Pharmacokinetics and Electroretinographic Findings After Mycophenolic Acid Intravitreal Injection in Rabbits

Abstract

Purpose: : Mycophenolate mofetil (MMF) is a potent immunomodulatory drug used in the treatment of patients with autoimmune uveitis. However, gastrointestinal side effects are the main reason for discontinuation, occurring in up to 20% of patients. Mycophenolic acid (MPA) is the active form of MMF. We injected MPA in the rabbit vitreous and evaluated pharmacokinetics, concentration in the serum, and retinal functional effects by electroretinogram (ERG).

Methods: : Aqueous suspension of MPA (Roche, Palo Alto, CA) was injected in the vitreous of 16 New Zealand rabbits (1mg/0.1ml - 5 folds the theoretical concentration of MPA present inside the eye after oral intake). As control, the contralateral eye of each rabbit was injected with aqueous vehicle. Animals were sacrificed after days 1, 7, 15, and 30. MPA vitreous and serum concentrations were measured by high performance liquid chromatography (HPLC). ERGs were recorded in 4 rabbits before and after injection, according to ISCEV protocol.

Results: : The HPLC method was validated. MPA half-life in the rabbit vitreous was 4.98 days (log curve, r²=0.993; P=0.0035) and the drug was detectable for 29 days (sensitivity 1µg/ml). MPA was not detected in the serum in any of the different time points. ERG records showed that MPA reduced a- and b-waves amplitudes but not significantly (P>0.05, Sign test). Photopic a-wave amplitude was reduced by 40%; b-wave amplitude was reduced by 21% on scotopic, 26% on maximum scotopic, and 26% on photopic responses. Photopic and scotopic a- and b-waves implicit times did not change after MPA injection. Vehicle injection did not alter ERG in any condition.

Conclusions: : MPA is detectable in the rabbit vitreous up to 29 days after intravitreal injection and presents undetectable systemic absorption by the HPLC method used. The high dose used may cause some degree of retinal toxicity. Although intravitreal injection of MPA is a potential treatment for patients with autoimmune uveitis, more studies should be carried out to determine its safety.

Keywords: retina • drug toxicity/drug effects • immunomodulation/immunoregulation