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. 2016 Dec 24;19(1):i1–i24. doi: 10.1093/neuonc/now197

Table 2.

Physicochemical and pharmacokinetic properties of new targeted therapies that may be useful for treatment of brain metastases in non–small cell lung cancer, breast cancer, and melanoma

Therapeutic Agent MW, Daa Log Pb BCRP and P-gp Median Inhibitory Concentration, ng/ml CSF Concentration in Patients with BM, ng/ml CSF Penetration Rate in Patients with BM, %c Drug Efflux Transporters Restricted CNS Penetration, BCRP/P-gpd Clinical Development Status
Substrate Inhibitor
Erlotinib 429.90 2.7 Yes183 Yes191 7.9 (EGFR-WT NSCLC)192 24−54 (N = 25)192–194 2.8−5.1192–194 Yes183 , 191 FDA approved for locally advanced or metastatic EGFR-mutant NSCLC and locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine
Gefitinib 446.9 3.2 Yes195 Yes196 0.13 (EGFR-WT NSCLC)197 3.7−6.2 (N = 30)194 ,198 1.1−1.4194 ,198 Yes195 FDA approved for locally advanced or metastatic EGFR-mutant NSCLC
Afatinib 485.9 3.7 Yes199 Yes199 0.5200 0.5 (N = 1) 200 <1 200 Unknown FDA approved for metastatic EGFR- mutant NSCLC
Crizotinib 450.3 1.8 Yes201 Yes198 108 (EML4-ALK E13;A20 translocation; NCI- H3122)202 ; 48 (H228)63 0.62 (N = 1) 202 0.26 202 Yes201 FDA approved for locally advanced or metastatic ALK-positive NSCLC
Ceritinib 558.1 5.0 Unknown Unknown 11 (Ba/F3 NPM-ALK WT) 203 ; 2 (H228); 0.08 (ALK enzymatic assay)63 Unknown Unknown Yes204 FDA approved for patients with ALK- positive NSCLC who have progressed on or are intolerant to crizotinib
Alectinib 482.6 5.5 Noe,205 Unknown 0.92 (ALK cell-free assay)67 1.367 8667 No205 FDA breakthrough therapy designation for patients with ALK-positive NSCLC who have progressed on crizotinib
Nivolumab 146000 N/A N/A N/A Not expected to cross intact BBB. Mechanism of action is in the periphery on T cells, which then cross the BBB FDA approved for: (1) advanced squamous NSCLC after platinum- based chemotherapy; and (2) unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF- V600-mutation positive, a BRAF inhibitor
Trastuzumab 145000 N/A N/A N/A 43.5 (p185HER2 extra-cellular domain)206 Not expected to cross intact BBB FDA approved for HER2-overexpressing breast cancer, and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma
Lapatinib 580.5 5.1207 Yes207 Yes207 6 (EGFR and HER2)207 1.3−4.5 (N = 2)208 0.9−1.3208 Yes207 FDA approved as part of combination treatment for advanced or metastatic (with an anthracycline, a taxane, and trastuzumab) and postmenopausal (with letrozole) HER2- overexpressing breast cancer
Vemurafenib 489.9 5.1 Yes209 , 210 Yes210 470 (N = 6)211 0.98211 Yes209 , 212 FDA approved for unresectable or metastatic melanoma with BRAF- V600E mutation
Dabrafenib 615.7 5.4 Yes162 , 213 Unknown Unknown Yes162 FDA approved for unresectable or metastatic melanoma with BRAF- V600E mutation and in combination with trametinib for BRAF- V600E and BRAF-V600K mutations
Ipilimumab 148000 N/A N/A N/A <148 (CTLA-4)214 Not expected to cross intact BBB. Mechanism of action is in the periphery on T cells, which then cross the BBB FDA approved for unresectable or metastatic melanoma
Pembrolizumab 149000 N/A N/A N/A Not expected to cross intact BBB. Mechanism of action is in the periphery on T cells, which then cross the BBB FDA approved for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF-V600 mutation positive, a BRAF inhibitor

Abbreviations: ALK, anaplastic lymphoma kinase; BBB, blood-brain barrier; BCRP, breast cancer resistance protein; BM, brain metastases; BRAF, v-Raf murine sarcoma viral oncogene homolog B; CNS, central nervous system; CSF, cerebrospinal fluid; CTLA-4, cytotoxic T-lymphocyte antigen; EGFR, epidermal growth factor receptor; EML4, echinoderm microtubule associated protein like 4; FDA, U.S. Food and Drug Administration; HER2, human epidermal growth factor receptor 2; MW, molecular weight; N/A, not applicable; NCI, National Cancer Institute; NPM, nucleophosmin; NSCLC, non–small cell lung cancer; P-gp, P-glycoprotein; WT, wild type.

aObtained from the PubChem Compound Database (http://www.ncbi.nlm.nih.gov/pccompound).

bObtained from the Drugbank database (http://www.drugbank.ca/) and Chemspider database (http://www.chemspider.com).

cAssessed using human blood and CSF samples.

dBased on nonclinical studies using mouse models.

eAlectinib was not transported by P-gp in cell transport assay, suggesting it is a poor or non-P-gp substrate.