Ninety-day Local Tolerability and Toxicity Study of ND0612, a Novel Formulation of Levodopa/Carbidopa, Administered by Subcutaneous Continuous Infusion in Minipigs

• Published in: Toxicologic pathology Vol. 45; no. 6; p. 764
• Main Authors: Ramot, Yuval, Nyska, Abraham, Maronpot, Robert R, Shaltiel-Karyo, Ronit, Tsarfati, Yonit, Manno, Rosa Anna, Sacco, Giuseppe, Yacoby-Zeevi, Oron
• Format: Journal Article
• Language: English
• Published: United States 01.08.2017
• Subjects: Animals; Carbidopa - administration & dosage; Carbidopa - blood; Carbidopa - toxicity; Dopamine Agonists - administration & dosage; Dopamine Agonists - blood; Dopamine Agonists - toxicity; Drug Combinations; Drug Evaluation, Preclinical; Drug Tolerance; Female; Infusions, Subcutaneous; Injection Site Reaction - etiology; Injection Site Reaction - pathology; Levodopa - administration & dosage; Levodopa - blood; Levodopa - toxicity; Male; Necrosis; Swine; Swine, Miniature; Toxicity Tests, Chronic; minipigs; 3Rs; levodopa; carbidopa; infusion site reaction; safety; tolerability; preclinical toxicity; Parkinson’s disease; toxicologic pathology
• ISSN: 1533-1601
• DOI: 10.1177/0192623317729891

A 90-day study in Göttingen minipigs was conducted to test the local tolerability and systemic toxicity of ND0612, a novel aqueous solution of carbidopa (CD)/levodopa (LD) intended for the treatment of Parkinson's disease by continuous subcutaneous administration using a discrete infusion pump. To evaluate tissue site reactions, we used a unique study design involving multiple infusion sites to evaluate the effect of dose per site (270/63, 360/45, and 360/84 mg LD/CD), volume of infusion per site (4.5 and 6 ml per site), formulation concentration (60/14 and 60/7.5 mg/ml LD/CD), daily rate of infusion per site (240 μl/hr for16 hr and 80 μl/hr for 8 hr, 320 μl/hr for 16 hr and 100 μl/hr for 8 hr, or 750 μl/hr for 8 hr), frequency (once every 5, 10, 15, or 20 days), and number of infusions (4, 6, or 9) to the same infusion site. No systemic adverse effects were observed. Histopathological changes at infusion sites started with localized minimal necrosis and acute inflammation that progressed to subacute and chronic inflammatory and reparative changes with evidence of progressive recovery following the final infusion. None of the infusion site effects were judged to be adverse, and clinical exposures to ND0612 are not expected to result in adverse responses.