Raltegravir Pharmacokinetics in Treatment-Naive Patients Is Not Influenced by Race: Results from the Raltegravir Early Therapy in African-Americans Living with HIV (REAL) Study

Abstract

Racial differences in antiretroviral treatment responses remain incompletely explained and may be a consequence of differential pharmacokinetics (PK) associated with race. Raltegravir, an inhibitor of HIV-1 integrase, is commonly used in the treatment of HIV-infected patients, many of whom are African-American. However, there are few data regarding the PK of raltegravir in African-Americans. HIV-infected men and women, self-described as African-American and naive to antiretroviral therapy were treated with raltegravir (RAL) at 400 mg twice a day, plus a fixed dose of tenofovir-emtricitabine (TDF/FTC) at 300 mg/200 mg once daily. Intensive PK sampling was conducted over 24 h at week 4. Drug concentrations at two trough values of 12 and 24 h after dosing (C 12 and C 24 ), area under the concentration-curve values (AUC), maximum drug concentration (C max ), and the time at which this concentration occurred (T max ) in plasma were estimated with noncompartmental pharmacokinetic methods and compared to data from a subset of white subjects randomized to the RAL twice a day (plus TDF/FTC) arm of the QDMRK study, a phase III study of the safety and efficacy of once daily versus twice daily RAL in treatment naive patients. A total of 38 African-American participants were enrolled (90% male) into the REAL cohort with the following median baseline characteristics: age of 36 years, body mass index (BMI) of 23 kg/m 2 , and a CD4 cell count of 339/ml. Plasma HIV RNA levels were below 200 copies/ml in 95% of participants at week 4. The characteristics of the 16 white QDMRK study participants were similar, although fewer (69%) were male, the median age was higher (45 years), and BMI was lower (19 kg/m 2 ). There was considerable interindividual variability in RAL concentrations in both cohorts. Median C 12 in REAL was 91 ng/ml (range, 10 to 1,386) and in QDMRK participants was 128 ng/ml (range, 15 to 1,074). The C max median concentration was 1,042 ng/ml (range, 196 to 10,092) for REAL and 1,360 ng/ml (range, 218 to 9,701) for QDMRK. There were no significant differences in any RAL PK parameter between these cohorts of African-American and white individuals. Based on plasma PK, and with similar adherence rates, the performance of RAL among HIV-infected African-Americans should be no different than that of infected patients who are white.

Raltegravir Pharmacokinetics During Pregnancy

“…In the REAL study, Wohl et al found the median concentration at 12 hours after dosing to be 0.091 µg/mL with a range of 0.010–1.386 µg/mL. 12 Despite the wide variability, 95% of subjects had an HIV RNA level below 200 copies/mL by week four of treatment. 12 In the QDMRK trial comparing once daily to twice daily dosing, the trough level with twice daily dosing was 0.128 µg/mL with a range of 0.015–1.074 µg/mL.…”

“…12 Despite the wide variability, 95% of subjects had an HIV RNA level below 200 copies/mL by week four of treatment. 12 In the QDMRK trial comparing once daily to twice daily dosing, the trough level with twice daily dosing was 0.128 µg/mL with a range of 0.015–1.074 µg/mL. 13 In this trial, trough levels correlated with virologic response with once daily dosing, but not with twice daily dosing.…”

Effects of raltegravir combined with tenofovir/emtricitabine on body shape, bone density, and lipids in African-Americans initiating HIV therapy

“…The primary aim of the study was to determine RAL pharmacokinetics in this population compared to those derived from white patients – results that have been previously been published. 26 A secondary objective was to describe the metabolic changes of participants experienced while receiving this antiretroviral combination. In addition to being AA, inclusion criteria included having had less than seven cumulative days of prior exposure to antiretroviral therapy, a plasma HIV RNA level >1,000 copies/ml at the time of screening, an estimated glomerular filtration rate by Modification of Diet in Renal Disease (MDRD) of at least 60 ml/min/1.73 m 2 , and hepatic transaminase levels no more than three times the upper limit of normal.…”

Effect of HIV Infection and Menopause Status on Raltegravir Pharmacokinetics in the Blood and Genital Tract

“…Additionally, the lack of an HIV-negative postmenopausal cohort makes discerning the effect of HIV infection vs menopausal status on raltegravir pharmacokinetics difficult. The differing proportion of black women among our cohorts are unlikely to confound the pharmacokinetic data presented herein, given that the Raltegravir early therapy in African-Americans living with HIV (REAL) study did not identify any raltegravir plasma pharmacokinetic differences based on race[15]. Finally, in our study premenopausal women received raltegravir in the fed state while postmenopausal women were in the fasted state.…”

“…The dynamic range for raltegravir in BP was 20-10,000ng/mL and in CVF was 50-10,000ng/mL with a minimum of 90% accuracy, and inter-and intra-day variability of 2.4-7.9% and 1.4-3.8%, respectively [15-17]. …”