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Determination of Salivary Efavirenz by Liquid Chromatography Coupled with Tandem Mass Spectrometry

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Determination of Salivary Efavirenz by Liquid Chromatography Coupled with Tandem Mass Spectrometry G Model CHROMB-17040; No. of Pages 5 ARTICLE IN PRESS Journal of Chromatography B, xxx (2010) xxx–xxx Contents lists available at ScienceDirect Journal of Chromatography B journal homepage: www.elsevier.com/locate/chromb Determination of salivary efavirenz by liquid chromatography coupled with tandem mass spectrometry Anri Theron a, Duncan Cromarty b, Malie Rheeders a, Michelle Viljoen a,∗ a Pharmacology, School of Pharmacy & Unit for Drug Research and Development North-West University, Private Bag X6001, Building G16, Room 113, Potchefstroom 2520, South Africa b Department of Pharmacology, Medical School, University of Pretoria, PO Box 2034, Pretoria 0001, South Africa article info abstract Article history: A novel and robust screening method for the determination of the non-nucleoside reverse transcriptase Received 12 May 2010 inhibitor, efavirenz (EFV), in human saliva has been developed and validated based on high perfor- Accepted 31 August 2010 mance liquid chromatography tandem mass spectrometry (LC–MS/MS). Sample preparation of the saliva Available online xxx involved solid-phase extraction (SPE) on C18 cartridges. The analytes were separated by high perfor- mance liquid chromatography (Phenomenex Kinetex C18, 150 mm × 3 mm internal diameter, 2.6 ␮m Keywords: particle size) and detected with tandem mass spectrometry in electrospray positive ionization mode Efavirenz with multiple reaction monitoring. Gradient elution with increasing methanol (MeOH) concentration Saliva LC–MS/MS was used to elute the analytes, at a flow-rate of 0.4 mL/min. The total run time was 8.4 min and the retention times for the internal standard (reserpine) was 5.4 min and for EFV was 6.5 min. The calibra- tion curves showed linearity (r2, 0.989–0.992) over the concentration range of 3.125–100 ␮g/L. Mean intra- and inter-assay relative standard deviation, accuracy, mean extraction recovery, limit of detec- tion (LOD) and limit of quantification (LOQ) were 0.46–9.43%, 80–120%, 60% (±7.95), 1.84 and 6.11 ␮g/L respectively. The working range was defined as 6.25–100 ␮g/L. This novel LC–MS/MS assay is suitable for reliable detection of low EFV concentrations in saliva and can be used as a screening tool for monitoring EFV compliance. © 2010 Elsevier B.V. All rights reserved. 1. Introduction opposed to the collection of saliva which can be done by non- invasive, painless methods and has a diminished risk of HIV transfer Efavirenz (EFV) is a non-nucleoside reverse transcriptase to the health care worker [8]. However, for the use of saliva for TDM, inhibitor, used in combination therapy for HIV-1-infected children a confirmed relationship should exist between the concentrations [1]. Marzolini and co-workers proposed a 1000–4000 ␮g/L plasma of the drug in the different body fluid matrixes [8]. An obstacle for range at mid-dosing interval as a suitable target for EFV drug lev- the determination of EFV in saliva, is the protein binding of EFV, els [2]. When EFV levels reach toxic levels (>4000 ␮g/L) a higher which is greater than 99% [1]. Saliva usually represents the free incidence of side-effects occurs such as insomnia, dizziness, abnor- drug concentration of a drug [9], thus the salivary concentrations mal dreams and loss of concentration [2,3], while subtherapeutic are very low (<1% of plasma levels). Methods to determine sali- levels (<1000 ␮g/L) can lead to treatment failure due to viral resis- vary levels of nevirapine [8,10] and indinavir [11] were previously tance [4,5]. It is thus important to ensure that EFV plasma levels are reported, but none yet for EFV. To further investigate the possibility within the therapeutic window. of assaying salivary EFV to monitor adherence or for therapeutic Therapeutic drug monitoring (TDM) of antiretroviral (ARV) drug monitoring of EFV, a validated analytical LC–MS/MS based plasma concentrations can be useful in the optimization of HIV method for the analysis of EFV in saliva, was developed. treatment [6,7], however, the collection of plasma is invasive, causes discomfort and is painful [8] especially in young children, 2. Materials and methods 2.1. Chemicals ∗ Corresponding author at: Pharmacology, School of Pharmacy & Unit for Drug Solvents used as eluents were high purity water and HPLC Research and Development North-West University, 11 Hoffmanstreet, Private Bag grade methanol (MeOH) (Burdick and Jackson Laboratory Co.); X6001, Building G16, Room 113, Potchefstroom 2520, South Africa. Tel.: +27 18 299 2232; fax: +27 18 299 2225. acetic acid (SAARCHEM) and ammonium formate (Agilent Tech- E-mail address: [email protected] (M. Viljoen). nologies). EFV for