Pharmacokinetics Services

Metabolism involves the biotransformation of a drug into active or inactive metabolites, primarily mediated by enzymatic systems such as cytochrome P450 (CYP450) isoforms in the liver, though extrahepatic metabolism (including in ocular tissues) is increasingly recognized in preclinical ophthalmic research. Metabolic kinetics are characterized by clearance (CL), the volume of plasma cleared of drug per unit time, and metabolite profiling, which helps identify potential toxic intermediates or pharmacologically active metabolites. Excretion is the final process by which drugs and their metabolites are eliminated from the body, primarily via renal or biliary pathways, with elimination half-life (t½) denoting the time required for plasma drug concentration to decrease by 50%, a key parameter for dosing interval optimization.

In preclinical research, PK studies are conducted under strict Good Laboratory Practices (GLP) using validated analytical methods and appropriate animal models to ensure data reproducibility and regulatory compliance. The integration of PK data with pharmacodynamic (PD) and toxicological findings forms a comprehensive preclinical profile, enabling researchers to select lead candidates with favorable efficacy-safety balances. Mathematical modeling and simulation further enhance the value of preclinical PK data, facilitating interspecies scaling to predict human pharmacokinetics and inform first-in-human dose selection — a critical step in reducing clinical development risks.

Pharmacokinetics in Ophthalmic Diseases

Our Services

At Protheragen, we have established a dedicated team of experts in the field of ophthalmic disease pharmacokinetics, offering a comprehensive suite of services to support the development of innovative ocular therapies.

Preclinical Animal Model-Specific PK Evaluations

Protheragen offers species-specific preclinical PK studies using animal models optimized for ophthalmic research, including rabbits, rodents (mice, rats), dogs, and non-human primates, based on the client's target indication and research objectives. For anterior segment diseases (e.g., glaucoma, conjunctivitis), rabbit models are utilized to assess topical, subconjunctival, and intracameral drug delivery, with serial sampling of aqueous humor, cornea, conjunctiva, and iris-ciliary body to quantify absorption and distribution kinetics. Rodent models are employed for posterior segment diseases (e.g., retinitis pigmentosa, diabetic retinopathy), enabling evaluation of intravitreal, subretinal, and suprachoroidal administration routes, with tissue-specific analysis of retina, choroid, sclera, and vitreous humor. Protheragen's team provides expert guidance on model selection, ensuring that the chosen species recapitulates key aspects of human ocular physiology and drug disposition to maximize the translatability of preclinical data. All studies include comprehensive PK parameter calculation, including Cmax (maximum drug concentration), AUC (area under the concentration-time curve), tmax (time to reach Cmax), t½, CL, and Vd, tailored to ocular matrices and administration routes.

Ocular Matrix Sampling and Bioanalysis

Protheragen provides specialized ocular matrix sampling and bioanalytical services to quantify drug concentrations in a full range of ocular tissues and fluids, addressing the challenge of limited sample volumes and complex matrices. Our services include collection of aqueous humor, vitreous humor, cornea, conjunctiva, iris-ciliary body, lens, retina, choroid, sclera, and optic nerve at predefined time points following drug administration, with strict protocols to maintain sample integrity and prevent cross-contamination. Bioanalytical testing is performed using validated LC-MS/MS methods, optimized for sensitivity (detection limits as low as pg/mL) and specificity to quantify drugs and their metabolites in ocular matrices. For biomolecule-based therapeutics (e.g., proteins, peptides, gene therapies), Protheragen offers enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) services to measure drug concentrations and assess gene expression profiles, respectively. All bioanalytical methods undergo rigorous validation in accordance with ICH guidelines, including assessments of accuracy, precision, linearity, specificity, recovery, and stability, to ensure regulatory acceptability of results.

Formulation-Driven PK Evaluations

Protheragen supports formulation optimization through specialized PK evaluations tailored to different ophthalmic dosage forms, including topical solutions, suspensions, gels, ointments, nanoparticles, nanomicelles, liposomes, and intravitreal implants. For topical formulations, studies assess the impact of rheological properties (e.g., viscosity, shear-thinning behavior), mucoadhesive agents, and particle size on precorneal residence time and intraocular bioavailability. For example, evaluations of submicron vs. micronized gel formulations quantify differences in dissolution kinetics and ocular tissue penetration, providing data to guide formulation refinement. For sustained-release formulations such as intravitreal implants, PK studies measure drug release rates over extended periods (weeks to months), assessing tissue distribution and systemic exposure to optimize implant design and dosing frequency. Protheragen also evaluates the PK of combination formulations, quantifying potential drug-drug interactions in ocular tissues and ensuring that each component achieves therapeutic concentrations at the target site.

Toxicokinetic (TK) Integration with PK Evaluations

Protheragen integrates toxicokinetic assessments with PK evaluations to establish the relationship between ocular and systemic drug exposure and observed toxic effects, a critical component of preclinical safety assessment. TK studies are conducted alongside repeated-dose toxicity studies, quantifying drug concentrations in ocular tissues, plasma, and key systemic organs (liver, kidneys) at predefined intervals to assess accumulation potential and exposure-response relationships. For example, TK evaluations of intravitreal drugs identify correlations between vitreous humor drug concentrations and retinal toxicity, guiding the selection of safe doses for clinical trials. Protheragen's team analyzes TK parameters in conjunction with toxicological endpoints (e.g., ocular irritation, histological changes, intraocular pressure alterations) to define safety margins and support regulatory submissions. These integrated evaluations provide a comprehensive understanding of the safety profile of ophthalmic drug candidates, ensuring that potential risks are identified and mitigated early in development.

PK Modeling and Simulation

Protheragen offers advanced PK modeling and simulation services to enhance the predictive value of preclinical data, supporting interspecies scaling, dose optimization, and clinical trial design. Population PK models are developed to characterize variability in drug disposition across animal models, identifying factors such as age, gender, and disease state that influence PK parameters. Physiologically based pharmacokinetic (PBPK) models are constructed to simulate drug distribution in ocular tissues, integrating anatomical and physiological data (e.g., ocular blood flow, tissue volumes, barrier permeability) to predict human PK profiles. These models enable researchers to extrapolate preclinical results to humans, optimizing first-in-human doses and dosing intervals to maximize therapeutic efficacy while minimizing safety risks. Protheragen's modeling experts collaborate with clients to refine models based on experimental data, providing actionable insights to guide decision-making throughout preclinical and early clinical development.

In Vitro ADME Evaluations

Our in vitro capabilities encompass a broad range of ADME assessments, including studies on physicochemical properties, permeability, transporter interactions, protein binding, and metabolic stability. These early-stage evaluations provide critical insights into a drug candidate's potential for ocular penetration and distribution, helping to guide formulation development and candidate selection.

In Vivo Pharmacokinetic Studies

We leverage our expertise in animal models to conduct robust in vivo pharmacokinetic studies, measuring drug concentrations in various ocular tissues following different routes of administration. Our skilled scientists can perform precise microdissection and sampling of individual eye structures, such as the cornea, aqueous humor, vitreous, retina, and choroid, to map the detailed distribution profile of your compound.

Routes for Ocular Drug Delivery

Effective ocular drug delivery is contingent upon the selection of appropriate administration routes. Protheragen's services cover:

We design studies tailored to client's specific needs, whether it's early-stage drug discovery or late-stage formulation optimization. If you are interested in our services, please feel free to contact us for more details and quotation information of related services.

Reference

• Del Amo, Eva M., et al. "Pharmacokinetic aspects of retinal drug delivery." Progress in retinal and eye research 57 (2017): 134-185.