Lack of a Pharmacokinetic Effect of Raltegravir on Midazolam: In Vitro/In Vivo Correlation

Iwamoto, Marian; Kassahun, Kelem; Troyer, Matthew D.; Hanley, William D.; Lü, Ping; Rhoton, Alisha; Petry, Amelia S.; Ghosh, Kalyan; Mangin, Eric; DeNoia, Emanuel P.; Wenning, Larissa; Stone, Julie A.; Gottesdiener, Keith; Wagner, John A.

doi:10.1177/0091270007310382

Cited by 75 publications

(60 citation statements)

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“…RAL is not a cytochrome P450 (CYP450) substrate and does not interact with midazolam in vitro and in vivo (8). Metabolism of RAL is dependent on the activity of UDP-glucuronosyltransferase 1A1 (UGT1A1) (11).…”

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confidence: 99%

Pharmacokinetic Modeling of Plasma and Intracellular Concentrations of Raltegravir in Healthy Volunteers

Wang

Soon

Seng

et al. 2011

Antimicrob Agents Chemother

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Raltegravir is a potent inhibitor of HIV integrase. Persistently high intracellular concentrations of raltegravir may explain sustained efficacy despite high pharmacokinetic variability. We performed a pharmacokinetic study of healthy volunteers. Paired blood samples for plasma and peripheral blood mononuclear cells (PBMCs) were collected predose and 4, 8, 12, 24, and 48 h after a single 400-mg dose of raltegravir. Samples of plasma only were collected more frequently. Raltegravir concentrations were determined using liquid chromatography-mass spectrometry. The lower limits of quantitation for plasma and PBMC lysate raltegravir were 2 nmol/liter and 0.225 nmol/liter, respectively. Noncompartmental analyses were performed using WinNonLin. Population pharmacokinetic analysis was performed using NONMEM. Six male subjects were included in the study; their median weight was 67.4 kg, and their median age was 33. RAL is not a cytochrome P450 (CYP450) substrate and does not interact with midazolam in vitro and in vivo (8). Metabolism of RAL is dependent on the activity of UDP-glucuronosyltransferase 1A1 (UGT1A1) (11). These facts suggested that RAL has a low propensity of drug-drug interactions. Nevertheless, there is high variability in the systemic exposure of RAL in human subjects, especially in the concentration 12 h after the dose was given (C 12 ) with coefficients of variation of 212 and 122% for intersubject and intrasubject variability, respectively (14). This variability can be caused by several factors such as food intake (14), gastric pH (9), and genetic polymorphisms, although the effects of UGT1A1 polymorphisms are likely to be modest (22). So far, no strong pharmacokinetic (PK)-pharmacodynamic relationship has been defined despite this considerable PK variability, and RAL remains highly efficacious in most patients. Our hypothesis was that the consistent efficacy of RAL is due to the accumulation of RAL in lymphocytes. This could allow less frequent dosing of raltegravir. However, limited information is available on the intracellular PK of RAL, especially beyond 12 h postdose. This spurred us to investigate the PK profile of RAL in peripheral blood mononuclear cells (PBMCs), the target site of action.We performed a pilot study to model the association of the plasma and intracellular RAL concentrations for 48 h after a single 400-mg RAL dose by determining the time course and half-life of intracellular RAL and modeling the intracellular accumulation of RAL after a single dose. MATERIALS AND METHODS Subjects.We enrolled six healthy male subjects between 21 and 65 years of age. Other inclusion criteria included smoking less than 10 cigarettes per day and laboratory values fulfilling the following criteria: hemoglobin level of Ͼ10.9 g/dl, platelet count of Ն125,000/mm 3 , creatinine clearance of Ն60 ml/min, and lipase or pancreatic amylase level of Ͻ1.1ϫ upper limit of normal. We excluded any significant acute or chronic medical illness that would interfere with the conduct or interpretation of the study. Exc...

