CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

428 Inflammation Investigated as a Source of Atazanavir Pharmacokinetic Variability Charles Venuto 1 ; PeterW. Hunt 2 ; Grace A. McComsey 3 ; Gene D. Morse 4 ; Susan Messing 1 1 Univ of Rochester Med Cntr, Rochester, NY, USA; 2 Univ of California San Francisco, San Francisco, CA, USA; 3 Case Western Reserve Univ, Cleveland, OH, USA; 4 State Univ of New York at Buffalo, Buffalo, NY, USA Background: Inflammation is associated with the downregulation of drug metabolizing enzymes and transporters including cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp). Thus, the chronic inflammatory state associated with HIV-infection may be a source of pharmacokinetic variability of antiretrovirals that are substrates or inhibitors of CYP3A or P-gp. We analyzed plasma atazanavir (ATV) and inflammatory marker concentration obtained from AIDS Clinical Trials Group (ACTG) protocols A5202 and A5224s to determine if changes in inflammatory markers were associated with ATV clearance. Methods: ACTG protocol A5202 randomized treatment-naïve adults to ATV/ritonavir (ATV/r) or efavirenz, with blinded tenofovir disproxil fumarate/emtricitabine or abacavir/ lamuvidine. Plasma ATV clearance for each individual was estimated by population PK modeling. Several biomarkers were measured at weeks 0, 24, and 96: high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor alpha and its soluble receptors (TNF-α, sTNFR-I, -II), soluble vascular cellular and intracellular adhesion molecules (sVCAM-1, sICAM-1), and total bilirubin. Statistical analysis was performed by a matrix of Spearman correlation coefficients between ATV clearance and biomarkers at weeks 24 and 96, and changes from baseline. Results: There were 107 participants with both available ATV clearance and biomarker concentrations. Significant correlations were observed between ATV clearance and changes in sTNFR-II fromweeks 0 to 24 (rho = -0.24, P = 0.01), in sVCAM-1 fromweeks 0 to 96 (rho = -0.24, P = 0.02) and in bilirubin fromweeks 0 to 96 (rho = 0.22, P = 0.04). Bilirubin concentrations were inversely correlated with each of the inflammatory markers at weeks 24 and 96 (rho: -0.17 – -0.51, P < 0.002) except hsCRP (P = 0.45). Conclusions: The clearance of ATV was not significantly correlated with the majority of measured inflammatory biomarker changes. Inflammatory-mediated inhibition of CYP3A may have been attenuated due to ATV-associated increases of bilirubin, which has known anti-inflammatory properties and indeed was negatively correlated with most inflammatory markers in this study. The effects of chronic inflammation due to HIV infection on the pharmacokinetics of antiretrovirals should be further assessed in CYP3A metabolized agents that do not alter bilirubin concentrations. 429 Recommended Efavirenz Concentration for Therapeutic Drug Monitoring Is Too High Catherine Orrell 1 ; Andrzej Bienczak 1 ; Karen Cohen 1 ; David R. Bangsberg 2 ; RobinWood 1 ; Gary Maartens 1 ; Paolo Denti 1 1 Univ of Cape Town, Cape Town, South Africa; 2 Harvard Med Sch, Boston, MA, USA Background: The therapeutic range for efavirenz plasma concentrations is unclear, with some studies failing to find a correlation with virologic outcomes. EFV concentrations are highly variable, driven in part by polymorphisms in cytochrome P450 (CYP) 2B6, which make it an attractive candidate for therapeutic drug monitoring (TDM) if therapeutic ranges could be established. We hypothesised that EFV mid-dosing concentrations, together with cytochrome P450 (CYP) 2B6 metaboliser genotype status, could predict virological outcomes in an ART-naïve cohort. Methods: ART-naïve participants from a South African outpatient antiretroviral therapy (ART) clinic were monitored for the first 48 weeks on EFV-based ART. CD4 cell count and HIV-RNA were determined at baseline, week 16 and 48. Samples for EFV concentrations at mid-dose interval were drawn at weeks 16 and 48. CYP 2B6 genotyping (516G  T and 983T  C) data was used to determine metaboliser status. Cox proportional hazards modelling was used to predict virological outcome. Comparison of Akaike Information Criterion (AIC) values was used to determine the most predictive lower limit of mid-dosing EFV concentration. Results: 180 participants with both EFV concentrations and HIV-RNA available were included in the study. Median EFV concentrations were 2.3mg/L (IQR1.6-4.6) and 2.21mg/L (IQR1.5-3.9) at weeks 16 and 48. 