understanding what limits/allows the brain penetration of lapatinib(tykerb)

[Lani]

Drug Metab Dispos. 2008 Dec 4. [Epub ahead of print]

An Unexpected Synergist Role of P-glycoprotein and Breast Cancer Resistance Protein on the CNS Penetration of the Tyrosine Kinase Inhibitor Lapatinib (GW572016).

Polli JW, Olson KL, Chism JP, St John-Williams LA, Yeager RL, Woodard SM, Otto VR, Castellino S, Demby VE.
GlaxoSmithKline.
Lapatinib is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing human epidermal receptor 2 (HER2, ErbB2). This work investigated the role of P-glycoprotein (Pgp, the protein from the Mdr1a/b gene) and Breast cancer resistance protein (Bcrp, the protein from the Bcrp1 gene) in modulating the CNS penetration of lapatinib at steady state conditions in FVBn mice (wild-type), Mdr1a/b(-/-), Bcrp1(-/-) and Mdr1a/b(-/-)/Bcrp1(-/-) knockout mice. Following an intravenous infusion of lapatinib for 24 hours to a targeted steady state plasma concentration of 700 ng/mL (0.3 mg/kg/h) or 7000 ng/mL (3 mg/kg/h), lapatinib brain-to-plasma ratios were approximately 3- to 4-fold higher in Mdr1a/b(-/-) knockout mice (ratio range 0.09 to 0.16) compared to wild-type mice (ratio range 0.03 to 0.04). There was no difference in the brain-to-plasma ratio in the Bcrp1(-/-) knockout mice (ratio range 0.03 to 0.04) compared to wild-type mice. In contrast, Mdr1a/b(-/-)/Bcrp1(-/-) triple knockout mice had a 40-fold higher brain-to-plasma ratio (ratio range 1.2 to 1.7), suggesting that Pgp and Bcrp work in concert to limit the brain-to-plasma ratio of lapatinib in mice. This finding has important potential consequences for the treatment of brain tumors in breast cancer patients treated with tyrosine kinase inhibitors as well as the basic understanding of ABC transporters expressed in the blood-brain barrier on the central nervous system disposition of drugs.
PMID: 19056914

[StephN]

Hope this means that someone is getting to the bottom of WHY Tykerb showed more promise than actually occurred in human patients.

At the American Society of Cancer Researchers meetin in April we (Christine, Maryann, Joe and me) met several people who said they were working on this topic.

We need drugs to work for MORE of us.

[Lani]

for pGP and BCRP SNPs/genotype prior to deciding what drug to give--in order to skip the ineffective drug and give the drug/drugs most likely to work in THAT PARTICULAR PATIENT as it is uncertain that there is one best drug that will work in ALL patients with brain mets.

[StephN]

HALLELIUJA!!!

Testing like that WOULD be a giant step forward and save many of our beautiful friends here.

[Ceesun]

Could someone clarify this for me as well as Steph's comment in simpler language. thanks Ceesun

[yankeebikachic]

yes, please clarify! I'm glad I'm not the only one re-reading that stuff just to end up scratching my head.
Beth

[Lani]

pGP and BCRP work like pumps at interfaces allowing in some compounds and rejecting and pumping back out others

various parts of the body where what is let in makes a life and death difference have specialized cells which contain them eg, cells in the absorbing parts of the gastrointestinal system, cells lining the airways (often NKT cells in those two loations) as well as the blood-brain barrier.

This study bred mice to lack either one or the other or both and found that when both were not available one had the most penetration of lapatinib, with more of it being pumped out and unavailable to the brain if only one or the other were lacking in the mice and the least penetration if both pGp and BRCP were present ie, not genetically bred out.

Hope this helps!