Abstract B48: Subcutaneous delivery of docetaxel and carboplatin accumulate preferentially in lymphatic circulation as compared to intravenous delivery in rats with surgically created lymph and venous fistulae
Authors: Worley Deanna R. , Hansen Ryan J. , Chubb Laura S. , Gustafson Daniel L. 
Published: May 2015

Abstract
Purpose: Intravenous delivery of chemotherapy is an indisputable pillar of cancer therapy, but associated with unfavorable systemic toxicity. Locally delivered chemotherapy – via subcutaneous, surgical placement, or intracavitary routes – is effective in animal models of breast cancer and in client-owned dogs receiving treatment for bone tumors. There are unexplained beneficial effects of chemotherapy delivered via nontraditional routes resulting in decreased systemic toxicity and positive tumor control at dosages less than traditionally given. One role of the lymphatic system is to return large particulate matter and proteins in the interstitial space to the vascular system which cannot be absorbed by adjacent blood capillaries. This unidirectional circulatory pathway for particles deposited in areas outside of blood capillaries has not been characterized to date for nontraditionally delivered chemotherapy agents.
Experimental Design: In this study the pharmacokinetics of docetaxel and carboplatin in the blood and lymph following subcutaneous (SQ) versus intravenous (IV) delivery was determined in a surgical lymphatic and hemovascular cannulated rat model. In anesthetized adult male Sprague Dawley rats, fixed length polyurethane catheters were surgically placed simultaneously into a jugular vein and the lymphatic thoracic duct in each animal. Either docetaxel (5 mg/kg) or carboplatin (14 or 28 mg/kg) were delivered IV via tail vein catheter or SQ into the mammary fat pad. Rats were permitted free movement and access to water and food ad libitum. Paired blood and lymph samples were serially collected in animals at 0, ½, 1, 2, 3, 4, 12, and 24 hrs. Drug levels were determined via LC/MS/MS or ICP/MS for docetaxel and carboplatin, respectively. Pharmacokinetic parameters were determined via noncompartmental analysis.
Results: The maximum concentration measured (Cmax) and the area under the time-concentration curve (AUC0-24hr) in the plasma and lymph for docetaxel delivered IV were 2.86 µg/ml and 1160 hr*ng/ml, and 172 ng/ml and 1020 hr*ng/m, respectively. When administered SQ, the Cmax and AUC0-24hr were 0.644 µg/ml and 815 hr*ng/ml, and 107 ng/ml and 1650 hr*ng/ml, for plasma and lymph respectively, which demonstrates preferential lymphatic accumulation when delivered SQ. The terminal half-life (t1/2) in lymph for docetaxel is greater with either IV or SQ delivery (18.3 hr and 22.6 hr, respectively) as compared to t1/2 in blood for docetaxel with either IV or SQ delivery (9.6 hr and 6.0 hr, respectively), possibly suggesting lipophilic docetaxel resides in the lymph for longer periods.
The Cmax and AUC0-24hr in the plasma and lymph for total platinum following delivery of carboplatin (14 mg/kg) IV were 23.0 µg/ml and 28.8 hr*µg/ml, and 16.4 µg/ml and 36.1 hr*µg/m, respectively. When delivered SQ, the Cmax and AUC0-24hr for the plasma and lymph were 6.99 µg/ml and 16.6 hr*µg/ml, and 9.39 µg/ml and 24.3 hr*µg/ml, respectively. While a dose response was observed in the plasma regardless of route of administration with the Cmax in the plasma following carboplatin (28 mg/kg) of 40.0 µg total platinum/ml when given IV and 12.9 µg total platinum/ml when given SQ, the AUC0-24hr did not when administered IV.
Additionally, the AUC0-24hr in the lymph was 31.0 hr*µg/ml following IV dosing at 28 mg/kg which is similar to that observed in the plasma. However, when dosed SQ at 28 mg/kg, the Cmax and AUC0-24hr for total platinum in the lymph responded in a dose dependent manner with 17.3 µg/ml and 76.7 hr*µg/ml, respectively. This demonstrates preferential lymphatic accumulation of carboplatin delivered SQ and that there is a dose response with regards to the level of total platinum in the lymph when delivered SQ.
Conclusions: Nontraditional SQ delivery of docetaxel and carboplatin achieves targeted lymphatic accumulation greater than with traditional IV delivery. This study has broad implication for dosing strategies of chemotherapeutics for cancers metastasizing predominantly via lymphatic pathways and for cancer patients susceptible to toxicity resulting from peak maximum hemovascular concentrations that may be lessened via SQ delivery.
Citation Format: Deanna R. Worley, Ryan J. Hansen, Laura S. Chubb, Daniel L. Gustafson. Subcutaneous delivery of docetaxel and carboplatin accumulate preferentially in lymphatic circulation as compared to intravenous delivery in rats with surgically created lymph and venous fistulae. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B48.