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confidence: 99%

Pharmacokinetic Modeling of Plasma and Intracellular Concentrations of Raltegravir in Healthy Volunteers

Wang

Soon

Seng

et al. 2011

Antimicrob Agents Chemother

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“…A 2-period study assessed the influence of raltegravir (800 mg/day) on the pharmacokinetics of midazolam (single 2-mg oral dose), a marker of CYP3A4 activity (Class II). 22 Midazolam AUC and C max in the presence and absence of raltegravir remained within bioequivalence limits, suggesting that raltegravir does not affect CYP3A4 activity.…”

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confidence: 87%

Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS

Birbeck¹,

French²,

Perucca³

et al. 2012

Neurology

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“…In vivo and in vitro studies using isoform selective chemical inhibitors and cDNA-expressed UGTs showed that UGT1A1 is the primary enzyme responsible for the formation of raltegravir-glucuronide (87) (Merck & Co, 2007;Kassahun et al, 2007). In vitro studies demonstrate that raltegravir is not a substrate for cytochrome P450 (CYP) enzymes and does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A or induce 3A4 (Iwamoto et al, 2008). Similarly, raltegravir is not an inhibitor of UGTs (UGT1A1 and UGT2B7) or P-glycoprotein (P-gp)-mediated transport (Merck & Co, 2007).…”

Section: Integrase Inhibitors (Inis)mentioning

confidence: 99%

Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

Andrade

Freitas

Oliveira

2011

Braz. J. Pharm. Sci.

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From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.Uniterms: AIDS/treatment. Drugs/anti-HIV. Drugs/metabolism. Antiretroviral drugs. Biotransformation.Da identificação do HIV como o agente causador da AIDS, ao desenvolvimento de fármacos antirretrovirais eficazes, os avanços científicos na pesquisa sobre o HIV nos últimos vinte e seis anos foram marcantes. Atualmente, existem vinte e cinco fármacos anti-HIV formalmente aprovados pelo FDA para utilização clínica no tratamento da AIDS. Estes compostos são divididos em seis classes: inibidores nucleosídeos de transcriptase reversa (INTR), inibidores nucleotídeos de transcriptase reversa (INtTR), inibidores não-nucleosídeos de transcriptase reversa (INNTR), inibidores de protease (IP), inibidores da entrada celular ou inibidores de fusão (IF), inibidores de co-receptores (ICR) e inibidores de integrase (INI). O metabolismo consiste em um dos maiores determinantes do perfil farmacocinético de um fármaco. A formação de metabólitos ativos ou tóxicos terá impacto nas respostas farmacológicas ou toxicológicas do fármaco. Portanto, é amplamente reconhecido que estudos do metabolismo de uma nova entidade química devem ser realizados durante as fases iniciais do processo de desenvolvimento de fármacos. Este artigo descreve uma abordagem do metabolismo dos fármacos anti-HIV atualmente disponíveis na terapêutica.Unitermos: AIDS/tratamento. Fármacos/anti-HIV. Fármacos/antirretrovirais. Fármacos/metabolismo. Biotransformação. INTRODUCTIONThe human immunodeficiency virus (HIV) has been established as the causative agent of the acquired immunodeficiency syndrome (AIDS) for over twentysix years now (Barré-Sinoussi et al., 1983). During this time, an unprecedented success has been achieved in discovering anti-HIV drugs as reflected by the fact that there are now more drugs approved for the treatment of HIV than for all other viral infections put together (Mehellou, De Clercq, 2009). Despite this progress...

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Lack of a Pharmacokinetic Effect of Raltegravir on Midazolam: In Vitro/In Vivo Correlation

Cited by 75 publications

References 8 publications

Pharmacokinetic Modeling of Plasma and Intracellular Concentrations of Raltegravir in Healthy Volunteers

Pharmacokinetic Modeling of Plasma and Intracellular Concentrations of Raltegravir in Healthy Volunteers

Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS

Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

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