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Open Access 01-06-2020 | Pharmacokinetics | PRECLINICAL STUDIES

The influence of the coadministration of the p-glycoprotein modulator elacridar on the pharmacokinetics of lapatinib and its distribution in the brain and cerebrospinal fluid

Authors: Agnieszka Karbownik, Katarzyna Sobańska, Włodzimierz Płotek, Tomasz Grabowski, Agnieszka Klupczynska, Szymon Plewa, Edmund Grześkowiak, Edyta Szałek

Published in: Investigational New Drugs | Issue 3/2020

Summary

Background Lapatinib is a small-molecule tyrosine kinase inhibitor of human epidermal receptor 2 (HER2) and EGFR that has currently been approved for the treatment of HER2-positive advanced and metastatic breast cancer (BC). The ATP-binding cassette (ABC) family of transporters includes P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2), which substantially restrict the penetration of drugs, including chemotherapeutics, through the blood-brain barrier and blood-cerebrospinal fluid barrier. The aim of this study was to investigate the effects of elacridar, an ABCB1 and ABCG2 inhibitor, on the brain and cerebrospinal fluid uptake of lapatinib. Methods Rats were divided into two groups: one group received 5 mg/kg elacridar and 100 mg/kg lapatinib (an experimental group), and the other group received 100 mg/kg lapatinib (a control group). Lapatinib concentrations in the blood plasma (BP), cerebrospinal fluid (CSF) and brain tissue (BT) were measured by liquid chromatography coupled with tandem mass spectrometry. Results Elacridar significantly increased lapatinib penetration into the CSF and BT (C_max increase of 136.4% and 54.7% and AUC_0-∞ increase of 53.7% and 86.5%, respectively). The C_max of lapatinib in BP was similar in both experimental groups (3057.5 vs. 3257.5 ng/mL, respectively). Conclusion This study showed that elacridar influenced the pharmacokinetics of lapatinib. The inhibition of ABCB1 and ABCG2 transporters by elacridar substantially enhanced the penetration of lapatinib into the CSF and BT. The blocking of protein transporters could become indispensable in the treatment of patients with breast cancer and brain metastases.

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Redig AJ, McAllister SS (2013) Breast cancer as a systemic disease: a view of metastasis. J Intern Med 274(2):113–126. https://doi.org/10.1111/joim.12084 CrossRefPubMedPubMedCentral

Schouten LJ, Rutten J, Huveneers HA, Twijnstra A (2002) Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 94(10):2698–2705CrossRefPubMed

Stemmler HJ, Heinemann V (2008) Central nervous system metastases in HER-2-overexpressing metastatic breast cancer: a treatment challenge. Oncologist 13(7):739–750. https://doi.org/10.1634/theoncologist.2008-0052 CrossRefPubMed

Kühnöl J, Kühnöl C, Vordermark D (20016) Radiotherapy of brain metastases from breast cancer: treatment results and prognostic factors. Oncol Lett 11(5):3223–3227

Hurvitz SA, O'Shaughnessy J, Mason G, Yardley D, Jahanzeb M, Brufsky AM, Rugo HS, Swain SM, Kaufman PA, Tripathy D, Chu L, Li H, Antao V, Cobleigh M (2018) Central nervous system metastasis in patients with HER2-positive metastatic breast Cancer: patient characteristics, treatment, and survival from SystHERs. Clin Cancer Res pii: clincanres.2366.2018. https://doi.org/10.1158/1078-0432.CCR-18-2366

Petrelli F, Ghidini M, Lonati V, Tomasello G, Borgonovo K, Ghilardi M, Cabiddu M, Barni S (2017) The efficacy of lapatinib and capecitabine in HER-2 positive breast cancer with brain metastases: a systematic review and pooled analysis. Eur J Cancer 84:141–148. https://doi.org/10.1016/j.ejca.2017.07.024 CrossRefPubMed

Canonici A, Qadir Z, Conlon NT, Collins DM, O'Brien NA, Walsh N, Eustace AJ, O'Donovan N, Crown J (2018) The HSP90 inhibitor NVP-AUY922 inhibits growth of HER2 positive and trastuzumab-resistant breast cancer cells. Investig New Drugs 36(4):581–589. https://doi.org/10.1007/s10637-017-0556-7 CrossRef

Medina PJ, Goodin S (2008) Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther 30(8):1426–1447. https://doi.org/10.1016/j.clinthera.2008.08.008 CrossRefPubMed

Koo T, Kim IA (2016) Brain metastasis in human epidermal growth factor receptor 2-positive breast cancer: from biology to treatment. Radiat Oncol J 34(1):1–9. https://doi.org/10.3857/roj.2016.34.1.1 CrossRefPubMedPubMedCentral

10.

