Physicochemical Properties Of Drug Research Articles

Local delivery of usnic acid loaded Rhamnolipid vesicles by gelatin / tragacanth gum / montmorillonite/ vanillin cryogel scaffold for expression of osteogenic biomarkers and antimicrobial activity

Treatment of osteomyelitis as a destructive disease with strong, systemic, and high-dose antibiotics always faces tough challenges and severe side effects. The present study aimed to design dual-purpose cryogel nanocomposite scaffolds with antibacterial and bone regenerative properties. The gelatin/tragacanth gum/montmorillonite/vanillin cryogel scaffold (GTM/V) was prepared and enriched with Usnic acid (UA) encapsulated in Rhamnolipid (RH) biosurfactant nanoparticles as a dispersing agent with antioxidant and antimicrobial properties. The physicochemical properties of drug loaded nanoparticles, mechanical, rheological, and biological properties of the cryogel were evaluated. Biological evaluations, including cell proliferation (by MTT assay), cell attachment (by SEM), osteogenic activity (by Alizarin Red staining and alkaline phosphatase assay), and osteogenic gene expression (by quantitative real-time polymerase chain reaction) were studied using MG-63 cells. The antibiofilm effect of the cryogel was studied on Staphylococcus aureus. The results showed the mechanical profile of UA/RH loaded GTM/V scaffold was 3.08 ± 0.20 MPa compressive strength at 70% strain and the elastic modulus was 19.69 ± 1.57 MPa. Biocompatible UA/RH containing cryogel scaffolds showed osteogenic effect through increasing the ALP activity, and the Alizarin-red staining on days 7 and 14 compared to the control group (P < 0.05). The relative increase in expression of bone repair markers, including COL1A1, BGLAP, and SPP1F were shown by RT-PCR. The scaffold had strong antibacterial effects on S. aureus, with an inhibition zone of 1.40 ± 0.21 cm and antibiofilm activity of 43.76 ± 1.65%. In conclusion, our findings support the application of UA/RH loaded GTM/V scaffold for the treatment of osteomyelitis and bone regeneration.

Challenges and Perspectives in the Discovery of Dengue Virus Entry Inhibitors.

Dengue virus (DENV) disease has become one of the major challenges in public health. Currently, there is no antiviral treatment for this infection. Since human transmission occurs via mosquitoes of the Aedes genus, most efforts have been focused on the control of this vector. However, these control strategies have not been totally successful, as reflected in the increasing number of DENV infections per year, becoming an endemic disease in more than 100 countries worldwide. Consequently, the development of a safe antiviral agent is urgently needed. In this sense, rational design approaches have been applied in the development of antiviral compounds that inhibit one or more steps in the viral replication cycle. The entry of viruses into host cells is an early and specific stage of infection. Targeting either viral components or cellular protein targets are an affordable and effective strategy for therapeutic intervention of viral infections. This review provides an extensive overview of the small organic molecules, peptides, and inorganic moieties that have been tested so far as DENV entry direct-acting antiviral agents. The latest advances based on computer-aided drug design (CADD) strategies and traditional medicinal chemistry approaches in the design and evaluation of DENV virus entry inhibitors will be discussed. Furthermore, physicochemical drug properties, such as solubility, lipophilicity, stability, and current results of pre-clinical and clinical studies will also be discussed in detail.

Polyrotaxane-Based Supramolecular Material for Improvement of Pharmaceutical Properties of Protein Drugs

Pharmaceutical excipients, such as surfactants, amino acids, and polymers, have often been used to improve the physicochemical properties of protein drugs. However, the effects of these additives are limited because of factors such as their weak interactions with protein drugs. In the present study, we evaluated the application of a supramolecular polymer, aminated polyrotaxane (NH2-PRX), which can strongly interact with protein drugs via its dynamic and transformable properties, as a new pharmaceutical excipient for these agents. As a conventional control polymer with low mobility and average complexation ability, aminated dextran (NH2-DEX) was also prepared. NH2-PRX significantly reduced the aggregation of antibodies induced by shaking, compared with NH2-DEX. The adsorption of insulin onto glass and polypropylene containers was also reduced by the addition of NH2-PRX. In addition, the in vivo bioactivity of insulin was completely retained in the presence of NH2-PRX. Moreover, severe adverse effects were not observed following the administration of NH2-PRX. These findings indicate the potential use of NH2-PRX as a transformable pharmaceutical excipient for protein drugs.

