Table I.
Reported cerebrospinal fluid (CSF) penetration of selected chemotherapeutic agents from clinical.
| Drug Class/Drug | Regimen | Disease State (no. of patients) | Method of assessing CSF penetration | Results | Reference |
|---|---|---|---|---|---|
| Alkylating agents | |||||
| Temozolomide | 150 mg/m2 PO | Primary/metastatic CNS tumors (7) | Median brain ECF/plasma conc | 0.178 ± 0.133 | [37] |
| Temozolomide | 75–200 mg/m2/d x 5 PO, 75–200 mg/m/d PO | Recurrent glioma (7) | Tissue/plasma conc | ~1.3 | [40] |
| Ifosfamide | 1300–2000 mg/m2 IV | Intracerebral lymphoma (9), metastatic breast cancer (3) | Median CSF/plasma conc | 0.38 (0.18–0.72; parent); 3.07 (0.62–29.12; 4-OH-IFO) | [45] |
| Nucleoside Analogues | |||||
| Gemcitabine | 5–10 mg IVT | Neoplastic meningitis (8) | Peak CSF conc | 939 ± 384 μM | [54] |
| Gemcitabine | 500–1000 mg/mg2 IV | Recurrent glioblastoma multiforme (10) | Tumor tissue conc | 0.06–3.58 nmol/g (parent); 29–72 nmol/g (dFdU) | [56] |
| Capecitabine | 1250 mg/m2 PO | Metastatic breast cancer (8) | Median tumor/serum conc | 0.28 (0.031–0.81; parent); 5.64 (1.67–12.9; 5-FU) | [59] |
| Camptothecins | |||||
| Topotecan | 0.25–1 mg/m2/d IV | Primary or secondary CNS malignancies (15) | CSF/plasma conc | 0.218 (total topotecan) | [65] |
| Topotecan | 0.1–0.2 mg/dose/d IVT or intralumbar | Pediatric leukemia (2), pediatric CNS tumors (16) | Peak CSF conc | 16.58 μM (2.48–46.69; IVT inj.); 0.12 μM (0.006–1.89; intralumbar inj) | [66] |
| Tyrosine Kinase Inhibitors | |||||
| Gefitinib | 500 mg/d PO | Glioblastoma (7) | Median CSF/plasma conc | 37.62 | [73] |
| Gefitinib | 250 mg/d PO | LA (22) | Mean CSF/plasma conc | 0.013 ± 0.007 | [74] |
| Gefitinib | 250 mg/d PO | NSCLC (1), LA mets (7) | Mean CSF/plasma conc | 0.0113 ± 0.004 | [77] |
| Erlotinib | 150 mg/d PO | NSCLC (1), LA (8) | Mean CSF/plasma conc | 0.0277 ± 0.005 | [77] |
| Erlotinib | 78 mg/m2/d PO | Pediatric glioblastoma (1) | CSF/plasma conc | 0.069 (parent); 0.086 (OSI-420) | [79] |
| Erlotinib | 150 mg/d PO | NSCLC (8) | Mean CSF/plasma conc | 0.045 ± 0.015 | [82, 83] |
| Erlotinib | 100–150 mg/d PO | NSCLC (3) | Mean CSF/plasma conc | 0.063 ± 0.061 | [130] |
| Erlotinib | 150 mg/d PO | LA (6) | CSF/plasma conc | 0.02 ±0.005 (single agent); 0.023 ± 0.002 (combination) | [84] |
| Lapatinib | 900 mg/m2 PO BID | Pediatric CNS tumors (3) | Mean tumor/plasma conc | 0.17 (0.11–0.22) | [87] |
| Lapatinib | 750 mg/d PO | Recurrent glioblastoma (44) | Mean tumor tissue/plasma conc | 0.61 ± 0.6 (0.03–2.16) | [88] |
| Lapatinib | 1250 mg/d PO | Metastatic breast cancer (4) | Unbound tumor tissue/serum conc | 0.19–9.8 | [59] |
| Lapatinib | 1250 mg/d PO | Metastatic breast cancer (2) | Mean CSF/plasma conc | 0.00105 (0.008–0.0013) | [131] |
| Vandetanib | 65 mg/m2 PO | Pediatric DIPG (2) | CSF/plasma conc | 0.018 (0.012–0.024) | [132] |
| Dasatinib | 65 mg/m2 PO | Pediatric DIPG (2) | CSF/plasma conc | 0.022 (0.016–0.028) | [132] |
| Dasatinib | 140 mg/d, 60–160 mg/m2/d PO | Adult CML (6), adult ALL (4), pediatric ALL (4) | CSF/plasma conc | 0.137 (0.05–0.28) | [133] |
| Dasatinib | 100–170 mg/d PO | CML | CSF/plasma conc | 0.01–0.04 | [134] |
| Anti-folates | |||||
| Methotrexate | 2 or 5 g/m2 IV | Pediatric ALL (153) | Median CSF/serum conc | 0.025 (0.017–0.03) | [99] |
| Methotrexate | 5 or 8 g/m2 IV | Pediatric ALL (353) | Mean CSF/plasma conc | 0.018 (0.002–0.12) | [100] |
| Methotrexate | 12 g/m2 IV | Recurrent high grade glioma (4) | ECF/plasma conc | 0.28, 0.31 (contrast enhanced region); 0.032, 0.094 (non-contrast enhanced region) | [101] |
| Pemetrexed | 500–1050 mg/m2 IV | Adults with brain or leptomeningeal metastases (21) | Median CSF/plasma conc | 0.0046 (0.0002–0.035) | [107] |
| Antibodies | |||||
| Rituximab | 375 mg/m2 IV | Multiple sclerosis (2), mononeuritis multiplex (1) | Median CSF/serum conc | 0.0016 (0.0004–0.0024) | [112] |
| Rituximab | 800 mg/week IV | NHL (1) | CSF/serum conc | 0.01–0.17 | [113] |
| Rituximab | 375 mg/m2 IV | NHL (1) | CSF/plasma conc | 0.002 | [115] |
| Rituximab | 10, 25, 50 mg IVT | CNS lymphoma (10) | Mean peak CSF conc | 194 μg/ml (10 mg); 580 μg/ml (25 mg) | [114] |
| Trastuzumab | Weekly: 2 mg/kg (4 mg/kg loading dose) Triweekly: 6 mg/kg (8 mg/kg loading dose) | Metastatic breast cancer (8) | CSF/serum conc | Before RT: 0.0024 Post RT: 0.013 Meningeal Carcinomatosis: 0.02 | [135] |
| Small molecules | |||||
| Cilengitide | N/A | Pediatric high grade glioma (1) | CSF/plasma conc | 0.012 | [136] |
| Cilengitide | 200 mg, 500 mg IV | Recurrent glioma (4) | CSF/plasma conc | 0.002–0.128 | [137] |
| Smoothened inhibitors | |||||
| Vismodegib | 85–170 mg/m2 | Pediatric medulloblastoma (3) | Median CSF/plasma conc | 0.0026 (0.0014–0.0062) (total plasma); 0.53 (0.26–0.78) (unbound plasma) | [120] |
PO=oral; IV=intravenous; IVT=intraventricular; LA= lung adenocarcinoma; NSCLC=non-small cell lung carcinoma; ALL= acute lymphoblastic leukemia; CML= chronic myelogenous leukemia; DIPG= diffuse intrinsic pontine glioma; NHL= non-Hodgkin’s lymphoma; CSF= cerebrospinal fluid; conc= concentration;