Liao J, Gallas M, Pegram M, Slingerland J (2010) Lapatinib: new opportunities for management of breast cancer. Breast Cancer (Dove Med Press) 15(2):79–91. https://doi.org/10.2147/BCTT.S5929 CrossRef

11.

Gril B, Palmieri D, Bronder JL, Herring JM, Vega-Valle E, Feigenbaum L, Liewehr DJ, Steinberg SM, Merino MJ, Rubin SD, Steeg PS (2008) Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst 100(15):1092–1103. https://doi.org/10.1093/jnci/djn216 CrossRefPubMedPubMedCentral

12.

Taskar KS, Rudraraju V, Mittapalli RK, Samala R, Thorsheim HR, Lockman J, Gril B, Hua E, Palmieri D, Polli JW, Castellino S, Rubin SD, Lockman PR, Steeg PS, Smith QR (2012) Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res 29(3):770–781. https://doi.org/10.1007/s11095-011-0601-8 CrossRefPubMed

13.

van der Noll R, Smit WM, Wymenga AN, Boss DS, Grob M, Huitema AD, Rosing H, Tibben MM, Keessen M, Rehorst H, Beijnen JH, Schellens JH (2015) Phase I and pharmacological trial of lapatinib in combination with gemcitabine in patients with advanced breast cancer. Investig New Drugs 33(6):1197–1205. https://doi.org/10.1007/s10637-015-0281-z CrossRef

14.

Zhang J, Zhang L, Yan Y, Li S, Xie L, Zhong W, Lv J, Zhang X, Bai Y, Cheng Z (2015) Are capecitabine and the active metabolite 5-Fu CNS penetrable to treat breast cancer brain metastasis? Drug Metab Dispos 43(3):411–417. https://doi.org/10.1124/dmd.114.061820 CrossRefPubMed

15.

Montesinos RN, Moulari B, Gromand J, Beduneau A, Lamprecht A, Pellequer Y (2014) Coadministration of P-glycoprotein modulators on loperamide pharmacokinetics and brain distribution. Drug Metab Dispos 42(4):700–706. https://doi.org/10.1124/dmd.113.055566 CrossRefPubMed

16.

Kallem R, Kulkarni CP, Patel D, Thakur M, Sinz M, Singh SP, Mahammad SS, Mandlekar S (2012) A simplified protocol employing elacridar in rodents: a screening model in drug discovery to assess P-gp mediated efflux at the blood brain barrier. Drug Metab Lett 6(2):134–144CrossRefPubMed

17.

Nakamura Y, Hirokawa Y, Kitamura S, Yamasaki W, Arihiro K, Tatsugami F, Iida M, Kakizawa H, Date S, Awai K (2013) Effect of lapatinib on hepatic parenchymal enhancement on gadoxetate disodium (EOB)-enhanced MRI scans of the rat liver. Jpn J Radiol 31(6):386–392. https://doi.org/10.1007/s11604-013-0208-6 CrossRefPubMed

18.

Fridén M, Ljungqvist H, Middleton B, Bredberg U, Hammarlund-Udenaes M (2010) Improved measurement of drug exposure in the brain using drug-specific correction for residual blood. J Cereb Blood Flow Metab 30(1):150–161. https://doi.org/10.1038/jcbfm.2009.200 CrossRefPubMed

19.

Oberoi RK, Mittapalli RK, Elmquist WF (2013) Pharmacokinetic assessment of efflux transport in sunitinib distribution to the brain. J Pharmacol Exp Ther 347(3):755–764. https://doi.org/10.1124/jpet.113.208959 CrossRefPubMedPubMedCentral

20.

Franchino F, Rudà R, Soffietti R (2018) Mechanisms and therapy for Cancer metastasis to the brain. Front Oncol 8:161. https://doi.org/10.3389/fonc.2018.00161 CrossRefPubMedPubMedCentral

21.

Verheijen RB, Yaqub M, Sawicki E, van Tellingen O, Lammertsma AA, Nuijen B, Schellens JHM, Beijnen JH, Huitema ADR, Hendrikse NH, Steeghs N (2018) Molecular imaging of ABCB1 and ABCG2 inhibition at the human blood-brain barrier using Elacridar and ¹¹C-Erlotinib PET. J Nucl Med 59(6):973–979. https://doi.org/10.2967/jnumed.117.195800 CrossRefPubMed

22.

