Drug Res (Stuttg) 2021; 71(01): 36-42
DOI: 10.1055/a-1252-2476
Original Article

DBS Assay with LC-MS/MS for the Determination of Idelalisib, A Selective PI3K-δ Inhibitor in Mice Blood and Its Application to a Pharmacokinetic Study

Harsha K. Tripathy
1   Karnataka College of Pharmacy, Thirumenahalli, Bangalore
,
Nair S.V. Manju
1   Karnataka College of Pharmacy, Thirumenahalli, Bangalore
,
2   Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore
,
Ashok Zakkula
2   Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore
,
Ramesh Mullangi
2   Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore
› Author Affiliations
Funding: This work was funded by the Advanced Research Wing, Rajiv Gandhi University of Health Sciences, Bangalore, India (Grant order no. RGU: RGU/ADV.RES/BR/018/2018-19, dated 11.01.2019).

Abstract

Idelalisib is a selective and second-generation PI3K-δ inhibitor, approved for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia. In this paper, we present a fully validated dried blood spot (DBS) method for the quantitation of idelalisib from mice blood using an LC-MS/MS, which was operated under multiple reaction monitoring mode. To the punched DBS discs, acidified methanol enriched with internal standard (IS; larotrectinib) was added and extracted using tert-butyl methyl ether as an extraction solvent with sonication. Chromatographic separation of idelalisib and the IS was achieved on an Atlantis dC18 column using a mixture of 10 mM ammonium formate:acetonitrile (25:75, v/v). The flow-rate and injection volume were 0.80 mL/min and 2.0 µL, respectively. Idelalisib and the IS were eluted at ~0.98 and 0.93 min, respectively and the total run time was 2.00 min. Idelalisib and the IS were analyzed using positive ion scan mode and parent-daughter mass to charge ion (m/z) transition of 416.1→176.1 and 429.1→342.1, respectively was used for the quantitation. The calibration range was 1.01−4 797 ng/mL. No matrix effect and carry over were observed. Haematocrit did not influence DBS idelalisib concentrations. All the validation parameters met the acceptance criteria. The applicability of the validated method was shown in a mice pharmacokinetic study.

Supplementary Material



Publication History

Received: 05 August 2020

Accepted: 30 August 2020

Article published online:
29 September 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 Davies A. Idelalisib for relapsed/refractory indolent B-cell non-Hodgkin’s lymphoma: An overview of pharmacokinetics and clinical trial outcomes. Exp Rev Hematol 2015; 8: 581-593
  • 2 Lannutti BJ, Meadows SA, Herman SE. et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 2011; 117: 591-594
  • 3 Yang Q, Modi P, Ramanathan S. et al. Idelalisib for the treatment of B-cell malignancies. Exp Opin Orphan. Drugs 2015; 3: 109-123
  • 4 Brown JR, Byrd JC, Coutre SE. et al. Idelalisib, an inhibitor of phosphatidylinositol 3- kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014; 123: 3390-3397
  • 5 Zydelig® (idelalisib). Highlights of Prescribing Information. Accessed on 15 June 2020 https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206545lbl.pdf
  • 6 Veeraraghavan S, Thappali S, Viswanadha S. et al. Simultaneous quantification of idelalisib, fludarabine andlenalidomide in rat plasma by using high-performance liquid chromatography coupled with heated electrospray ionization tandem mass spectrometry. J Chromatogra B 2014; 949-950: 63-69
  • 7 Suneetha A, Sharmila D. Method development and validation for the estimation of idelalisib in rabbit plasma by HPLC. Int J Pharm Sci Res 2016; 7: 4998-5005
  • 8 Huynh HH, Roessle C, Sauvageon H. et al. Quantification of idelalisib in human plasma by ultra-performance liquid chromatography coupled to mass spectrometry in negative ionization mode. Ther Drug Monit 2018; 20: 237-244
  • 9 Wang C, Jia F, Zhang Y. Simultaneous determination of idelalisib and its metabolite GS-563117 in dog plasma by LC-MS/MS: Application to a pharmacokinetic study. Biomed Chomatogra 2019; 33: e4511
  • 10 Arumugam A, Mani A, Chirinos J. A full replicate in vivo bioequivalence study of two idelalisib 150 mg tablets in fasted healthy human subjects. J Bioequiv Availab 2020; 12: 391
  • 11 Linder C, Neideman M, Wide K. et al. Dried blood spot self-sampling by guardians of children with epilepsy is feasible: comparison with plasma for multiple antiepileptic drugs. Ther Drug Monit 2019; 41: 509-518
  • 12 Kim HM, Park JH, Long NP. et al. Simultaneous determination of cardiovascular drugs in dried blood spot by liquid chromatography- tandem mass spectrometry. J Food and Drug Analy 2019; 27: 906-914
  • 13 Dixit A, Kiran V, Gabani BB. et al. Validated LC-MS/MS method for quantitation of a selective JAK1 inhibitor, filgotinib in rat plasma and its application to a pharmacokinetics study in rats. ADMET & DMPK 2020; 8: 139-148
  • 14 Sulochana SP, Daram P, Srinivas NR. et al. Review of DBS methods as quantitative tool for anticancer drugs. Biomed Chromatogra 2019; 33: e4445
  • 15 Velghe S, Deprez S, Stove CP. Fully automated therapeutic drug monitoring of anti-epileptic drugs making use of dried blood spots. J Chromatogra A 2019; 1601: 95-103
  • 16 Foerster KI, Huppertz A, Meid AD. et al. Dried blood spot technique to monitor direct oral anticoagulants: Clinical validation of an UPLC-MS/MS based assay. Anal Chem 2018; 90: 9395-9402
  • 17 Moretii M, Freni F, Valentini B. et al. Determination of antidepressants and antipsychotics in dried blood spots (DBSs) collected from post-mortem samples and evaluation of the stability over a three-month period. Molecules 2019; 24: 3636
  • 18 Malsagova K, Kopylov A, Stepanov A. et al. Dried blood spot in laboratory: Directions and prospects. Diagnostics 2020; 10: 248
  • 19 US DHHS, FDA, CDER, CVM, Guidance for Industry: Bioanalytical Method Validation, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CV), (2018), Rockville, MD, USA
  • 20 Santos EW, de Oliveira DC, Hastreiter A. et al. Hematological and biochemical reference values for C57BL/6, Swiss Webster and BALB/C mice. Braz J Vet Res. Anim Sci 2016; 53: 138-145
  • 21 Tripathy HK, Manju NSV, Dittakavi S. et al. A dried blood spot assay with HPLC-MS/MS for the determination of larotrectinib in mice blood and its application to a pharmacokinetic study. Biomed Chromatogra 2020; e4953