Evaluation of the Drug-Drug Interaction Potential of Ensitrelvir Fumaric Acid with Cytochrome P450 3A Substrates in Healthy Japanese Adults.

BACKGROUND: Management of drug-drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor. OBJECTIVES: The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir. METHODS: This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day - 2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. RESULTS: The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day - 2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals with ensitrelvir were reported during the study. CONCLUSION: The inhibitory effect for CYP3A was confirmed after the last dose of ensitrelvir, and the effect diminished over time. In addition, ensitrelvir at 375/125 mg showed CYP3A inhibitory potential similar to that at 750/250 mg. These findings can be used as a clinical recommendation for prescribing ensitrelvir with regard to concomitant medications. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT2031210202.

A Systematic Review and Meta-Analysis of Pharmacogenetic Studies in Patients with Chronic Kidney Disease.

Chronic kidney disease (CKD) is an important global public health problem due to its high prevalence and morbidity. Although the treatment of nephrology patients has changed considerably, ineffectiveness and side effects of medications represent a major issue. In an effort to elucidate the contribution of genetic variants located in several genes in the response to treatment of patients with CKD, we performed a systematic review and meta-analysis of all available pharmacogenetics studies. The association between genotype distribution and response to medication was examined using the dominant, recessive, and additive inheritance models. Subgroup analysis based on ethnicity was also performed. In total, 29 studies were included in the meta-analysis, which examined the association of 11 genes (16 polymorphisms) with the response to treatment regarding CKD. Among the 29 studies, 18 studies included patients with renal transplantation, 8 involved patients with nephrotic syndrome, and 3 studies included patients with lupus nephritis. The present meta-analysis provides strong evidence for the contribution of variants harbored in the ABCB1, IL-10, ITPA, MIF, and TNF genes that creates some genetic predisposition that reduces effectiveness or is associated with adverse events of medications used in CKD.

Pharmacoproteomic analysis of topical dapsone and prednisolone interventions in the aqueous humor of anterior uveitis.

Uveitis is the inflammation of uveal tract comprising of iris, ciliary body and choroid. Blood ocular barriers maintaining the homeostasis of eye breach during uveitis, leads to high risk for sight-threatening complications. The purpose of this study was to compare the anti-inflammatory activity enabled by two diverse pharmacological agents (prednisolone and dapsone) using their effect on aqueous humor proteome. Wistar rats of either sex (150-200g) were used and randomly divided into various groups. Normal group was injected with 0.1ml normal saline (NS), endotoxin (LPS) (200 µg/0.1ml NS) was injected into endotoxin induced inflammatory groups followed by 0.1% dapsone and 1% prednisolone treatment in endotoxin induced uveitis (EIU) groups, respectively. Aqueocentesis was performed post 24 hour inflammation and samples were subjected for clinical parameter evaluation, cytokine analysis as well as global proteomic analysis using High-resolution mass spectrometer. Following which spectrum analysis, production spectra of peptides were matched against R. Norvegicus Protein Database (Uniport) using Proteome Discoverer (v2.2). Upon clinical evaluation, the anterior segment images post dapsone and prednisolone treatment have shown marked decrease in hyperaemia, miosis and iridial vessels vasodilation in rat eyes as compared to inflammation group. The result of cytokine analysis revealed 0.1% dapsone and prednisolone both significantly decreased the TNF-α levels. HRMS studies analysis expressed 140, 160, 158 and 141 proteins unique to normal, EIU, Dapsone and prednisolone group respectively. To conclude aqueous humor pharmacoproteomic revealed the anti-inflammatory activity of the dapsone comparable to the prednisolone treatment in endotoxin induced uveitis. The topical dapsone may be used as an alternative therapeutic option in treating uveitis without elevating intraocular pressure.

Generation of Ophthalmic Nanosuspension of Prednisolone Acetate Using a Novel Technology.

PURPOSE: Prednisolone Acetate (PAC) is currently marketed as micronized ophthalmic suspension. The microsuspension has poor dose accuracy and efficacy due to aggregation, slow dissolution rate and limited corneal residence. The ophthalmic nanosuspension of PAC shall show enhanced solubility, dissolution rate and corneal adhesion due to small particle size and increased surface area. METHODS: In the current work, we prepared ophthalmic formulation of PAC using a novel, spray drying based technology. Firstly, PAC nanocrystalline solid dispersions (NCSD) were prepared using Mannitol (MAN) as the crystallization inducing excipient and two separate stabilizers, Polyvinyl Alcohol (PAC_MAN_PVA) and Vitamin E Tocopheryl Polyethylene Glycol Sulphosuccinate (PAC_MAN_TPGS). The NCSD was dispersed in an aqueous vehicle to obtain an ophthalmic nanosuspension. RESULTS: The composition, PAC_MAN_PVA (0.3:0.67:0.03%), was pursued due to absence of crystal growth on storage at 40°C/75%RH for 3 months. The resulting nanosuspension showed crystal size, osmolality and viscosity of 590 ± 165 nm, 297 ± 6 mOsm/L and 11 ± 8cP respectively. In 1%w/v SLS media, the nanosuspension showed rapid and complete dissolution of PAC in 120 s. Ex-vivo goat corneal permeation and adhesion study revealed that in comparison to microsuspension, a higher fraction (6.2 times) of nanosuspension adhered to the cornea. Safety studies performed using corneal histopathology and Hen Egg Test- Chorio Allantoic Membrane (HET-CAM) assay showed no physical change in cornea or capillary damage, respectively. CONCLUSIONS: The NCSD can be explored for generation of ophthalmically acceptable nanosuspensions of poorly soluble drugs.

