The blood–brain barrier (BBB) limits entry of most chemotherapeutic agents into the CNS, resulting in inadequate exposure within CNS tumor tissue. Intranasal administration is a proposed means of delivery that can bypass the BBB, potentially resulting in more effective chemotherapeutic exposure at the tumor site. The objective of this study was to evaluate the feasibility and pharmacokinetics (plasma and CSF) of intranasal delivery using select chemotherapeutic agents in a non-human primate (NHP) model. Three chemotherapeutic agents with known differences in CNS penetration were selected for intranasal administration in a NHP model to determine proof of principle of CNS delivery, assess tolerability and feasibility, and to evaluate whether certain drug characteristics were associated with increased CNS exposure. Intravenous (IV) temozolomide (TMZ), oral (PO) valproic acid, and PO perifosine were administered to adult male rhesus macaques. The animals received a single dose of each agent systemically and intranasally in separate experiments, with each animal acting as his own control. The dose of the agents administered systemically was the human equivalent of a clinically appropriate dose, while the intranasal dose was the maximum achievable dose based on the volume limitation of 1 mL. Multiple serial paired plasma and CSF samples were collected and quantified using a validated uHPLC/tandem mass spectrometry assay after each drug administration. Pharmacokinetic parameters were estimated using non-compartmental analysis. CSF penetration was calculated from the ratio of areas under the concentration–time curves for CSF and plasma (AUCCSF:plasma). Intranasal administration was feasible and tolerable for all agents with no significant toxicities observed. For TMZ, the degrees of CSF drug penetration after intranasal and IV administration were 36 (32–57) and 22 (20–41)%, respectively. Although maximum TMZ drug concentration in the CSF (Cmax) was lower after intranasal delivery compared to IV administration due to the lower dose administered, clinically significant exposure was achieved in the CSF after intranasal administration with the lower doses. This was associated with lower systemic exposure, suggesting increased efficiency and potentially lower toxicities of TMZ after intranasal delivery. For valproic acid and perifosine, CSF penetration after intranasal delivery was similar to systemic administration. Although this study demonstrates feasibility and safety of intranasal drug administration, further agent-specific studies are necessary to optimize agent selection and dosing to achieve clinically-relevant CSF exposures.
This work was presented in part at the 2015 Society of Neuro-Oncology and the Society of CNS Interstitial Delivery of Therapeutics (SNO-SCIDOT) Joint Conference on Therapeutic Delivery to the CNS in San Antonio, TX. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.
The views expressed in this article are those of the author(s) and do not reflect the official policy or views of the National Cancer Institute, the National Institutes of Health, the U.S. Department of Health and Human Services, the Department of the Army/Navy/Air Force, Department of Defense, or any other agency of the U.S. Government.
Compliance with ethical standards
Conflict of interest
Authors James C. League-Pascual, Cynthia M. Lester-McCully, Shaefali Shandilya, Lukas Ronner, Louis Rodgers, Rafael Cruz, Cody J. Peer, William D. Figg, and Katherine E. Warren all individually declare no conflict of interest.
Research involving human and animal rights
The National Cancer Institute Animal Care and Use Committee approved this study. All applicable institutional guidelines for the care and use of animals were followed. This study does not contain any studies with human participants.
Costantino HR et al (2007) Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm 337(1–2):1–24CrossRefPubMedGoogle Scholar
Panagiotou I, Mystakidou K (2010) Intranasal fentanyl: from pharmacokinetics and bioavailability to current treatment applications. Expert Rev Anticancer Ther 10(7):1009–1021CrossRefPubMedGoogle Scholar
Mittal D et al (2014) Insights into direct nose to brain delivery: current status and future perspective. Drug Deliv 21(2):75–86CrossRefPubMedGoogle Scholar
Djupesland PG (2013) Nasal drug delivery devices: characteristics and performance in a clinical perspective-a review. Drug Deliv Transl Res 3(1):42–62CrossRefPubMedGoogle Scholar
Attkins NJ et al (2009) Predictability of intranasal pharmacokinetics in man using pre-clinical pharmacokinetic data with a dopamine 3 receptor agonist, PF-219061. Xenobiotica 39(7):523–533CrossRefPubMedGoogle Scholar
Dhuria SV, Hanson LR, Frey WH 2nd (2010) Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 99(4):1654–1673CrossRefPubMedGoogle Scholar
Lochhead JJ, Thorne RG (2012) Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 64(7):614–628CrossRefPubMedGoogle Scholar
Illum L (2000) Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci 11(1):1–18CrossRefPubMedGoogle Scholar
Johnson NJ, Hanson LR, Frey WH (2010) Trigeminal pathways deliver a low molecular weight drug from the nose to the brain and orofacial structures. Mol Pharm 7(3):884–893CrossRefPubMedPubMedCentralGoogle Scholar
Merkus FW, van den Berg MP (2007) Can nasal drug delivery bypass the blood–brain barrier?: questioning the direct transport theory. Drugs R D 8(3):133–144CrossRefPubMedGoogle Scholar
Thorne RG et al (2008) Delivery of interferon-beta to the monkey nervous system following intranasal administration. Neuroscience 152(3):785–797CrossRefPubMedGoogle Scholar
van Woensel M et al (2013) Formulations for intranasal delivery of pharmacological agents to combat brain disease: a new opportunity to tackle GBM? Cancers (Basel) 5(3):1020–1048CrossRefGoogle Scholar
Shingaki T et al (2010) Transnasal delivery of methotrexate to brain tumors in rats: a new strategy for brain tumor chemotherapy. Mol Pharm 7(5):1561–1568CrossRefPubMedGoogle Scholar
Djupesland PG, Messina JC, Mahmoud RA (2014) The nasal approach to delivering treatment for brain diseases: an anatomic, physiologic, and delivery technology overview. Ther Deliv 5(6):709–733CrossRefPubMedGoogle Scholar
Peterson A et al (2014) A systematic review of inhaled intranasal therapy for central nervous system neoplasms: an emerging therapeutic option. J Neurooncol 116(3):437–446CrossRefPubMedGoogle Scholar
CO, D.A.F. et al (2013) Long-term outcome in patients with recurrent malignant glioma treated with Perillyl alcohol inhalation. Anticancer Res 33(12):5625–5631Google Scholar
Patel M et al (2003) Plasma and cerebrospinal fluid pharmacokinetics of intravenous temozolomide in non-human primates. J Neurooncol 61(3):203–207CrossRefPubMedGoogle Scholar
Stapleton SL et al (2008) Plasma and cerebrospinal fluid pharmacokinetics of valproic acid after oral administration in non-human primates. Cancer Chemother Pharmacol 61(4):647–652CrossRefPubMedGoogle Scholar
Cole DE et al (2015) Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model. Cancer Chemother Pharmacol 75(5):923–928CrossRefPubMedGoogle Scholar
Albus U (2012) Guide for the care and use of laboratory animals (8th edn). Lab Anim 46(3):267–268CrossRefGoogle Scholar
Mygind N, Upper airway: structure, function and therapy, in in aerosol in medicine. Princples, diagnoses, and therapy. 1985, Elsevier, Amsterdam, pp 1–20Google Scholar
Peer CJ et al (2016) Quantification of temozolomide in nonhuman primate fluids by isocratic ultra-high performance liquid chromatography-tandem mass spectrometry to study brain tissue penetration following intranasal or intravenous delivery. Separations 3(1):4Google Scholar