CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Conclusion: The relative concentrations of both integrase (RAL) and protease (ATV) inhibitors were higher in ileum compared to rectum. In a limited number of participants, concentrations of RAL were significantly lower in lymph nodes compared to gut mucosa, confirming prior observations. These results support and add to the current limited data on tissue ART drug concentrations and have potential implications on HIV cure strategies. 408 PLASMA AND INTRACELLULAR PK OF TENOFOVIR IN PATIENTS SWITCHED FROM TDF TO TAF Anthony Podany , Sara H. Bares, Joshua Havens, Ravi Dyavar Shetty, Jennifer O’Neill, Sarah Lee, Courtney Fletcher, Susan Swindells, Kimberly K. Scarsi Univ of Nebraska, Omaha, NE, USA Background: Tenofovir alafenamide (TAF), a pro-drug of tenofovir (TFV), has higher intracellular penetration and lower plasma concentrations than tenofovir disoproxil fumarate (TDF). Intraindividual comparisons of plasma and intracellular pharmacokinetics (PK) of TFV and its intracellular metabolite, tenofovir-diphosphate (TFV-DP) have not been described in patients switching from TDF to TAF. Methods: We conducted a prospective, non-randomized, cross-over, PK study in participants receiving a TDF-based antiretroviral therapy (ART) regimen (TDF 300mg/FTC 200mg/COBI 150mg/EVG 150mg) who were switching to a TAF containing regimen (TAF 10mg/FTC 200mg/COBI 150mg/EVG 150mg). Single, sparse plasma and PBMC samples were collected prior to switching therapy and 4 to 8 weeks post-switch to TAF. Plasma TFV and cell associated TFV-DP concentrations were determined with validated liquid chromatography tandemmass spectrometry methods. PBMC cell enumeration was performed by quantification of RNase P (RPP30) copy numbers by a highly sensitive droplet digital PCR assay. Patient characteristics are summarized as median (interquartile range, IQR); PK data are summarized as geometric mean (IQR), and compared pre- and post- switch using a geometric mean ratio (GMR) of TAF:TDF, and Wilcoxon signed rank test. Results: 30 participants completed both study visits: 4 (13%) female, 10 (33%) black non-hispanic, and 39 (25-58) years of age. All participants had undetectable (<20cpm) HIV-1 RNA prior to switching ART and median CD4+ count of 632 (429-713) cells/mm3. Time of blood sampling post dose was 11.2 (4.1-18.6) hrs during TDF-based ART and 10.8 (2.7-17.4) hrs during TAF-based ART. TFV plasma concentrations during TDF-based ART were 100.0 (57.1-147.3) ng/mL and 10.2 (9.8-13.7) ng/mL during TAF-based ART (GMR 0.10; p<0.001). TFV-DP concentrations during the TDF-based regimen were 346.9 (149.3-617.4) fmol/million cells and 834.7 (526.0-1110.9) fmol/million cells in participants receiving TAF-based ART (GMR = 2.4, p=0.004). Conclusion: Plasma TFV concentrations significantly decreased after switching to TAF, coinciding with the lower dose of tenofovir contained in the TAF-based ART regimen. Conversely, intracellular TFV-DP concentrations were significantly increased with the TAF-based regimen. This study provides the first intraindividual plasma and intracellular PK data in virologically suppressed HIV+ individuals switching from TDF to TAF. 409 COBICISTAT, BUT NOT RITONAVIR, INCREASES DABIGATRAN EXPOSURE Kristina M. Brooks 1 , Lori A. Gordon 2 , Scott Penzak 3 , Anela Kellogg 4 , Maryellen McManus 1 , Khanh Nghiem 1 , Jay Lozier 1 , Jomy M. George 1 , Colleen Hadigan 5 , Parag Kumar 1 1 NIH, Bethesda, MD, USA, 2 Xavier Univ of Louisiana, New Orleans, LA, USA, 3 Univ of North Texas, Fort Worth, TX, USA, 4 Leidos Biomed Rsr, Inc, Bethesda, MD, USA, 5 NIAID, Bethesda, MD, USA Background: Ritonavir (RTV) and cobicistat (COBI) are antiretroviral pharmacokinetic (PK) enhancers that can inhibit several drug transporters, including P-glycoprotein (P-gp) and renal multidrug and toxin extrusion-1 (MATE-1). Dabigatran etexilate (DE) is the prodrug form of the oral direct thrombin inhibitor, dabigatran, and is a substrate for these transporters. Thus, this study aimed to evaluate the effects of separated and simultaneous administration of RTV and COBI on dabigatran PK. Methods: This was a single-center, open-label, fixed-sequence study in HIV-negative healthy volunteers. Subjects received either RTV 100 mg (Arm A) or COBI 150 mg (Arm B) once daily (Days 5 - 26±1). Each armwas comprised of 3 phases (Ph): (1) DE 150 mg x1 alone (Day 0) followed by a 5-day washout, (2) DE 150 mg x1 2 hours before RTV or COBI (Day 19±1), and (3) DE 150 mg x1 simultaneously with RTV or COBI (Day 26±1). Blood samples were collected serially over 24 hours after each DE dose, and were analyzed using a UPLC-MS/MS method. PK parameters were determined using noncompartmental methods (Phoenix WinNonlin, v6.4). Geometric mean ratios with 90% confidence intervals (CI) were compared between phases and p-values were calculated using a 2-tailed paired t-test. Results: A total of 36 subjects were enrolled, with 16 fully completing each arm. With RTV, dabigatran area-under-the-concentration-time curve from 0 to ∞ (AUC0-∞) and peak concentrations (Cmax) were decreased by 29% (p<0.01, 90% CI [0.60-0.82]) and 27% (p<0.01, [0.61-0.85]), respectively, between Ph 2 vs. 1, with no change in half-life (t1/2). No significant changes in dabigatran PK were observed in Ph 3 vs. 1. In contrast, COBI increased dabigatran AUC0-∞ by 110% (p<0.0001, [1.65-2.54]) and Cmax by 99% (p<0.0001, [1.42-2.56]) in Ph 2 vs. 1, and increased both dabigatran AUC0-∞ and Cmax by 127% in Ph 3 vs. 1 (p<0.0001 for both, [1.81-2.73] and [1.59-2.96], respectively). The t1/2 in Ph 2 and 3 was reduced marginally by 7% and 8%, respectively, vs. Ph 1 (p<0.05 for both). Conclusion: No significant changes in dabigatran exposure were observed with simultaneous RTV administration, possibly due to mixed induction and inhibition of P-gp by RTV. Conversely, COBI resulted in significant increases in dabigatran exposure that persisted despite separating administration, most likely due to intestinal P-gp inhibition. These findings suggest RTV and DE can likely be coadministered, whereas use of DE and COBI may require reduced dosing and prudent clinical monitoring.

Poster and Themed Discussion Abstracts

409a EARLY TERMINATION OF A PK STUDY BETWEEN DOLUTEGRAVIR AND WEEKLY ISONIAZID/RIFAPENTINE Kristina M. Brooks 1 , Alice K Pau 2 , Jomy M. George 1 , Raul Alfaro 1 , Anela Kellogg 3 , Mary McLaughlin 2 , Maryellen McManus 1 , Colleen Hadigan 2 , Joseph A. Kovacs 1 , Parag Kumar 1

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