Goutal S, Gerstenmayer M, Auvity S, Caillé F, Mériaux S, Buvat I, Larrat B, Tournier N (2018) Physical blood-brain barrier disruption induced by focused ultrasound does not overcome the transporter-mediated efflux of erlotinib. J Control Release 292:210–220. https://doi.org/10.1016/j.jconrel.2018.11.009 CrossRefPubMed

23.

Kort A, Durmus S, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH (2015) Brain and testis accumulation of Regorafenib is restricted by breast Cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1). Pharm Res 32(7):2205–2216. https://doi.org/10.1007/s11095-014-1609-7 CrossRefPubMed

24.

Lagas JS, van Waterschoot RA, van Tilburg VA, Hillebrand MJ, Lankheet N, Rosing H, Beijnen JH, Schinkel AH (2009) Brain accumulation of dasatinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by elacridar treatment. Clin Cancer Res 15(7):2344–2351. https://doi.org/10.1158/1078-0432.CCR-08-2253 CrossRefPubMed

25.

Tang SC, Nguyen LN, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH (2014) Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer 134(6):1484–1494. https://doi.org/10.1002/ijc.28475 CrossRefPubMed

26.

Gori S, Lunardi G, Inno A, Foglietta J, Cardinali B, Del Mastro L, Crinò L (2014) Lapatinib concentration in cerebrospinal fluid in two patients with HER2-positive metastatic breast cancer and brain metastases. Ann Oncol 25(4):912–913. https://doi.org/10.1093/annonc/mdu041 CrossRefPubMed

27.

Devriese LA, Koch KM, Mergui-Roelvink M, Matthys GM, Ma WW, Robidoux A, Stephenson JJ, Chu QS, Orford KW, Cartee L, Botbyl J, Arya N, Schellens JH (2014) Effects of low-fat and high-fat meals on steady-state pharmacokinetics of lapatinib in patients with advanced solid tumours. Investig New Drugs 32(3):481–488. https://doi.org/10.1007/s10637-013-0055-4 CrossRef

28.

Polli JW, Humphreys JE, Harmon KA, Castellino S, O'Mara MJ, Olson KL, John-Williams LS, Koch KM, Serabjit-Singh CJ (2008) The role of efflux and uptake transporters in N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) disposition and drug interactions. Drug Metab Dispos 36(4):695–701. https://doi.org/10.1124/dmd.107.018374 CrossRefPubMed

29.

Sato H, Siddig S, Uzu M, Suzuki S, Nomura Y, Kashiba T, Gushimiyagi K, Sekine Y, Uehara T, Arano Y, Yamaura K, Ueno K (2015) Elacridar enhances the cytotoxic effects of sunitinib and prevents multidrug resistance in renal carcinoma cells. Eur J Pharmacol 746:258–266. https://doi.org/10.1016/j.ejphar.2014.11.021 CrossRefPubMed

30.

Ward KW, Azzarano LM (2004) Preclinical pharmacokinetic properties of the P-glycoprotein inhibitor GF120918A (HCl salt of GF120918, 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl]-4-acridine-carboxamide) in the mouse, rat, dog, and monkey. J Pharmacol Exp Ther 310(2):703–709. https://doi.org/10.1124/jpet.104.068288 CrossRefPubMed

31.

Polli JW, Olson KL, Chism JP, John-Williams LS, Yeager RL, Woodard SM, Otto V, Castellino S, Demby VE (2009) An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos 37(2):439–442. https://doi.org/10.1124/dmd.108.024646 CrossRefPubMed

32.

Hudachek SF, Gustafson DL (2013) Physiologically based pharmacokinetic model of lapatinib developed in mice and scaled to humans. J Pharmacokinet Pharmacodyn 40(2):157–176. https://doi.org/10.1007/s10928-012-9295-8 CrossRefPubMedPubMedCentral

Title: The influence of the coadministration of the p-glycoprotein modulator elacridar on the pharmacokinetics of lapatinib and its distribution in the brain and cerebrospinal fluid
Authors: Agnieszka Karbownik
Katarzyna Sobańska
Włodzimierz Płotek
Tomasz Grabowski
Agnieszka Klupczynska
Szymon Plewa
Edmund Grześkowiak
Edyta Szałek
Publication date: 01-06-2020
Publisher: Springer US
Keywords: Pharmacokinetics
Breast Cancer
Tyrosine Kinase Inhibitors
Breast Cancer
Tyrosine Kinase Inhibitors
Lapatinib
Published in: Investigational New Drugs / Issue 3/2020
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-019-00806-3

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