Browsing by Author "Friedman, Allon"

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    2541. Steady-state PK of Fixed Dose Dolutegravir+Rilpivirine in Hemodialysis
    (Oxford University Press, 2023-11-27) Gupta, Samir K.; Friedman, Allon; Zeruesenay, Desta; Medicine, School of Medicine
    Background: Fixed dose combination (FDC) dolutegravir (DTG) plus rilpivirine (RPV) is an approved antiretroviral treatment regimen for people with HIV. The steady-state PK of FDC DTG+RPV in those requiring hemodialysis (HD) has not been previously studied. Methods: We performed a single-center, prospective evaluation of the steady-state PK of FDC DTG (50mg)+RPV(25mg) in HIV-negative adults either requiring HD (n=4; 2 men, 2 women) or with normal renal function, defined as CrCl ≥ 75mL/min (n=2; 1 man, 1 woman). All participants received DTG+RPV daily for 10-14 days with food before undergoing an intensive 24-hour PK evaluation (performed between dialysis days for those requiring HD). Plasma drug and metabolite concentrations were measured using a validated LC/MS/MS assay method (QTRAP 6500+LC-MS/MS system) with turboelectrospray source operating in both positive (confirmation) and negative (quantification) modes. We did not evaluate dialysis extraction of DTG+RPV. Descriptive PK parameters were calculated. Results: No participant experienced serious or grade 3-4 adverse events; there were no study discontinuations. The 4 HD and 2 normal renal function participants were of similar ages (range, 50-60 vs 53-58 years) and BMI (range, 18.5-28.2 vs 20.3-24.0 kg/m2). The Table shows the PK parameters assessed in the study population for circulating plasma DTG, DTG-glucuronide (DTG’s primary metabolite), and RPV. Conclusion: In this study, HD did not lead to clinically appreciable differential exposures to DTG and RPV; the markedly increased exposure to DTG-glucoranide (which is considered inert) in HD suggests increased UGT1A1 activation. All participants maintained exposures throughout the dosing interval greater than the reported IC90 efficacy values for DTG (64ng/mL) and RPV (12ng/mL). These data suggest no dosing modifications are needed for the FDC DTG+RPV regimen in HD.
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    Value of Urinary Albumin-to-Creatinine Ratio as a Predictor of Type 2 Diabetes in Pre-Diabetic Individuals
    (2008-12) Friedman, Allon; Marrero, David G.; Ma, Yong; Ackermann, Ronald; Narayan, KM Venkat; Barrett-Connor, Elizabeth; Watson, Karol; Knowler, William C.; Horton, Edward S.
    OBJECTIVE: The albumin-to-creatinine ratio (ACR) reflects urinary albumin excretion and is increasingly being accepted as an important clinical outcome predictor. Because of the great public health need for a simple and inexpensive test to identify individuals at high risk for developing type 2 diabetes, it has been suggested that the ACR might serve this purpose. We therefore determined whether the ACR could predict incident diabetes in a well-characterized cohort of pre-diabetic Americans. RESEARCH DESIGN AND METHODS: A total of 3,188 Diabetes Prevention Program (DPP) participants with a mean BMI of 34 kg/m(2) and elevated fasting glucose, impaired glucose tolerance, and baseline urinary albumin excretion measurements were followed for incident diabetes over a mean of 3.2 years. RESULTS: Of the participants, 94% manifested ACR levels below the microalbuminuria range and 21% ultimately developed diabetes during follow-up. Quartiles of ACR (median [range] within quartiles: 1, 3.0 [0.7-3.7]; 2, 4.6 [3.7-5.5]; 3, 7.1 [5.5-9.7]; and 4, 16.5 [9.7-1,578]) were positively associated with age, markers of adiposity and insulin secretion and resistance, blood pressure, and use of antihypertensive agents with antiproteinuric effects and inversely related to male sex and serum creatinine. An elevated hazard rate for developing diabetes with doubling of ACR disappeared after adjustment for covariates. Within the DPP intervention groups (placebo, lifestyle, and metformin), we found no consistent trend in incident diabetes by quartile or decile of ACR. CONCLUSIONS: An ACR at levels below the microalbuminuria range does not independently predict incident diabetes in adults at high risk of developing type 2 diabetes.