Pharmacokinetics of Orbital Topotecan After Ophthalmic Artery Chemosurgery and Intravenous Infusion in the Swine Model

Abstract

Purpose: Surgery, multiagent systemic chemotherapy, and radiation are used for patients with orbital retinoblastoma but are associated with unacceptable short- and long-term toxicity (including death). We studied orbital and systemic exposure of topotecan in the swine model after ophthalmic artery chemosurgery (OAC) and intravenous (IV) delivery.

Methods: Landrace pigs (n = 3) underwent 30-minute OAC of topotecan (4 mg), and samples were serially obtained from the femoral artery and from a microdialysis probe inserted into the lateral rectus muscle sheath of the infused eye as a surrogate of the orbital irrigation. Animals were recovered, and, after a wash-out period, plasma and microdialysate samples from the contralateral eye were collected after a 30-minute IV infusion of topotecan (4 mg). Samples were quantified by high-performance liquid chromatography, and population pharmacokinetic analysis was conducted using MonolixSuite.

Results: After OAC, median topotecan exposure in the orbit was 5624 ng × h/mL (range 3922-12531) compared to 23 ng × h/mL (range 18-75) after IV infusion. Thus, topotecan exposure in the orbit was 218-fold (range 75-540) higher after OAC than after IV infusion despite comparable systemic exposure (AUCpl) between routes (AUCpl, OAC: 141 ng × h/mL [127-191] versus AUCpl, IV: 139 ng × h/mL [126-186]). OAC was more selective to target the orbit because the median (range) orbital-to-plasma exposure ratio was 44 (28-65) after OAC compared to 0.18 (0.13-0.40) after IV infusion.

Conclusions: OAC of topotecan resulted in higher orbital exposure than after IV infusion and was a more selective route for local drug delivery. Patients with orbital retinoblastoma may benefit from a multimodal treatment strategy including OAC therapy.

Figure 1.

Representative angiographies. A. Arteriography of the left carotid trunk obtained as an anteroposterior projection. (A) common carotid, (B) ascending pharyngeal artery, (C) rete mirabilis, (D) external carotid artery, (E) internal maxillary artery, (F) ophthalmic artery, (G) lingual artery, (H) choroidal blush of the left eye. B and C: representative super-selective artreiographies of the left eye of pigs.

Figure 2.

Topotecan disposition after OAC and intravenous infusion. Orbital and plasma concentration versus time profiles after (A) OAC or (B) IV infusion of 4 mg of topotecan. Green triangles represent individual concentrations in the orbit after OAC whereas blue triangles after IV infusion. After both routes of topotecan administration, black circles represent individual concentrations in plasma and the lines the best predicted concentrations according to the pharmacokinetic model for each animal. (C) Orbital-to-plasma ratio of topotecan after OAC (green) and IV infusion (blue). Box and whiskers represent quartiles and range of data, respectively.

Figure 3.

Topotecan exposure after OAC and intravenous infusion. Area under the concentration versus time profile of topotecan in the orbit (A) and in plasma (B), (C) OAC-to-IV exposure in the orbit and plasma. Box and whiskers represent quartiles and range of data, respectively.