Determination of the HIV integrase inhibitor, MK-0518 (raltegravir), in human plasma using 96-well liquid–liquid extraction and HPLC-MS/MS

Merschman, Sheila A; Vallano, Patrick T.; Wenning, Larissa; Matuszewski, B.K.; Woolf, Eric

doi:10.1016/j.jchromb.2007.06.032

Cited by 64 publications

(85 citation statements)

References 9 publications

(7 reference statements)

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“…When raltegravir is administered by a single 400 mg dose, plasma concentrations are expected in the 0.01 to 4.71 mg/ml range. [16][17][18] In this study, raltegravir concentrations at steady state following multiple-dose administration ranged from 1.2 to 5.2 mg/ml.…”

Section: Lc-ms Chromatogramsmentioning

confidence: 70%

“…Both inter-and intraday RSDs for raltegravir were less than 10.4%, which is similar to previously reported values. 16) Recovery of raltegravir was more than 80.6%. These results indicate our newly developed method achieves the same level of reproducibility and accuracy as the LC-MS/MS method.…”

Section: Discussionmentioning

confidence: 94%

“…Until now there has been a methodological report for the determination of raltegravir using LC-MS/MS. 16) However, this method has several disadvantages in terms of cost performance and essential equipment; for example, the authors used isotoped labeled raltegravir and/or the setting of the LC-MS-MS equipment.…”

Section: Discussionmentioning

confidence: 99%

“…The RSDs calculated for raltegravir in the interand intraday assays ranged from 1.3 to 10.4%, which are similar to previously reported values. 16) Accuracies ranged from 97.2 to 103.4%. Recoveries from plasma ranged from 80.6 to 87.4%.…”

Section: Lc-ms Chromatogramsmentioning

confidence: 99%

“…16) However, the MS-MS detector needs to be delicately set and LC-MS/MS equipment is very expensive. In addition, isotope labeled raltegravir as an internal standard (IS) is needed.…”

mentioning

confidence: 99%

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A Conventional LC-MS Method Developed for the Determination of Plasma Raltegravir Concentrations

Takahashi

Konishi

Kudaka

et al. 2008

Biological & Pharmaceutical Bulletin

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Raltegravir belongs to a new class of antiretrovirals acting for a human immunodeficiency virus (HIV)-1 integrase inhibition. Clinical trials of this drug have demonstrated potent antiviral activity in both therapy naïve and experienced patients. Thus, raltegravir has become an important component of combination treatment regimens used to treat patients with multidrug-resistant HIV-1. The quantification of raltegravir in human plasma is important to support clinical studies and determine pharmacokinetic parameters of raltegravir in HIV-1 infected patients. Recently, the LC-MS/MS superfine system was developed to determine plasma concentration of raltegravir; however, the system needs to be delicately set and the equipment is very expensive. Therefore, we developed a conventional LC-MS method to overcome these difficulties. Subsequently the method was validated by estimating the precision and accuracy for inter-and intraday analysis in the concentration range of 0.010-7.680 m mg/ml. The calibration curve was linear in this range. Average accuracy ranged from 97.2 to 103.4%. Relative standard deviations of both inter-and intraday assays were less than 10.4%. Recovery of raltegravir was more than 80.6%. This novel LC-MS method is accurate and precise enough to determine raltegravir levels in human plasma samples.

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Section: Lc-ms Chromatogramsmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Lc-ms Chromatogramsmentioning

confidence: 99%

“…16) However, the MS-MS detector needs to be delicately set and LC-MS/MS equipment is very expensive. In addition, isotope labeled raltegravir as an internal standard (IS) is needed.…”

mentioning

confidence: 99%

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A Conventional LC-MS Method Developed for the Determination of Plasma Raltegravir Concentrations

Takahashi

Konishi

Kudaka

et al. 2008

Biological & Pharmaceutical Bulletin

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Atazanavir increases the plasma concentrations of 1200 mg raltegravir dose

