Microdose clinical trial: Quantitative determination of fexofenadine in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry

Yamane, Naoe; Tozuka, Zenzaburou; Sugiyama, Yuichi; Tanimoto, Toshiko; Yamazaki, Akira; Kumagai, Yoshito

doi:10.1016/j.jchromb.2007.08.011

Cited by 70 publications

(53 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As part of a wider strategy to address the current high rate of attrition for new chemical entities that proceed to clinical development, both the European Agency for the Evaluation of Medicinal Products (EMEA) and the US Food and Drug Administration (FDA) have issued guidance documents to support the use of exploratory (Phase 0) studies in the early evaluation of the PK and PD properties of such compounds in humans [25,26,28].In this regard, an emerging literature reveals how microdose studies using highly sensitive analytical methods, namely LC/MS/MS and accelerator MS (AMS) can be used to extrapolate the PK profile of compounds and metabolites (assuming linearity of exposure with dose) to higher clinically relevant doses [22,27,[29][30][31]. However, few microdose investigations have been reported specifically in the context of drug development and their value to the overall process has yet to be fully established [20,22,23].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, additional cost saving was realized by the development of a highly sensitive analytical assay based on HPLC/MS/MS methodology, which avoided the need to synthesize a radiolabelled compound for quantitative measurement using accelerator mass spectrometry (AMS). Other recent studies have similarly demonstrated the convenience and sensitivity of LC/MS/MS methodology for the quantitative analysis of low molecular weight compounds following microdose administration [30,31,47,48]. Another advantage of using LC/MS/MS over AMS was the ability to have rapid turnaround (within a few days of the microdose sessions) for analysis of plasma samples and the resulting data.…”

Section: Figurementioning

confidence: 98%

See 1 more Smart Citation

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Ostenfeld

Beaumont

Bullman

et al. 2012

Brit J Clinical Pharma

View full text Add to dashboard Cite

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The microdose administration of novel drug candidates to humans in early development is currently undergoing evaluation as a cost‐efficient approach to the early assessment of pharmacokinetics (PK) before the commitment of resources required to support formal phase 1 studies.• The microdose approach assumes that PK can be extrapolated linearly over the full range of exposures achieved with sub‐pharmacological doses up to the therapeutic dose range.• Few microdose studies have been undertaken in the context of pharmaceutical drug development and their precise role in the selection of candidates for further clinical evaluation at therapeutic doses has yet to be fully substantiated.WHAT THIS STUDY ADDS• The present study describes the elective application of a human microdose study with a novel EP1 receptor antagonist, GSK269984A, to address a critical development liability posed by uncertainty with respect to the predicted human PK profile.• Microdose data revealed a favourable PK profile, consistent with a clinically acceptable dosing regimen. These data support the value of undertaking a microdose study early in the drug discovery process to facilitate risk evaluation and to enable decision‐making.AIM The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP1 antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg).METHOD GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography‐tandem mass spectrometry method following solid phase extraction.RESULTS Following the i.v. microdose, the geometric mean values for clearance (CL), steady‐state volume of distribution (Vss) and terminal elimination half‐life (t1/2) of GSK269984A were 9.8 l h−1, 62.8 l and 8.2 h. Cmax and AUC(0,∞) were 3.2 ng ml−1 and 10.2 ng ml−1 h, respectively; the corresponding oral parameters were 1.8 ng ml−1 and 9.8 ng ml−1 h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre‐clinical species (rat, dog and monkey).CONCLUSION For drug development programmes characterized by inconsistencies between pre‐clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 98%

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Ostenfeld

Beaumont

Bullman

et al. 2012

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Fexofenadine, a non-radiolabeled compound, is an antihistamine drug that was orally administrated at a dose of 100 µg/ man/d in the first microdose clinical study in Japan in 2005; subsequently, the concentration of fexofenadine in human plasma was measured by LC-MS/MS. 5,6) The lower limit of quantification (LLOQ) was 10 pg/mL when the concentration of fexofenadine in human plasma, prepared by solid-phase extraction (SPE), was determined using LC-MS/MS. Previous studies have frequently used the protein precipitation method using an organic solvent for sample treatment and the LLOQs in the "ng/mL" range to determine the concentration of fexofenadine in biological samples by LC-MS/MS.…”

mentioning

confidence: 99%

“…[7][8][9][10][11][12][13][14] However, the drug concentration of samples in a microdose study cannot be measured at an LLOQ of only ng/mL because of lack of sensitivity. 5,6,[15][16][17][18][19][20] In case of employing SPE or liquid-liquid extraction for sample preparation, it is possible to set the LLOQ at pg/mL, but total sample analysis is required, which demands increased time as the procedure of sample preparation is quite complex. 6,[15][16][17][18] If an online SPE method could be established to reduce the time required for sample preparation, Regular Article * To whom correspondence should be addressed.…”

mentioning

confidence: 99%

“…5,6,[15][16][17][18][19][20] In case of employing SPE or liquid-liquid extraction for sample preparation, it is possible to set the LLOQ at pg/mL, but total sample analysis is required, which demands increased time as the procedure of sample preparation is quite complex. 6,[15][16][17][18] If an online SPE method could be established to reduce the time required for sample preparation, Regular Article * To whom correspondence should be addressed. e-mail: yukari.tanaka@shionogi.co.jp the investment in system would increase.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Development of a Highly Sensitive Methodology for Quantitative Determination of Fexofenadine in a Microdose Study by Multiple Injection Method Using Ultra-High Performance Liquid Chromatography with Tandem Mass Spectrometry

Tanaka

Yoshikawa

Yasui

2012

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

An ultra high-sensitivity method for quantifying fexofenadine concentration in rat plasma samples by multiple injection method (MIM) was developed for a microdose study. In this study, MIM involved continuous injections of multiple samples containing the single compound into a column of the ultra-HPLC (UHPLC) system, and then, temporary trapping of the analyte at the column head. This was followed by elution of the compound from the column and detection by mass spectrometer. Fexofenadine, used as a model compound in this study, was extracted from the plasma samples by a protein precipitation method. Chromatographic separation was achieved on a reversed-phase C18 column by using a gradient method with 0.1% formic acid and 0.1% formic acid in acetonitrile as the mobile phase. The analyte was quantified in the positive-ion electrospray ionization mode using selected reaction monitoring. In this study, the analytical time per fexofenadine sample was approximately 2 min according to the UHPLC system. The method exhibited the linear dynamic ranges of 5-5000 pg/mL for fexofenadine in rat plasma. The intra-day precisions were from 3.2 to 8.7% and the accuracy range was 95.2-99.3%. The inter-day precisions and accuracies ranged from 3.5 to 8.4% and from 98.6 to 102.6%, respectively. The validated MIM was successfully applied to a microdose study in the rats that received oral administration of 100 µg/kg fexofenadine. We suggest that this method might be beneficial for the quantification of fexofenadine concentrations in a microdose clinical study.

show abstract

Evolving Role of Mass Spectrometry in Drug Discovery and Development

Ramanathan

LeLacheur

2008

Mass Spectrometry in Drug Metabolism and Pharmacokinetics

View full text Add to dashboard Cite

Microdose clinical trial: Quantitative determination of fexofenadine in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry

Cited by 70 publications

References 9 publications

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Development of a Highly Sensitive Methodology for Quantitative Determination of Fexofenadine in a Microdose Study by Multiple Injection Method Using Ultra-High Performance Liquid Chromatography with Tandem Mass Spectrometry

Evolving Role of Mass Spectrometry in Drug Discovery and Development

Contact Info

Product

Resources

About