Raltegravir Plasma Concentrations in Treatment-Experienced Patients Receiving Salvage Regimens Based on Raltegravir with and without Maraviroc Coadministration

Baroncelli, Silvia; Villani, Paola; Weimer, Liliana Elena; Ladisa, Nicoletta; Francisci, Daniela; Tommasi, Chiara; Vullo, Vincenzo; Preziosi, Roberta; Cicalini, Stefania; Cusato, Maria; Galluzzo, Clementina Maria; Floridia, Marco; Regazzi, Mario

doi:10.1345/aph.1m688

Cited by 15 publications

(17 citation statements)

References 17 publications

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“…For the same reasons, C 0 ‐based approaches cannot be applied to monitor RAL exposure in clinical trials. Therefore, it can not be excluded that findings from recent studies aimed at investigating potential drug‐to‐drug interactions between RAL and other HAART in HIV‐infected individuals might have been biased by the use of RAL trough concentration as the only pharmacokinetic biomarker of daily drug exposure 10 – 12 …”

Section: Discussionmentioning

confidence: 99%

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Limited Sampling Strategies for the Estimation of Raltegravir Daily Exposure in HIV‐Infected Patients

Cattaneo

Ripamonti²,

Gervasoni

et al. 2012

The Journal of Clinical Pharma

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Stepwise multiple regression analyses were applied to 50 raltegravir pharmacokinetic profiles from 50 HIV patients with the goal to identify limited sampling strategies for the prediction of drug area under the time-concentration curve (AUC(0-12)). Raltegravir single sampling point-based equations failed to reliably predict daily drug exposure. Conversely, different algorithms based on few samples and associated with good correlation, acceptable bias, and imprecision with the measured raltegravir AUC(0-12) were identified. These models could used to predict raltegravir exposure for clinic or research purposes.

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Section: Discussionmentioning

confidence: 99%

“…RAL trough plasma concentration is increasingly used as biomarker of daily patient exposure to the drug 10 – 12 . Nevertheless, the value of trough concentrations to predict daily exposure to RAL in a reliable way is still unproven.…”

mentioning

confidence: 99%

Limited Sampling Strategies for the Estimation of Raltegravir Daily Exposure in HIV‐Infected Patients

Cattaneo

Ripamonti²,

Gervasoni

et al. 2012

The Journal of Clinical Pharma

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“…The mechanism behind this modest reduction in raltegravir levels is unclear. In a study of 54 heavily treatment‐experienced HIV‐infected patients taking raltegravir as part of a salvage regimen, median raltegravir C 12h values did not substantially differ in those also taking maraviroc (243 nM, n = 11) versus those not taking maraviroc (211 nM, n = 43) 87 . The effect of multiple doses of raltegravir on the multiple‐dose pharmacokinetics of maraviroc was also assessed and found to be minimal.…”

Section: Entry Inhibitorsmentioning

confidence: 99%

Clinical Pharmacology Profile of Raltegravir, an HIV-1 Integrase Strand Transfer Inhibitor

Brainard

Wenning

Stone

et al. 2011

The Journal of Clinical Pharmacology

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Raltegravir is an HIV-1 integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. Data from healthy volunteers demonstrate that raltegravir is rapidly absorbed with a mean half-life of approximately 7 to 12 hours, with steady state achieved in approximately 2 days. Raltegravir is characterized by both high intra- and interindividual variabilities, although neither gender, race, age, body mass index, food intake, nor renal or hepatic insufficiency has a clinically meaningful effect on raltegravir pharmacokinetics. Raltegravir lacks activity as a perpetrator of drug-drug interactions and demonstrates a low propensity to be subject to drug-drug interactions. Raltegravir is metabolized primarily by UGT1A1 and is not affected by P450 inhibitors or inducers. Inhibitors of UGT1A1 (eg, atazanavir) can increase plasma concentrations of raltegravir, although this increase has not been found to be clinically meaningful. Likewise, inducers of UGT1A1 (eg, rifampin) can reduce plasma concentrations of raltegravir, and the clinical significance of this reduction is being investigated in ongoing clinical studies. Raltegravir demonstrates favorable clinical pharmacology and a drug interaction profile that permits administration to a wide, demographically diverse patient population and coadministration with many other therapeutic agents, including antiretroviral agents and supportive medications, without restrictions or dose adjustment.

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“…RAL absorption is rapid and is affected by food intake (5) as well as by coadministered medications that affect gastric pH (3,8,10). It is highly bound to plasma proteins (83%) (8) and eliminated primarily by UDP glucuronosyltransferase 1A1 (UGT1A1), with minor contributions from UGT1A3 and UGT1A9 (22).…”

mentioning

confidence: 99%

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

Arab‐Alameddine

Fayet-Mello

Lubomirov

et al. 2012

Antimicrob Agents Chemother

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iThe 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 onceand 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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Raltegravir Plasma Concentrations in Treatment-Experienced Patients Receiving Salvage Regimens Based on Raltegravir with and without Maraviroc Coadministration

Cited by 15 publications

References 17 publications

Limited Sampling Strategies for the Estimation of Raltegravir Daily Exposure in HIV‐Infected Patients

Limited Sampling Strategies for the Estimation of Raltegravir Daily Exposure in HIV‐Infected Patients

Clinical Pharmacology Profile of Raltegravir, an HIV-1 Integrase Strand Transfer Inhibitor

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

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