Pharmacokinetic Analysis of 3,4-Diaminopyridine in the Cynomolgus Monkey
Abstract
The purpose of this study was to evaluate the pharmacokinetics of 3,4-diaminopyridine free base (3,4-DAP) in the cynomolgus monkey following single or repeat administration of 3,4-diaminopyridine phosphate (3,4-DAPP) via intravenous (IV), subcutaneous (SC), and oral (PO) routes. To accomplish this, male cynomolgus monkeys (of Mauritius origin) were surgically implanted with vascular access ports (VAPs) for ease of repeated blood collection. Animals were then dosed at the 1.03, 2.06, and 4.12 mg/kg of 3,4-diaminopyridine phosphate (amifampridine phosphate drug substance; 3,4-DAPP) for each dose route investigated. Dosing was performed as either a single administration or a repeat administration with a second dose administered approximately 4 hours after the first dose. Baseline blood samples were collected prior to animals receiving their first or second dose (as applicable). Post-administration blood samples collected from animals at 5, 15, 30, and 60 minutes and 2, 4, and 6 hours after receiving their first or second dose (as applicable). Animals were allowed a washout period of at least 3 days between escalating to the next dose levels for a given route, with an additional washout period of at least 2 weeks before proceeding to the next dosing route. Collected blood samples were processed to plasma and submitted for analysis of 3,4-diaminopyridine (free base, aka 3,4-DAP) concentrations, as the phosphate salt form of the test article is known to rapidly dissociate when formulated in solution. Samples were analyzed using developed methods for high performance liquid chromatography tandem mass spectrometry (LC-MS/MS). The concentrations of 3,4-DAP in collected samples were then submitted for pharmacokinetic evaluation. Endpoints used to evaluate potential toxicity were survival and clinical observations.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 30, 2022
- Accession Number
- AD1167454
Entities
People
- Phillip H. Beske
Organizations
- Battelle Memorial Institute