Aole Zheng 1,2, Tian Han 3, Qingfeng He 2, Xiaoqiang Xiang 2, Tingjie Guo 1
1 Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research (LACDR), Leiden University (Leiden, Netherlands), 2 Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University (Shanghai, China), 3 Eye, Ear, Nose and Throat Hospital, Fudan University (Shanghai, China)
Objectives
Atropine is widely used in ophthalmology for mydriasis, cycloplegia, and amblyopia treatment. Recently, low-dose atropine has gained increasing attention for slowing myopia progression in children and adolescents[1,2]. While most randomized clinical trials attest to its myopia-preventive efficacy, the precise underlying mechanisms and pharmacokinetic behavior within human eyes remain elusive. Investigating ophthalmic drug pharmacokinetic (PK) is challenging due to complex experimental procedures, intricate ocular physiology, and high costs. Ethical considerations further hinder comprehensive ocular PK studies of atropine in humans. Given these limitations, this study aimed to developed a physiological based pharmacokinetics (PBPK) -Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® to characterize atropine PK behavior in rabbit eyes, subsequently extrapolate the model to the human ocular tissue and explore the potential PK mechanisms of atropine.
Methods
In a prospective clinical study, myopic patients undergoing implantable collamer lens surgery were enrolled. Prior to surgery, 0.01% atropine was administered for mydriasis. After ≥30 minutes, aqueous humor (50 μL) was collected during corneal incision, and sampling time was recorded.
The PBPK-OCAT model comprises 13 physiological compartments and incorporated nasolacrimal drainage, melanin binding, and ocular permeability. Model development followed three stages: 1) the development of the ocular PBPK model for atropine in rabbits; 2)validation using published rabbit ocular concentration-time profiles; 3) extrapolation to human and validation using observed human aqueous humor concentrations.
Physicochemical parameters (logP, pKa, fu,p) were obtained from literature. Ocular physiological parameters were drawn from GastroPlus® default settings for rabbits and humans. Key kinetic parameters included tissue permeabilities and elimination rates, which were optimized during model calibration. Subsequent to primary model development, three sets of ocular tissue concentration data obtained after topical atropine in rabbit eyes were used to validate the primary PBPK model[3-5]. The primary criterion for model validation is whether the simulated concentration-time curves fall within the standard deviation of the measured data. The final validated PBPK-OCAT model for rabbits was extrapolated to human subsequently to predict the biodistribution of atropine in human eyes. Human extrapolation accounted for species-specific anatomical differences, particularly melanin distribution in the iris-ciliary body, retinal pigment epithelium, and choroid. A melanin binding study reported an in vitro fu, melanin of 59% for atropine, a parameter integrated into human ocular PBPK modeling[6]. Subsequently, the predicted atropine aqueous humor concentration was verified by clinical observed data. The validated human PBPK-OCAT model is used to simulate atropine ocular distribution in different concentrations, including 0.05mL 0.01%, 0.05mL 0.025%, and 0.05mL 0.05% atropine.
Results
The PBPK model enables the extrapolation of pharmacokinetic characteristics among different species depending on their physiology and anatomy. The developed and validated OCAT-PBPK model demonstrated good agreement with observed data from rabbit ocular tissues and human aqueous humor. Fifty-eight percent of simulations fell within the standard deviation range of experimental data. The extrapolated human PBPK model for accurately predicted the ocular exposure and distribution following the administration of low-concentration atropine. The results conclude that the tissues in descending order of atropine concentration were conjunctiva, cornea, iris-ciliary body, sclera, retina, and vitreous humor. The concentration of atropine in each ocular tissue peaked at 0.08, 0.16, 0.88, 0.4, 19.68, and 7.6 hours, respectively. It is believed that atropine targets biological receptors in both the retina and sclera to curtail myopia progression. Following the administration of 0.05 mL 0.01%, 0.05 mL 0.025%, and 0.05 mL 0.05% atropine, the Cmax values in the retin were 43 ng/mL, 107 ng/mL, and 213 ng/mL, respectively, with the AUC0-t values of 1492 ng*h /mL, 3730 ng*h /mL, and 7460 ng*h /mL, respectively. In sclera, the Cmax values were 142 ng/mL, 356 ng/mL, and 1275 ng/mL, respectively, with the AUC0-t values of 4171 ng*h /mL, 10430 ng*h /mL, and 20850 ng*h /mL, respectively.
Conclusions
In conclusion, the first ocular PBPK model for atropine was developed based on animal ocular pharmacokinetic data and extrapolated to humans successfully. This approach can support the hypothesis of racial differences and enhances our understanding of how relative parameters affect in vivo exposure to ophthalmic products. Furthermore, it serves as a valuable tool for gaining deep insight into the mechanisms of ophthalmic drugs.
References:
1. Gong Q, Janowski M, Luo M, et al. Efficacy and Adverse Effects of Atropine in Childhood Myopia: A Meta-analysis. JAMA Ophthalmol. Jun 1 2017;135(6):624-630. doi:10.1001/jamaophthalmol.2017.1091
2. Ha A, Kim SJ, Shim SR, Kim YK, Jung JH. Efficacy and Safety of 8 Atropine Concentrations for Myopia Control in Children: A Network Meta-Analysis. Ophthalmology. Mar 2022;129(3):322-333. doi:10.1016/j.ophtha.2021.10.016
3. Meisner D, Pringle J, Mezei M. Liposomal ophthalmic drug delivery. III. Pharmacodynamic and biodisposition studies of atropine. International Journal of Pharmaceutics. 1989/10/15/ 1989;55(2):105-113. doi:10.1016/0378-5173(89)90030-6
4. Wang LZ, Syn N, Li S, et al. The penetration and distribution of topical atropine in animal ocular tissues. Acta Ophthalmologica. 2019/03/01 2019;97(2):e238-e247. doi:10.1111/aos.13889
5. Ji M, Liu H, Ma S, et al. Stable Atropine Loaded Film As a Potential Ocular Delivery System For Treatment Of Myopia. Pharmaceutical Research. 2021/11/01 2021;38(11):1931-1946. doi:10.1007/s11095-021-03135-4
6. Hellinen L, Bahrpeyma S, Rimpelä A-K, Hagström M, Reinisalo M, Urtti A. Microscale Thermophoresis as a Screening Tool to Predict Melanin Binding of Drugs. Pharmaceutics. 2020/06/16 2020;12(6):554. doi:10.3390/pharmaceutics12060554
Reference: PAGE 34 (2026) Abstr 11855 [www.page-meeting.org/?abstract=11855]
Poster: Drug/Disease Modelling - Absorption & PBPK