Understanding the role of electrostatic interactions on the association of 5-fluorouracil to chitosan-TPP nanoparticles

Judicious design strategies should be considered powerful tools to better control the properties of chitosan (CS) and tripolyphosphate (TPP) particles. This study focused on understanding the role of the charge properties of 5-fluorouracil (5-FU) on the formation and properties of CS-TPP nanoparticles. The effect of synthesis variables of CS-TPP nanoparticles (CS to TPP ratio and order of addition) under pH 4.5 and 5.5 was evaluated, where CS and TPP were charged, and 5-FU had two different charges (positive and negative), maximizing the interactions between them for the formation of nanoparticles. The order of addition and drug location resulted in changes in the interaction forces, influencing the particle size and size distribution. 5-FU addition into CS resulted in stronger interactions, favoring the formation of smaller particles. The pH of reactional medium and CS to TPP ratio affected the properties of particles, in terms of size and potential zeta, which led to greater 5-FU entrapment. These results demonstrated that the particle properties still depends of the synthesis factors, but the physicochemical properties of drug also influence the reactions/interactions involved in the formation of CS-TPP nanoparticles.

Prediction of Maternal and Fetoplacental Concentrations of Cefazolin, Cefuroxime, and Amoxicillin during Pregnancy Using Bottom-Up Physiologically Based Pharmacokinetic Models.

Concerns over maternal and fetal drug exposures highlight the need for a better understanding of drug distribution into the fetus through the placental barrier. This study aimed to predict maternal and fetal drug disposition using physiologically based pharmacokinetic (PBPK) modeling. The detailed maternal-placental-fetal PBPK model within the Simcyp Simulator V20 was used to predict the maternal and fetoplacental exposure of cefazolin, cefuroxime, and amoxicillin during pregnancy and at delivery. The mechanistic dynamic model includes physiologic changes of the maternal, fetal, and placental parameters over the course of pregnancy. Placental kinetics were parametrized using permeability parameters determined from the physicochemical properties of these compounds. Then, the PBPK predictions were compared with the observed data. Fully bottom-up fetoplacental PBPK models were developed for cefuroxime, cefazolin, and amoxicillin without any parameter fitting. Predictions in nonpregnant subjects and in pregnant subjects fall within 2-fold of the observed values. Predictions matched observed pharmacokinetic data reported in nine maternal (five fetoplacental) studies for cefuroxime, 10 maternal (five fetoplacental) studies for cefazolin, and six maternal (two fetoplacental) studies for amoxicillin. Integration of the fetal and maternal system parameters within PBPK models, together with compound-related parameters used to calculate placental permeability, facilitates and extends the applications of the maternal-placental-fetal PBPK model. The developed model can also be used for designing clinical trials and prospectively used for maternal-fetal risk assessment after maternally administered drugs or unintended exposure to environmental toxicants. SIGNIFICANCE STATEMENT: This study investigates the performance of an integrated maternal-placental-fetal PBPK model to predict maternal and fetal tissue exposure of renally eliminated antibiotics that cross the placenta through a passive diffusion mechanism. The transplacental permeability clearance was predicted from the drug physicochemical properties. Results demonstrate that the PBPK approach can facilitate the prediction of maternal and fetal drug exposure simultaneously at any gestational age to support its use in the maternal-fetal exposure assessments.

Drug Physicochemical Properties Relevant to Powder Flowability in Pharmaceutical Appliance: A Review

Background: Studies have shown that the powder flowability rate significantly impacts the content uniformity and weight of the active pharmaceutical ingredients in drug tableting procedures. The aim was studying the physicochemical properties relevant to the powder flowability in some pharmaceutical instruments. Powders with good flow characteristics are required to ensure a continuous flow through the die and other compartments of the pharmaceutical appliances used for manufacturing. Several factors, such as size, density, adhesiveness, shape, surface conditions, and electrostatic chargeability of the drug ingredients, tend to influence the flowability of a drug. Conclusion: The study highlights that particle size is one of the major determinants of powder flowability. Large particles are expected to aid better flowability resulting in a clearer feeder during the manufacturing process. The flowability of the powder could be improved by adding a small number of fine particles and granules as excipients.