49 (27.2%), 84 (46.7%) and 39 (21.7%) participants had extensive, intermediate and slow or ultra-slow CYP2B6 metaboliser genotype respectively. Only log 2 EFV concentrations [adjusted hazard ratio (aHR) 0.81, 95% confidence interval (95%CI) 0.72-0.92] and baseline CD4 cell count [aHR 0.99, 95% CI 0.99-1.0] were predictive of virological outcome. For every doubling in drug concentration there was a 21% decrease in the hazard of viral failure (p=0.001); and for every 50 cell increase in baseline CD4 count there was a 31% reduction in the hazard of non-suppression. The most predictive lower limit for mid-dosing EFV concentration was 0.7 mg/L. Conclusions: Mid-dosing EFV concentrations are predictive of virological outcome, but the currently recommended lower therapeutic limit (1 mg/L) for TDM is higher than our finding. Knowledge of CYP2B6 metaboliser genotype is not required for prediction of virological outcomes, suggesting that adherence is the key determinant. 430 Cobicistat Increases the Effects of Dabigatran on Thrombin Time in Healthy Volunteers Kristina M. Brooks 1 ; Colleen Hadigan 2 ; Lori A. Gordon 3 ; Scott Penzak 4 ; Anela Kellogg 5 ; Khanh Nghiem 6 ; Jay Lozier 6 ; James Mikula 5 ; Parag Kumar 1 1 Clinical Pharmacokinetics Rsr Lab, Clinical Cntr, NIH, Bethesda, MD, USA; 2 NIAID, NIH, Bethesda, MD, USA; 3 Xavier Univ of Louisiana Coll of Pharm, New Orleans, LA, USA; 4 Univ of North Texas System Coll of Pharm, Fort Worth, TX, USA; 5 Leidos Biomed Rsr, Inc, Bethesda, MD, USA; 6 Clinical Cntr, NIH, Bethesda, MD, USA Background: Dabigatran etexilate (DE) is an oral direct thrombin inhibitor and substrate of intestinal Permeability-glycoprotein (P-gp) and renal multidrug and toxin extrusion-1 (MATE-1) transporters. Cobicistat (COBI) is a pharmacokinetic (PK) enhancer and inhibitor of P-gp and renal MATE-1 transporters, which may result in increased DE exposure when co-administered. Using thrombin time (TT), we sought to characterize the pharmacodynamic (PD) effects of COBI on DE, and if this potential interaction may be mitigated by separated administration. Methods: This was a single-center, open-label, fixed sequence, intra-subject study conducted in healthy volunteers. The study was comprised of 3 phases: (1) DE 150 mg x1 alone (day 0), (2) DE 150 mg x1 two hours prior to COBI 150 mg (day 19±1), and (3) DE 150 mg x1 with COBI 150 mg (day 26±1). Subjects underwent a 5-day washout period following phase 1, followed by COBI 150 mg once daily throughout Phases 2 and 3 (days 5 - 26±1). Blood was collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on DE dosing days. TT was determined using STA®-Thrombin reagent (Diagnostica Stago, Asnières-sur-Seine, France). Noncompartmental methods were used to derive DE PD parameters (TT area- under-the-effect-curve [AUEC] and thrombin time at 24 hours [TT-last]). Geometric mean ratios (GMR) with 90% confidence intervals [CI] were compared between phases and p-values were calculated using a two-tailed paired t-test. Results: A total of 13 subjects have been enrolled, with 11 completing the study and 2 without phase 3 data due to lack of study compliance. There was a 32% and 33% increase in AUEC GMR between Phase 2 and Phase 1 (p<0.0001, 90% CI [1.21, 1.43]), and Phase 3 and Phase 1 (p<0.001, 90% CI 1.21-1.44), respectively. Significant increases in TT-last GMR of 57% and 29%were also observed between Phase 2 and Phase 1 (p<0.001, 90% CI [1.34, 1.72]) and Phase 3 and Phase 1 (p<0.001, 90% CI [1.37, 1.88]), respectively. No significant differences were noted between Phase 3 and Phase 2 in GMR of AUEC (p=0.9466, 90% CI [0.92, 1.10]) or TT-last (p=0.6685, 90% CI [0.91, 1.21]). Conclusions: COBI co-administration resulted in significant increases in TT AUEC and TT-last compared to DE alone. These effects were preserved despite separating COBI and DE administration by 2 hours, supporting the putative mechanisms of P-gp and MATE-1 inhibition by COBI. Further analyses of changes in DE PK-PD relationships are needed to explore the clinical implications of this interaction.

Poster Abstracts


CROI 2016

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