\Population Pharmacokinetic Analysis and Pharmacogenetics of Raltegravir in HIV-Positive and Healthy Individuals

Division of Clinical Pharmacology and Toxicology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 02/2012; 56(6):2959-66. DOI: 10.1128/AAC.05424-11
Source: PubMed


The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

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    • "Moreover, the SVR rate is known to be lower in HIV-HCV coinfected than in HCV monoinfected patients. One possible explanation could be that, as for other drugs, HIV infected patients present a lower bioavailability of RBV [18]. The aim of this study was to determine early plasma exposure evaluated by the AUC0-4h after a first dose of RBV in a population of HIV-HCV coinfected patients and to compare the results to those obtained in HCV monoinfected patients. "
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    ABSTRACT: In HIV infected patients, the impact of ribavirin (RBV) pharmacology on sustained virologic response (SVR) to hepatitis C virus (HCV) treatment has not been fully investigated. The objective of this study was to compare the early RBV plasma exposure between a population of HIV-HCV coinfected patients and an HCV monoinfected group. Early RBV plasma exposure (expressed as Area Under the Curve (AUC) from 0 to 4 h) after a 600 mg first dose of RBV was measured in a population of HIV-HCV coinfected patients in comparison with an HCV monoinfected group. Peripheral blood samples were collected before the 600 mg RBV first dose (T0) to ensure no detectable baseline plasma RBV, and then 30 mn, 1, 2 and 4 hours after RBV intake (T0.5, T1, T2 and T4). Eighty-six patients with chronic hepatitis C entered the study among whom 23 (27%) were HIV-HCV coinfected. Coinfected patients had a significantly lower RBV-AUC 0-4h (median: 1469 mug*h/L [range 936-3677]) compared with monoinfected patients (2030 mug*h/L [851-7700]; p = 0.018). This RBV under exposure in coinfected patients persisted after normalization of AUC to RBV dose per kilogram of body weight (182 mug*h/L [110-425] versus 271 mug*h/L [82-1091], p = 0.001). These results suggest that lower early bioavailability of RBV could be one of the reasons for lower SVR in HIV-HCV coinfected patients treated with pegylated interferon/RBV combination therapy. RBV plasma underexposure seems to be associated with the immunological status of the patients with lower AUC0-4h values observed in the more immunosuppressed coinfected patients.
    BMC Infectious Diseases 03/2014; 14(1):150. DOI:10.1186/1471-2334-14-150 · 2.61 Impact Factor
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    ABSTRACT: Medicinal herbs may cause clinically relevant drug interactions with antiretroviral agents. Ginkgo biloba extract is a popular herbal product among HIV-infected patients because of its positive effects on cognitive function. Raltegravir, an HIV integrase inhibitor, is increasingly being used as part of combined antiretroviral therapy. Clinical data on the potential inhibitory or inductive effect of ginkgo biloba on the pharmacokinetics of raltegravir were lacking, and concomitant use was not recommended. We studied the effect of ginkgo biloba extract on the pharmacokinetics of raltegravir in an open-label, randomized, two-period, crossover phase I trial in 18 healthy volunteers. Subjects were randomly assigned to a regimen of 120 mg of ginkgo biloba twice daily for 15 days plus a single dose of raltegravir (400 mg) on day 15, a washout period, and 400 mg of raltegravir on day 36 or the test and reference treatments in reverse order. Pharmacokinetic sampling of raltegravir was performed up to 12 h after intake on an empty stomach. All subjects (9 male) completed the trial, and no serious adverse events were reported. Geometric mean ratios (90% confidence intervals) of the area under the plasma concentration-time curve from dosing to infinity (AUC(0-∞)) and the maximum plasma concentration (C(max)) of raltegravir with ginkgo biloba versus raltegravir alone were 1.21 (0.93 to 1.58) and 1.44 (1.03 to 2.02). Ginkgo biloba did not reduce raltegravir exposure. The potential increase in the C(max) of raltegravir is probably of minor importance, given the large intersubject variability of raltegravir pharmacokinetics and its reported safety profile.
    Antimicrobial Agents and Chemotherapy 07/2012; 56(10):5070-5. DOI:10.1128/AAC.00672-12 · 4.48 Impact Factor
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    ABSTRACT: The pharmacokinetics of raltegravir (RAL) in HIV patients is characterised by high inter/intra-patient variability. We investigated the potential contribution of the drug pharmaceutical formulation on RAL pharmacokinetics.We firstly compared in vivo the pharmacokinetics of RAL from 67 patients in which the drug was administered by swallowing the intact tablet with those obtained from 13 HIV-infected patients that chewed the RAL tablet due to swallowing difficulties. Subsequently, we evaluated in vitro the dissolution of RAL tablets under different conditions.In the in vivo study we found that patients given RAL by chewing the tablets presented pharmacokinetic profiles characterised by significantly higher RAL absorption compared with patients receiving the drug by swallowing. The in vitro studies showed that when the whole tablets were exposed to an acidic medium the release of RAL was very low, whereas when crushed the profiles presented significantly higher concentrations of RAL. Crushed tablets tested in water or in a pH 6.8 buffer exhibited prompt and complete dissolution of RAL.HIV-infected patients receiving RAL by chewing the tablet showed higher drug absorption and reduced pharmacokinetic variability compared with patients swallowing the intact tablet. This is related to problems in the tablet disintegration and to erratic drug absorption. The amelioration of the RAL pharmaceutical formulation could improve drug pharmacokinetics.
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