A SHORT REVIEW ON ADVANCEMENT IN FAST DISSOLVING ORAL THIN FILMS

The pharmaceutical industry is pursuing the development of thin films as a novel method of drug administration. Thin films as an alternative to standard dosage forms have been described. They are a very adaptable platform capable of producing immediate, local, or systemic effects. Additionally, these systems are self-administered, which is advantageous for patients with dysphagia, elderly, pediatric, or bedridden patients and those who cannot administer with water. Thin film drug delivery methods are available for oral, buccal, sublingual, ophthalmic, and transdermal administration. This review explores oral thin films in all of their elements from a contemporary standpoint and provides insight into the world's expanding market share due to the expansion of study areas and technical advancements. Simultaneously, it presents an overview of the essential parameters that affect formulation design that affects thin films, including thin-film design, anatomical and physiological constraints, and the selection of suitable manufacturing processes, characterization methodologies, and the physicochemical properties of polymers and drugs are all covered in this section. Additionally, it provides insight onto the most recent thin-films produced by various pharmaceutical companies. KEYWORDS: Fast dissolving films, patient compliance, dysphagia, oral, buccal,sublingual.

Spectrophotometric determination of acid dissociation constants of some arylpropionic acids and arylacetic acids in acetonitrile-water binary mixtures at 25ºC

The acid dissociation constant of drug active compounds (arylpropionic and aryl acetic acids) were determined in acetonitrile and water binary mixtures (corresponding volume fractions of 0.40, 0.45, 0.50, and 0.55) by using a multi-wavelength spectrophotometric method. Drug active compounds, which were slightly soluble in water, were studied in these binary mixtures. The dissociation constants of drug active compounds are important in drug design studies and in any research of the biopharmaceutical and physicochemical properties of drugs. The STAR program was used for the determination of dissociation constants. The acidity constants of arylpropionic and aryl acetic acids were correlated with the Kamlet and Taft solvaatochromic parameters. Aqueous pKa values of these arylpropionic and aryl acetic acids were determined from pKa values obtained from acetonitrile and water binary mixtures with varying volume fractions. The studied drugs had a pKa value corresponding to base functional group. Results showed that the acid dissociation constant values of the drug active compounds increased with an increase in acetonitrile content in the medium.

The Perks and Drawbacks of Physiologically-Based Pharmacokinetic Modeling

Physiologically-based pharmacokinetic (PBPK) models use a mechanistic approach to integrate physiological parameters, physicochemical drug properties, and biochemical processes by means of mathematical equations to predict the concentration of a drug over time in blood and tissues. These models represent a robust tool for the pharmaceutical sciences, but also applications in chemical risk assessment for drugs and chemicals of forensic interest or in occupational hazards have been explored over the last decade. Much like other computational tools, PBPK models’ application face challenges concerning validity, transparency and lack of collaboration between professionals in different fields. The potential uses and challenges of PBPK modeling are discussed, as well as some ways to address the latter.

Microneedle patch with "spongy coating" to co-load multiple drugs to treat multidrug-resistant melanoma.

Melanoma is the most aggressive skin malignancy that continues to increase in worldwide. The transferability and multidrug resistance lead to a high fatality rate. Synergistic administration of hydrophilic carboplatin (CBP) and hydrophobic vorinostat (SAHA) can be a reliable way to treat multidrug-resistant melanoma. However, the different physicochemical properties of multiple drugs make it difficult to achieve a convenient co-loading and an ideal synergistic treatment efficacy. To solve the problem, a microneedle patch with a porous "spongy coating" (PF-MNP) was fabricated. Firstly, (polyacrylic acid/polyethyleneimine)10 multilayers were fabricated on polymethyl methacrylate MNP. Then a "spongy coating" was achieved by acid treatment and freeze-drying. Due to the capillary effect, hydrophobic SAHA and hydrophilic CBP could be conveniently adsorbed step-by-step. The two drugs could distribute evenly on the surface, and the morphology of MNP remained good. The loading content of SAHA and CBP was easily regulated by adjusting the concentration of the adsorption solution, and MNP could quickly release most drugs within 30 min. The final in vivo experiments proved that CBP/SAHA co-loaded PF-MNP had the best therapeutic efficiency for multidrug-resistant melanoma. The MNP with a "spongy coating" showed potential to be a safe and efficient transdermal delivery platform for multiple drugs.

