA + RPV LA every 4 (Q4W, n=33) or every 8 weeks (Q8W, n=5) and withdrew for any reason were required to switch to alternative antiretroviral therapy (ART) and enter LTFU (1 year), with PK sampling at 1, 3, 6, 9 and 12 months after final injections. Plasma CAB and RPV concentrations were determined by validated LC-MS/MS assays. RPV concentrations in subjects receiving oral RPV in LTFU were excluded from the results (n=6). Results: Figure 1 represents CAB and RPV plasma concentrations for subjects entering LTFU after having been on CAB LA+RPV LA from 4 to 72 weeks. Plasma
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