Validation of an effective implantable pump-infusion system for chronic convection-enhanced delivery of intracerebral topotecan in a large animal model

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>Intracerebral convection-enhanced delivery (CED) has been limited to short durations due to a reliance on externalized catheters. Preclinical studies investigating topotecan (TPT) CED for glioma have suggested that prolonged infusion improves survival. Internalized pump-catheter systems may facilitate chronic infusion. The authors describe the safety and utility of long-term TPT CED in a porcine model and correlation of drug distribution through coinfusion of gadolinium.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>Fully internalized CED pump-catheter systems were implanted in 12 pigs. Infusion algorithms featuring variable infusion schedules, flow rates, and concentrations of a mixture of TPT and gadolinium were characterized over increasing intervals from 4 to 32 days. Therapy distribution was measured using gadolinium signal on MRI as a surrogate. A 9-point neurobehavioral scale (NBS) was used to identify side effects.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>All animals tolerated infusion without serious adverse events. The average NBS score was 8.99. The average maximum volume of distribution (Vd<jats:sub>max</jats:sub>) in chronically infused animals was 11.30 mL and represented 32.73% of the ipsilateral cerebral hemispheric volume. Vd<jats:sub>max</jats:sub> was achieved early during infusions and remained relatively stable despite a slight decline as the infusion reached steady state. Novel tissue TPT concentrations measured by liquid chromatography mass spectroscopy correlated with gadolinium signal intensity on MRI (p = 0.0078).</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>Prolonged TPT-gadolinium CED via an internalized system is safe and well tolerated and can achieve a large Vd<jats:sub>max</jats:sub>, as well as maintain a stable Vd for up to 32 days. Gadolinium provides an identifiable surrogate for measuring drug distribution. Extended CED is potentially a broadly applicable and safe therapeutic option in select patients.</jats:p></jats:sec>

Lentiviral Vector Induced Modeling of High-Grade Spinal Cord Glioma in Minipigs

“…Current preclinical studies for therapeutic approaches including, but not limited to, oncolytic viral therapy, immunotherapy, convection-enhanced delivery, fluorescein dyes and laser interstitial thermal therapy in high-grade glioma rely on large animal models with no ability to evaluate therapeutic efficacy in disease models 7 . By using orthotopic intraparenchymal gene transfer in higher-order species, given the advantages of an immunocompetent porcine model, investigators can reasonably adjust transgenes and/or promoters to dissect the disease process and develop translationally relevant systems in a variety of glioma grades and subtypes.…”

“…The genetic profile, immune system, and the size and anatomy of the porcine brain and spinal cord is recognized to better model the human 25,29,31 . For these reasons, device implantation, stereotactic radiosurgery, and intrathecal and intraparenchymal drug delivery have all been performed in pigs 7,27,[32][33][34][35][36] . Furthermore, while the Food and Drug Administration (FDA) has recognized proof-of-principle data on therapeutic efficacy in highly characterized rodent models, the use of large animals is considered critical for clinical relevance.…”

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

“…Nevertheless, other preclinical studies have shown promising results [410], and continuous efforts have been made to improve the efficiency of CED, including works in catheter technology and optimal positioning [406]. Recently, a chronic CED administration system was used to infuse the topoisomerase inhibitor topotecan in a pig model for up to 32 days without toxicity [411]. The use of ABC inhibitors has been suggested as a strategy to improve CED and could be further explored.…”

Neuroimaging Studies Evaluating Effective Therapies for High-Grade Glioma

“…They demonstrated that high flow rates up to 4 mL/day lead to large and stable drug volumes distribution during a 32 days treatment period without inducing toxic effects. 172 While more work needs to be done to optimize pulsatile infusion schedules, this study represents an important stepping stone for the refinement of the CED technique in a clinically relevant animal model. 173 Finally, the results of the phase II clinical trial NCT00431561, assessing therapeutic response of recurrent/refractory HGG patients to the administration of an immune-oncology drug candidate with a CED system, were recently published.…”

“…Recently, D'Amico et al 172 successfully validated the effectiveness of an implantable pumpinfusion system for chronic CED of intracerebral topotecan in pigs. They demonstrated that high flow rates up to 4 mL/day lead to large and stable drug volumes distribution during a 32 days treatment period without inducing toxic effects.…”