Using drug chemical structures in the education of pharmacology and clinical therapeutics key concepts

Medicinal chemistry made it possible for pharmacists to propose pharmacodynamics and pharmacokinetics explanations of many existing drugs. Moreover, medicinal chemistry education provides pharmacy students with a reasonable understanding of drug physicochemical properties, mechanism of action (MOA), side effects, metabolism and structure-activity relationship (SAR). This paper highlights the importance of these medicinal chemistry key elements in understanding other pharmacy core courses, mainly pharmacology and clinical therapeutics. Such elements can be utilized as a tool for pharmacists while training or counseling their patients on the use of their treatments. Different new examples from the literature have been incorporated in this paper to show how chemical structures of existing drugs can provide essential information about main concepts in the education of pharmacology and clinical therapeutics, and the key structural elements for the discovery and development of other same class drugs.

An overview of Natural Superdisintegrants

The oral route is the most convenient route of administration for various drugs. It is viewed as the most convenient, most secure, and economical route for patients. Fast disintegrating tablets are popular these days as they disintegrate in the mouth within a few seconds without the use of water. The burdens of regularly used medications in pediatric and geriatric patients have been overwhelmed by quick-dissolving tablets. Natural superdisintegrants have been used for fast-dissolving tablets because they are biodegradable, chemically inert, non-harmful, more affordable, and generally accessible. Natural polymer improves the properties of the tablet as it is commonly used as diluents and binders. Natural super disintegrants decrease the release time and give healthful results to the patients. Most polymers are obtained from nature, they are cost-effective, non-toxic, and non-irritants. Disintegration is the most important step for releasing the drug from the tablet matrix to decrease the disintegration time. In this, drug and polymers come in contact with water, it swells, hydrate, and react chemically to release the drug in the mouth and gastrointestinal tract. Superdisintegrants are those substances that encourage the quick breaking down with a lesser amount contrasted with disintegrants. The quick disintegrants tablets are set up by utilizing suitable polymers which rely on the Physico-chemical properties of drugs and excipients, for example, drug and polymer compatibility, hardness and thickness of tablet, nature of drug and excipients, PH of drug and release parameters of drug formulation. Superdisintegrants are the vehicles added to tablet formulation to advance the breaking of tablets and capsules into small microparticles in aqueous media resulting in to increase in the surface area and promote quick drug release. The disintegrants have a significant capacity to oppose the efficacy of tablet binders and compression forces to form the tablet. Commonly there are three methods to incorporate disintegrants into the tablet: A. Inner addition, B. External expansion, C. Internal, and external addition. Most of the regularly based tablets are those expected to be swallow, disintegrate and release medicaments in the gastrointestinal tract but over a while tablets are manufactured to deliver medicaments in the mouth and gastrointestinal tract within few seconds of swallowing. It has been demonstrated that characteristic polymers are more effective than synthetic polymers. Some research is going to develop safe and effective medication with super disintegrating agents that can be dissolved rapidly to treat the disease.

SYNTHESIS OF COCRYSTALS OF BETULIN WITH SUBERIC ACID AND STUDY OF THEIR PROPERTIES

Lupane triterpenoids, betulin and its derivatives, are attracting great interest due to their wide range of biological and pharmacological activities. However, the poor solubility of betulin and its derivatives in aqueous media significantly reduces their bioavailability. Obtaining cocrystals, that is, multicomponent crystal systems containing active pharmaceutical ingredients and non-toxic partner molecules in their structure, is used in pharmacy to change the physicochemical properties of drugs, including the rate of dissolution and solubility. In this study, cocrystals of betulin with suberic acid were obtained by liquid-assisted grinding method using organic solvents of different polarity: ethanol, acetone, ethyl acetate, chloroform, toluene, dioxane. The formation of cocrystals was confirmed by X-ray diffraction analysis, IR spectroscopy, and thermal analysis. It has been shown that cocrystals of betulin with suberic acid contain water molecules in their structure; anhydrous cocrystals can be obtained by heating a physical mixture of reagents until the acid melts. The results of experiments on the dissolution of cocrystals of betulin with suberic acid in comparison with the data for cocrystals of betulin with adipic acid showed that an increase in the length of the aliphatic acid chain leads to a decrease in the rate of betulin release into solution.

