Neuroradiology Service, Hospital de Pediatría Prof. Dr. JP Garrahan, Buenos Aires, Argentina.
Pharmacology Department, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
Invest Ophthalmol Vis Sci. 2023 Sep 1;64(12):3. doi: 10.1167/iovs.64.12.3.
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.
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.
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.
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.
手术、多药全身化疗和放疗用于治疗眼眶视网膜母细胞瘤患者，但这些治疗方法存在不可接受的短期和长期毒性（包括死亡）。我们在猪模型中研究了眼动脉化疗（OAC）和静脉（IV）给药后拓扑替康的眼眶和全身暴露情况。
Landrace 猪（n = 3）接受 30 分钟 OAC 拓扑替康（4mg），并从股动脉和插入输注眼外侧直肌鞘的微透析探针中连续采集样本作为眼眶冲洗的替代物。动物恢复后，在洗脱期后，在静脉输注 30 分钟 IV 拓扑替康（4mg）后采集对侧眼的血浆和微透析液样本。样品通过高效液相色谱法进行定量，并使用 MonolixSuite 进行群体药代动力学分析。
OAC 后，眼眶中拓扑替康的中位数暴露量为 5624ng×h/mL（范围 3922-12531），而 IV 输注后为 23ng×h/mL（范围 18-75）。因此，尽管两种途径的全身暴露量（AUCpl）相似（AUCpl，OAC：141ng×h/mL[127-191]与 AUCpl，IV：139ng×h/mL[126-186]），但 OAC 后的眼眶暴露量是 IV 输注后的 218 倍（范围 75-540）。OAC 对眼眶的选择性更高，因为 OAC 后的中位数（范围）眼眶-血浆暴露比为 44（28-65），而 IV 输注后的比值为 0.18（0.13-0.40）。
OAC 拓扑替康的眼眶暴露量高于 IV 输注，是局部药物递送的更具选择性途径。眼眶视网膜母细胞瘤患者可能受益于包括 OAC 治疗在内的多模式治疗策略。
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