Toxicology Evaluation of Drugs Administered via Uncommon Routes: Intranasal, Intraocular, Intrathecal/Intraspinal, and Intra-Articular

Abstract

As the need for nasal, ocular, spinal, and articular therapeutic compounds increases, toxicology assessments of drugs administered via these routes play an important role in human safety. This symposium outlined the local and systemic evaluation to support safety during the development of these drugs in nonclinical models with some case studies. Discussions included selection of appropriate species for the intended route; conducting nonclinical studies that closely mimic the intended use with adequate duration; functional assessment, if deemed necessary; evaluation of local tissues with special histological staining procedure; and evaluations of safety margins based on local and systemic toxicity.

Keywords: analgesics; antispasticity; epidural; granuloma; intra-articular; intracameral; intranasal; intrathecal; intravitreal; local toxicity; safety evaluation; safety margins; spinal cord; toxicity.

Figure 1

Ocular delivery routes (©Copyright 2016 DrugDel Consulting, LLC. Used with permission).

Figure 2

Adverse finding of epiretinal membrane in retinal of monkey eye injected intraviteally with implants. Note thick epiretinal membrane with nodular and linear arrays of cells on inner retinal layer. Underlying separation of retinal nuclear layers.

Figure 3

Nonadverse finding in cornea near limbus of dog injected with intracameral implants. Note small focal area of minimal endothelial hyperplasia in response to mechanical contact with implants.

Figure 4

Frontal section of normal rat knee shows shape of medial (med) and lateral (lat) sides with synovium (S), menisci (M) and cruciate (C) ligaments. Black arrows show extent of synovial space extending up the sides of the femur and arrow head shows the same on tibia. The red arrow indicates a cystic area of bone in which synovial fluid and any injected material might be present. (Toluidine blue, 16X).

Figure 5

Frontal section of rat knee injected with a toxic material shows synovium (S) that is thickened as a result of fibrosis and inflammation. Black arrows indicate tibial (lower) and femoral (upper) surfaces completely denuded of hyaline cartilage as a result of chondrocyte death. Red arrows indicate cartilage proliferation in the marginal zones, a common response to load bearing cartilage loss. Bone sclerosis is present on both medial (med) and lateral (lat) sides. (Toluidine blue, 16X).

Figure 6

Need for Safety Margins Based on both Local Injection Concentration and Local “Steady-state” Concentrations in a Virtual Space.

Figure 7

Hypothetical Example of Scaling Nonclinical Dosing to Mimic Human Dosing for “Virtual Space” injections.