Krishna

East

Larson

et al. 2016

Biopharm & Drug Disp

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Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (b.i.d.). Raltegravir 1200 mg once-daily (q.d.) (investigational q.d. formulation of 2 × 600 mg tablets; q.d. RAL) was found to be generally well tolerated and non-inferior to the marketed 400 mg b.i.d. dose at 48 weeks in a phase 3 trial. Since raltegravir is eliminated mainly by metabolism via a uridine diphosphate glucuronosyltransferase (UGT) 1A1-mediated glucuronidation pathway, co-administration of UGT1A1 inhibitors may increase the plasma levels of q.d. RAL. To assess this potential, the drug interaction of 1200 mg raltegravir using atazanavir, a known UGT1A1 inhibitor, was studied. An open-label, randomized, 2-period, fixed-sequence phase 1 study was performed in adult healthy male and female (non-childbearing potential) subjects ≥ 19 and ≤ 55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤ 32.0 kg/m . Subjects (n = 14) received a single oral dose of 1200 mg raltegravir in period 1. After a washout period of at least 7 days, the subjects received oral doses of 400 mg atazanavir q.d. for 9 consecutive days, with a single oral dose of 1200 mg raltegravir co-administered on day 7 of period 2. Serial blood samples were collected for 72 h following raltegravir dosing and analysed using a validated bioanalytical method to quantify raltegravir plasma concentrations. Co-administration with atazanavir yielded GMRs (90% CIs) for raltegravir AUC , C and C of 1.67 (1.34, 2.10), 1.16 (1.01, 1.33) and 1.26 (1.08, 1.46), respectively. There was no effect of raltegravir on serum total bilirubin. In contrast, atazanavir increased the mean bilirubin by up to 200%, an effect that was preserved in the atazanavir/raltegravir treatment group. Administration of single q.d. RAL alone and co-administered with multiple oral doses of atazanavir were generally well tolerated in healthy subjects. The results show that atazanavir increased the PK exposure of raltegravir; therefore, co-administration of atazanavir with raltegravir q.d. is not recommended. Copyright © 2016 John Wiley & Sons, Ltd.

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Efavirenz does not meaningfully affect the single dose pharmacokinetics of 1200 mg raltegravir

Krishna

East

Larson

et al. 2016

Biopharm & Drug Disp

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Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once daily regimen (QD) at a dose of 1200 mg (2 x 600 mg) is under development and offers a new treatment option for HIV-1 infected treatment-naive subjects. Since raltegravir is eliminated mainly by metabolism via an UDP-glucuronosyltransferase (UGT) 1 A1-mediated glucuronidation pathway, co-administration of UGT1A1 inducers may alter plasma levels of raltegravir. Efavirenz, an UGT1A1 inducer, was used to assess the impact of altered UGT activity on a 1200 mg QD dose of raltegravir. An open label, randomized, 2-period fixed-sequence Phase 1 study was performed in adult healthy male and female subjects (non-childbearing potential) ≥ 19 and ≤55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤32.0 kg/m . Subjects (n = 21) received a single oral dose of 1200 mg raltegravir at bedtime on an empty stomach on Day 1 in Period 1. After a washout period of at least 7 days, subjects received oral doses of 600 mg efavirenz QD at bedtime for 14 consecutive days in Period 2. Subjects received a single oral dose of 1200 mg raltegravir co-administered with 600 mg efavirenz on Day 12 of Period 2. Pharmacokinetic (PK) samples were collected for 72 hours following raltegravir dosing and analyzed using a validated bioanalytical method to quantify raltegravir plasma concentrations. PK parameters were estimated using non-compartmental analysis. Administration of single 1200 mg oral doses of raltegravir alone and co-administered with multiple oral doses of efavirenz were generally well tolerated in healthy subjects. Co-administration with efavirenz yielded geometric mean ratios (GMRs) and their associated 90% confidence intervals (90% CIs) for raltegravir AUC C , and C of 0.86 (0.73, 1.01), 0.91 (0.70, 1.17), and 0.94 (0.76, 1.17), respectively. The results show that efavirenz modestly reduced the exposure of raltegravir. The reduction in raltegravir exposure is not considered clinically meaningful. Copyright © 2016 John Wiley & Sons, Ltd.

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Determination of the HIV integrase inhibitor, MK-0518 (raltegravir), in human plasma using 96-well liquid–liquid extraction and HPLC-MS/MS

Cited by 64 publications

References 9 publications

A Conventional LC-MS Method Developed for the Determination of Plasma Raltegravir Concentrations

A Conventional LC-MS Method Developed for the Determination of Plasma Raltegravir Concentrations

Atazanavir increases the plasma concentrations of 1200 mg raltegravir dose

Efavirenz does not meaningfully affect the single dose pharmacokinetics of 1200 mg raltegravir

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