Pharmacokinetics Following Intraventricular Administration of Chemotherapy in Patients with Neoplastic Meningitis

Abstract

Intraventricular administration of chemotherapy is one approach to overcoming the limited distribution of anticancer drugs and their active metabolites into the CNS. This form of regional chemotherapy has led to effective treatment of occult and overt meningeal leukaemia in humans. In contrast, the efficacy of this therapy is extremely limited in the treatment of leptomeningeal dissemination of various solid tumours. Pharmacokinetic studies of the commonly intraventricularly applied anticancer agents in humans have demonstrated that, using low drug doses, very high drug concentrations can be achieved in the cerebrospinal fluid (CSF) and relatively high concentrations in the leptomeninges but not in the brain tissue and the plasma. Therefore, this approach is not an effective treatment for bulky disease of brain tissue, and results in minimal systemic toxicity. In comparison with intralumbar administration, lower interpatient variability of CSF drug concentrations and improved clinical efficacy were observed. 'Concentration x time' schedules, i.e. frequent small drug doses over a short period, enable long-term CSF exposure to cytotoxic drug concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. The technique of ventriculolumbar cerebrospinal perfusion delivers continuously high drug concentrations throughout the CSF for several hours, but its widespread use is limited by the technical complexities of this approach. In this article, the dosages, schedules and pharmacokinetic data of routinely used intraventricular agents in humans, e.g. methotrexate, cytarabine, glucocorticoids and thiotepa, are outlined in detail. In addition, pharmacokinetic data of investigational agents for intraventricular administration (diaziquone, DTC 101, mercaptopurine, mafosfamide, etoposide, topotecan, nimustine [ACNU] and bleomycin) are presented. Better understanding of the CSF pharmacology of these drugs is an essential prerequisite for safe, effective administration of these drugs. Investigational efforts are underway to verify the feasibility and efficacy of different dosages, schedules and combination therapies of these new intra-CSF agents. Current and future clinical research should also focus on methods allowing the delivery of tumoricidal drug concentrations for extended periods into the CSF and the brain tissue while minimising neurotoxicity and systemic toxicity (e.g. liposomal drug preparations, monoclonal antibodies, immunotoxins and gene therapy).

Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

“…68 The most common dose used is 12 mg, which achieves therapeutic levels in the CSF (>1 μmol/L) for 24 to 48 hours. 68,69 IT MTX doses of 12.5 mg and 15 mg have also been reported. 4,13,67,68,70 Of note, studies supporting this approach 11,13,[70][71][72][73] have several limitations, including small sample sizes, absence of a control arm, and co-administration of systemic MTX.…”

Medulloblastoma in childhood: revisiting intrathecal therapy in infants and children

“…The information that was missing was physicochemical (7), cell cycle specificity (4) and neurotoxicity (7). The previous reviews [17,49,108] made no suggestions for this category of agents. Drugs, tested by the intrathecal route but with mixed reports of toxicity (n=7 Table 5), were based upon clinical case reports from both animal and human experimentation, limiting the scope of this group as a source of new drugs for testing.…”

“…The use of intrathecal chemotherapy in childhood leukaemia and CNS tumours has been the focus of reviews [17,49,108] and reports of phase 1 and 2 studies [17]. In leukaemia the intensification of systemic and intrathecal therapy has permitted exclusion of CNS radiotherapy for the majority of newly diagnosed cases with very low CNS relapse rates, acceptable late toxicity using methotrexate alone or in combination with cytosine and hydrocortisone.…”

Intracerebroventricular drug administration

“…[1] antineoplastic. [2] analgesic. [3] and antispasticity [4] drugs have been administered directly into the CSF.…”