How PBPK Can Help to Understand Old Drugs and Inform their Dosing in Elderly: Amantadine Case Study.

Amantadine, despite being on the market for 55 years, has several unknown aspects of its pharmacokinetics especially related to the influence of covariates such as age, disease, or interactions linked to amantadine's renal elimination. As amantadine is used in Parkinson's disease and is considered a potential candidate in COVID treatment and other diseases, there is an unmet need for thorough understanding of its pharmacokinetic in special populations, such as the elderly. We aimed to mechanistically describe amantadine pharmacokinetics in healthy subjects and shed some light on the differences in drug behavior between healthy volunteers (18-65 years) and an elderly/geriatric population (65-98 years) using PBPK modeling and simulation. The middle-out PBPK model includes mechanistic description of drug renal elimination, specifically an organic cation transporter (OCT)2-mediated electrogenic bidirectional transport (basolateral) and multidrug and toxic compound extrusion (MATE)1-mediated efflux (apical). The model performance was verified against plasma and urine data reported after single and multiple dose administration in healthy volunteers and elderly patients from 18 independent studies. The ratios of predicted vs. observed maximal plasma concentration and area under the concentration-time curve values were within 1.25-fold. The model illustrates that renal transporter activity is expected to decrease in healthy elderly compared to healthy volunteers, which is in line with literature proteomic data for OCT2. The model was applied to assess the potential of reaching toxicity-related plasma concentrations in different age groups of geriatric subjects.

Can 3D Printed Tablets Be Bioequivalent and How to Test It: A PBPK Model Based Virtual Bioequivalence Study for Ropinirole Modified Release Tablets.

As the field of personalized dosing develops, the pharmaceutical manufacturing industry needs to offer flexibility in terms of tailoring the drug release and strength to the individual patient's needs. One of the promising tools which have such capacity is 3D printing technology. However, manufacturing small batches of drugs for each patient might lead to huge test burden, including the need to conduct bioequivalence trials of formulations to support the change of equipment or strength. In this paper we demonstrate how to use 3D printing in conjunction with virtual bioequivalence trials based on physiologically based pharmacokinetic (PBPK) modeling. For this purpose, we developed 3D printed ropinirole formulations and tested their bioequivalence with the reference product Polpix. The Simcyp simulator and previously developed ropinirole PBPK model were used for the clinical trial simulations. The Weibull-fitted dissolution profiles of test and reference formulations were used as inputs for the model. The virtual bioequivalence trials were run using parallel design. The study power of 80% was reached using 125 individuals. The study demonstrated how to use PBPK modeling in conjunction with 3D printing to test the virtual bioequivalence of newly developed formulations. This virtual experiment demonstrated the bioequivalence of one of the newly developed formulations with a reference product available on a market.

3D printing combined with biopredictive dissolution and PBPK/PD modeling optimization and personalization of pharmacotherapy: Are we there yet?

Precision medicine requires selecting the appropriate dosage regimen for a patient using the right drug, at the right time. Model-Informed Precision Dosing (MIPD) is a concept suggesting utilization of model-based prediction methods for optimizing the treatment benefit-harm balance, based on individual characteristics of the patient, disease, treatment method, and other factors. Here, we discuss a theoretical workflow comprising several elements, beginning from the physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models, through 3D printed tablets with the model proposed dose, information range and flow, and the patient themselves. We also describe each of these elements, and the connection between them, highlighting challenges and potential obstacles.

Quality Control Dissolution Data Is Biopredictive for a Modified Release Ropinirole Formulation: Virtual Experiment with the Use of Re-Developed and Verified PBPK Model.

Physiologically based pharmacokinetic and absorption modeling are being used by industry and regulatory bodies to address various scientifically challenging questions. While there is high confidence in the prediction of exposure for the BCS class I drugs administered as immediate-release formulations, in the case of prolonged-release formulations, special attention should be given to the input dissolution data. Our goal was to develop and verify a PBPK model for a BCS class I compound, ropinirole, and check the biopredictiveness of the dissolution data for the prolonged-release formulation administered by Parkinson's patients. The model was built based on quality control dissolution data reported in the certificates of analysis and verified with the use of data derived from five clinical trial reports. The simulated pharmacokinetic parameters being within a two-fold range of the observed values confirmed acceptable model performance, in vivo relevance of the in vitro dissolution profiles, and indirectly indicated ropinirole stable release from the formulation in the patients' gastro-intestinal tract. Ropinirole PBPK model will be used for exploring potential clinical scenarios while developing a new formulation.