Influence of API physico-chemical properties on amorphization capacity of several mesoporous silica loading methods

The objective of this work was to evaluate the impact of physico-chemical properties of pharmaceutical drugs on the optimal mesoporous silica loading methods. Indeed, a good combination between drug and loading process has to be studied to promote the deepest penetration of the drug inside the mesopores, allowing high drug amorphization. Six molecules, namely lidocaine and its hydrochloride, ibuprofen, ketoprofen, artemether and miconazole, with different physico-chemical properties (the ionized character, the acid-base character, the HBDA number, the solubility in sc-CO2 and the behavior under subcritical CO2) were used to produce drug-silica formulations. Different impregnation processes (physical mixing, melting, wetting, sc-CO2 and subcritical CO2 impregnations) have been compared for each drug, in terms of drug recovery and crystallinity. Formulations showed drug percentage close to 100% except for supercritical soluble drug formulations impregnated by using sc-CO2. However, the basic drug character provided less or no drug loss during impregnation. Processing insoluble sc-CO2 molecule under supercritical conditions led to less crystallinity than the correspondent physical mixture suggesting an interesting repulsive effect that forces the drug penetration within the mesopores. Besides, it has been also highlighted that the HBDA number is not sufficient to predict the final drug loading. Melting methods have high interest considering the drugs tested and subcritical CO2 could increase the loading, especially for drugs with high molten viscosity. This study showed that a plethora of loading methods can be used to provide high drug loaded MS formulations with a wide choice of equipment.

Design of Biopolymer-Based Interstitial Therapies for the Treatment of Glioblastoma.

Glioblastoma multiforme (GBM) is the most common form of primary brain cancer and has the highest morbidity rate and current treatments result in a bleak 5-year survival rate of 5.6%. Interstitial therapy is one option to increase survival. Drug delivery by interstitial therapy most commonly makes use of a polymer implant encapsulating a drug which releases as the polymer degrades. Interstitial therapy has been extensively studied as a treatment option for GBM as it provides several advantages over systemic administration of chemotherapeutics. Primarily, it can be applied behind the blood–brain barrier, increasing the number of possible chemotherapeutic candidates that can be used and reducing systemic levels of the therapy while concentrating it near the cancer source. With interstitial therapy, multiple drugs can be released locally into the brain at the site of resection as the polymer of the implant degrades, and the release profile of these drugs can be tailored to optimize combination therapy or maintain synergistic ratios. This can bypass the blood–brain barrier, alleviate systemic toxicity, and resolve drug resistance in the tumor. However, tailoring drug release requires appropriate consideration of the complex relationship between the drug, polymer, and formulation method. Drug physicochemical properties can result in intermolecular bonding with the polymeric matrix and affect drug distribution in the implant depending on the formulation method used. This review is focused on current works that have applied interstitial therapy towards GBM, discusses polymer and formulation methods, and provides design considerations for future implantable biodegradable materials.

Evaluation of Drug Sorption on Laboratory Materials with Abraham Solvation Parameters of Drugs and its Prevention.

Undesired drug sorption on laboratory material surfaces reduces the performance of analytical methods and results in the generation of unreliable data. Hence, we characterized the sorption of drugs and evaluated the sorption extent using a linear free energy relationship (LFER) model with Abraham solvation parameters of drugs. Furthermore, to prevent sorption, the effects of additives, such as organic solvents and salts, were evaluated. The sorption of fifteen model drugs (concentration: 2μM), with various physicochemical properties, on materials in 0.2% dimethyl sulfoxide aqueous solutions was evaluated. Drug sorption extent on the materials was determined using high-performance liquid chromatography. The obtained results were analyzed using an LFER model with Abraham solvation parameters of the drugs. The effect of additives on the sorption of itraconazole, one of the most hydrophobic drugs among those tested in this study, was investigated. Sorption was dependent on the physicochemical properties of drugs, rather than the type of materials used, and additives altered the rate of drug sorption. Equations were developed to evaluate the sorption extent (nmol) of drugs to glass and polypropylene using the Abraham solvation parameters of the drugs. LFER modeling with Abraham solvation parameters of drugs enabled us to evaluate drug sorption on materials. All the additives altered the rate of drug sorption, and some organic solvents effectively prevented sorption. The developed LFER model would be useful for assessment of the sorption properties of compounds in in vitro evaluations in drug discovery research and various other biochemical fields.

