The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer

Abstract

Abstract. It has been demonstrated that erlotinib is effective in treating patients with brain metastasis from non-small-cell lung cancer. However, the number of studies determining the erlotinib concentration in these patients is limited. The purpose of this study was to measure the concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung carcinoma. Six patients were treated with the standard recommended daily dose of erlotinib (150 mg) for 4 weeks. All the patients had previously received chemotherapy, but no brain radiotherapy. At the end of the treatment period, blood plasma and cerebrospinal fluid samples were collected and the erlotinib concentration was determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS̸MS). The average erlotinib concentration in the blood plasma and the cerebrospinal fluid was 717.7±459.7 and 23.7±13.4 ng/ml, respectively. The blood-brain barrier permeation rate of erlotinib was found to be 4.4±3.2%. In patients with partial response (PR), stable disease (SD) and progressive disease (PD), the average concentrations of erlotinib in the cerebrospinal fluid were 35.5±19.0, 19.1±8.7 and 16.4±5.9 ng/ml, respectively. In addition, the efficacy rate of erlotinib for metastatic brain lesions was 33.3%, increasing to 50% in patients with EGFR mutations. However, erlotinib appeared to be ineffective in cases with wild-type EGFR. In conclusion, a relatively high concentration of erlotinib was detected in the cerebrospinal fluid of patients with brain metastases from non-small-cell lung cancer. Thus, erlotinib may be considered as a treatment option for this patient population.

Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when?

“…Several prospective studies have indicated that the first-generation TKIs, erlotinib and gefitinib, have clinical activity in patients with NSCLC and brain metastases, although there are limited data regarding direct intracranial activity [65,66]. These findings are consistent with observations that erlotinib and gefitinib can permeate the bloodbrain barrier, albeit inefficiently [67][68][69][70][71]. In an effort to increase drug concentrations in the brain, several studies have assessed high-dose regimens of gefitinib or erlotinib in patients with EGFR mutation-positive NSCLC and brain metastases [67,69].…”

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future

“…Nevertheless, despite their small molecular weight, both erlotinib and gefitinib, seem to reach limited concentrations into cerebrospinal fluid (CSF). In fact, at standard dose CSF levels are lower than plasma levels (68)(69)(70)(71)(72). Available data do not favor one EGFR-TKI over another but the concentration and the penetration in CSF are significantly higher with erlotinib than gefitinib (73)(74)(75).…”

“…Progressively increasing doses of erlotinib or gefitinib are able to control BM progression or relapse in NSCLC pts (70)(71)(72)(73)79,80). The greater penetration through the BBB when plasma concentrations are higher, also thanks to P-gp saturation, allows EGFR-TKIs to exert greater activity in CNS (76).…”

“…Literature data report that dose escalation, pulsate dose or switching TKIs, seem to improve TKIs concentration in CNS and to relieve resistance to standard TKIs treatment in pts with BM from EGFR mutated NSCLC (70)(71)(72)(73)76,(78)(79)(80)(81)(82)(83) ( Table 1).…”

Icotinib combined whole brain radiotherapy for patients with brain metastasis from lung adenocarcinoma harboring epidermal growth factor receptor mutation

“…The concomitant use of WBRT and gefitinib is well tolerated with a median OS time of 12.0 to 15.4 months (10,11). Some studies reported that the blood-brain barrier permeability of EGFR-TKIs could be increased in accordance with the escalated dose of WBRT (11,12). The cerebrospinal fluid-to-plasma ratio of NSCLC patients with brain metastasis reaches its peak (1.87%±0.72%) at a WBRT dose of 30 Gy (11).…”