the reference standards was supplied by the 1570-0232/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jchromb.2010.08.051 Please cite this article in press as: A. Theron, et al., J. Chromatogr. B (2010), doi:10.1016/j.jchromb.2010.08.051 G Model CHROMB-17040; No. of Pages 5 ARTICLE IN PRESS 2 A. Theron et al. / J. Chromatogr. B xxx (2010) xxx–xxx Table 1 Quality control (QC) samples (n = 4) were prepared at different Mass spectrometry parameters. concentrations (6.25, 12.5, 25, and 50 ␮g/L EFV), by spiking saliva Analyte MRM Collision energy Fragmentation with a separately made working solution. voltage (V) voltage (V) EFV 316 → 244a 10 120 2.4. Samples EFV 316 → 232b 15 120 Reserpine (IS) 609 → 195 45 200 2.4.1. Sample collection a Transition used in the quantification. Saliva samples were collected from HIV-infected children b Transition of qualifier. already on EFV based treatment regimens by sampling with a Salivette® swab that was chewed for 2 min and then placed into World Health Organization: International Chemical Reference Sub- the supplied collection tube and centrifuged for 10 min at 1500 × g. stances (Batch number 104229). Reserpine, the internal standard Saliva samples were then collected in Eppendorf® centrifuge tubes (IS), was acquired from Fluka (Batch number 1325032). All chem- and stored at −80 ◦C until further analysis. The exact time of saliva icals were stored at the appropriate storage temperatures and collection was recorded. Any food or drinks, except water were conditions. prohibited to be taken 30 min prior to saliva collection. 2.2. Liquid chromatography/tandem mass spectrometry 2.4.2. Sample preparation Samples, calibrants and QC’s were thawed at room temperature 2.2.1. Chromatographic systems on the day of analysis. Aliquots of 100 ␮L saliva, calibrants or QC’s The chromatographic system consisted of an Agilent G1312A were mixed with 20 ␮L of IS working solution, vortexed for 10 s binary pump, a G1379B micro-vacuum degasser and a ther- and sonicated for 10 min. Another 80 ␮L of the IS working solution mostated auto-sampler fitted with a six port injection valve and was added and vortexed for 10 s and sonicated for 10 min. Samples 100 ␮L capillary loop. EFV was separated from the internal standard (200 ␮L) were then centrifuged for 10 min at 3000 × g on a bench on a C18 column (Phenomenex Kinetex C18; 150 × 3 mm internal top centrifuge. diameter; 2.6 ␮m particle size). The temperature of the column was C18 solid phase extraction (SPE) cartridges (Varian Bond Elut maintained at 40 ◦C. EFV in the eluent was detected with an Agilent 100 mg and 1 mL) were placed on a vacuum elution manifold and 6410 triple quadrupole mass spectrometer using electrospray ion- conditioned with 1 mL MeOH, followed by 1 mL water, taking care ization (ESI) in positive mode. The most abundant fragment for each that the cartridges did not run dry at any stage. Only 170 ␮Lofthe compound was selected by performing enhanced product ion scans prepared sample was applied to a cartridge and drawn through of the standards during an infusion analysis. The selected multiple by applying low vacuum (±15 kPa). The loaded cartridges were reaction monitoring (MRM) transitions are reflected in Table 1. The washed with 1 mL water and then 1 mL MeOH was used to elute the collision energy voltage, fragmentation voltage and capillary volt- adsorbed analytes. The cartridge bed was suctioned dry for 5 min. age were adjusted to provide the highest sensitivity, refer to Table 1. The eluent was gently evaporated under a gentle stream of nitrogen Nitrogen was used as nebulizer gas and desolvation gas. The gas in a heater block at 48 ◦C. The dried residue was reconstituted with temperature (◦C), gas flow (L/min), capillary voltage (V) and nebu- 50 ␮L of a mixture of 10% Solvent B and 90% Solvent A. Aliquots of lizer pressure (kPa) were set at 300, 12, 4000 and 275.8 respectively. 5 ␮L were injected onto the LC–MS/MS system. Agilent Technologies MassHunter Workstation Software, Ver- sion B02.00, 2008, was used for system control, data collection and 2.5. Analytical method validation quantitative analysis. The method was validated to meet the general requirements of 2.2.2. Mobile phases ISO 17025 (2005) and SANS 17025 [12,13] and are discussed below. A mobile phase gradient pumped at 0.4 mL/min was used to elute the analytes from the column. Mobile phase A consisted of 2.5.1. Linearity methanol–water (10:90 (v/v)). Mobile phase B consisted of a 5 mM Daily standard calibration curves were constructed for EFV using ammonium formate buffer in 97% MeOH, pH adjusted to 5.5 with the ratio of the observed analyte response and the response of acetic acid. The elution started at 10% B held isocratically for 0.6 min the IS. The calibration curves were obtained by weighted (1/x) lin- increasing to 100% B at 1.5 min and returning to 10% B at 8.2 min.
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