Machine learning predicts the effect of food on orally administered medicines

Food-mediated changes to drug absorption, termed the food effect, are hard to predict and can have significant implications for the safety and efficacy of oral drug products in patients. Mimicking the prandial states of the human gastrointestinal tract in preclinical studies is challenging, poorly predictive and can produce difficult to interpret datasets. Machine learning (ML) has emerged from the computer science field and shows promise in interpreting complex datasets present in the pharmaceutical field. A ML-based approach aimed to predict the food effect based on an extensive dataset of over 311 drugs with more than 20 drug physicochemical properties, referred to as features. Machine learning techniques were tested; including logistic regression, support vector machine, k-Nearest neighbours and random forest. First a standard ML pipeline using a 80:20 split for training and testing was tried to predict no food effect, negative food effect and positive food effect, however this lead to specificities of less than 40%. To overcome this, a strategic ML pipeline was devised and three tasks were developed. Random forest achieved the strongest performance overall. High accuracies and sensitivities of 70%, 80% and 70% and specificities of 71%, 76% and 71% were achieved for classifying; (i) no food effect vs food effect, (ii) negative food vs positive food effect and (iii) no food effect vs negative food effect vs positive food effect, respectively. Feature importance using random forest ranked the features by importance for building the predictive tasks. The calculated dose number was the most important feature. Here, ML has provided an effective screening tool for predicting the food effect, with the potential to select lead compounds with no food effect, reduce the number of animal studies, and accelerate oral drug development studies.

Nanotherapeutics approaches to overcome P-glycoprotein-mediated multi-drug resistance in cancer

Multidrug resistance (MDR) in cancer chemotherapy is a growing concern for medical practitioners. P-glycoprotein (P-gp) overexpression is one of the major reasons for multidrug resistance in cancer chemotherapy. The P-gp overexpression in cancer cells depends on several factors like adenosine triphosphate (ATP) hydrolysis, hypoxia-inducible factor 1 alpha (HIF-1α), and drug physicochemical properties such as lipophilicity, molecular weight, and molecular size. Further multiple exposures of anticancer drugs to the P-gp efflux protein cause acquired P-gp overexpression. Unique structural and functional characteristics of nanotechnology-based drug delivery systems provide opportunities to circumvent P-gp mediated MDR. The primary mechanism behind the nanocarrier systems in P-gp inhibition includes: bypassing or inhibiting the P-gp efflux pump to combat MDR. In this review, we discuss the role of P-gp in MDR and highlight the recent progress in different nanocarriers to overcome P-gp mediated MDR in terms of their limitations and potentials.

Molecular descriptors – an useful tool for assessing the physico-chemical properties of hallucinogenic drugs of abuse

Molecular descriptors play a fundamental role in chemistry and pharmaceutical sciences, being defined as a way to transform molecules into a set of numbers, allowing the mathematical assessment of the chemical information characterizing a molecule. This study presents the usefulness of molecular descriptors for the determination of physico-chemical properties of a series of new hallucinogenic amphetamines. Molecular descriptors of these compounds was performed with the Dragon 5.5 software. The chemometric processing of the information allowed the determination of structural correlations (similarities) between this class of designer drugs and an unknown compound.

Experimental Data and PBPK Modeling Quantify Antibody Interference in PEGylated Drug Carrier Delivery.

Physiologically-based pharmacokinetic (PBPK) modeling is a popular drug development tool that integrates physiology, drug physicochemical properties, preclinical data, and clinical information to predict drug systemic disposition. Since PBPK models seek to capture complex physiology, parameter uncertainty and variability is a prevailing challenge: there are often more compartments (e.g., organs, each with drug flux and retention mechanisms, and associated model parameters) than can be simultaneously measured. To improve the fidelity of PBPK modeling, one approach is to search and optimize within the high-dimensional model parameter space, based on experimental time-series measurements of drug distributions. Here, we employ Latin Hypercube Sampling (LHS) on a PBPK model of PEG-liposomes (PL) that tracks biodistribution in an 8-compartment mouse circulatory system, in the presence (APA+) or absence (naïve) of anti-PEG antibodies (APA). Near-continuous experimental measurements of PL concentration during the first hour post-injection from the liver, spleen, kidney, muscle, lung, and blood plasma, based on PET/CT imaging in live mice, are used as truth sets with LHS to infer optimal parameter ranges for the full PBPK model. The data and model quantify that PL retention in the liver is the primary differentiator of biodistribution patterns in naïve versus APA+ mice, and spleen the secondary differentiator. Retention of PEGylated nanomedicines is substantially amplified in APA+ mice, likely due to PL-bound APA engaging specific receptors in the liver and spleen that bind antibody Fc domains. Our work illustrates how applying LHS to PBPK models can further mechanistic understanding of the biodistribution and antibody-mediated clearance of specific drugs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11538-021-00950-z.