Prednisolone and Prednisone Pharmacokinetics in Adult Renal Transplant Recipients.

BACKGROUND: Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase. METHODS: This single-center, prospective, observational study included stable renal Tx recipients, >18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval [n = 26 samples per area under the curve (AUC0-24)], within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. RESULTS: In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure [median, range AUC0-24 = 3821 (2232-5382) mcg h/L], paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio [median, range 11 (3-47)%]. A negative correlation (r = -0.83) between PL AUC0-24 and morning CL levels was observed. The best single PK variable to predict PL AUC0-24 was PL C6 (r2 = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC0-24 with a low percentage prediction error (PPE = 5.2 ± 1.5%) and a good correlation of determination (r2 = 0.91). PL AUC0-24 varied 3-fold among study participants, whereas CL AUC0-24 varied by 18-fold. CONCLUSIONS: The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC0-24 and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.

Physiologically Based Pharmacokinetic Modeling Involving Nonlinear Plasma and Tissue Binding: Application to Prednisolone and Prednisone in Rats.

The pharmacokinetics (PK) of prednisolone (PNL) exhibit nonlinearity related to plasma protein binding, tissue binding, metabolic interconversion with prednisone (PN), and renal elimination. Blood and 11 tissues were collected from male Wistar rats after steady-state (SS) infusion and after subcutaneous boluses of 50 mg/kg of PNL. Concentrations of PNL and PN were measured by liquid chromatography-tandem mass spectrometry. Plasma and tissue profiles were described using a complex physiologically based pharmacokinetics (PBPK) model. Concentrations of PN and PNL were in rapid equilibrium in plasma and tissues. The tissue partition coefficients (K p ) of PNL calculated from most subcutaneously dosed tissue and plasma areas were similar to SS infusion and in silico values. The blood-to-plasma ratio of PNL was 0.71 with similar red blood cell and unbound-plasma concentrations. Plasma protein binding (60%-90%) was related to corticosteroid-binding globulin (CBG) saturation. Tissue distribution was nonlinear. The equilibrium dissociation constant (K d ) of PNL shared by all tissues was 3.01 ng/ml, with the highest binding in muscle, followed by liver, heart, intestine, and bone and the lowest binding in skin, spleen, fat, kidney, lung, and brain. Fat and bone distribution assumed access only to interstitial space. Brain PNL concentrations (K p = 0.05) were low owing to presumed P-glycoprotein-mediated efflux. Clearances of CBG-free PNL were 1789 from liver and 191.2 ml/h from kidney. The PN/PNL ratio was nonlinear for plasma, spleen, heart, intestine, bone, fat, and linear for the remaining tissues. Our PBPK model with multiple complexities well described the PK profiles of PNL and PN in blood, plasma, and diverse tissues. SIGNIFICANCE STATEMENT: Because steroids, such as prednisolone and prednisone, have similar and complex pharmacokinetics properties in various species, receptors in most tissues, and multiple therapeutic and adverse actions, this physiologically based pharmacokinetics (PBPK) model may provide greater insights into the pharmacodynamic complexities of corticosteroids. The complex properties of these compounds require innovative PBPK modeling approaches that may be instructive for other therapeutic agents.

Graft copolymerization of polyvinylpyrollidone onto Azadirachta indica gum polysaccharide in the presence of crosslinker to develop hydrogels for drug delivery applications.

In this work, graft-copolymerization of poly vinylpyrollidone onto Azadirachta indica gum polysaccharide in the presence of crosslinker has been carried out to prepare the hydrogel for use in drug delivery. The polymers were characterized by cryo-SEM, AFM, FTIR, and 13C NMR. The gel strength, cross-link density, mesh size, thrombogenicity, antioxidant and mucoadhesion properties of the gum-PVP hydrogels were determined along with the evaluation of drug release profile of methyl prednisolone, a colonic anti-inflammatory agent, from the drug loaded hydrogels. Cryo SEM images showed the porous crosslinked structure of the polymer network. The drug release from the polymer followed non-Fickian diffusion mechanism. The polymers showed 71.47 ±â€¯4.63% haemo-compatibility and 05.52 ±â€¯0.59 Nmm gel strength. The value of DPPH radical scavenging assay (73.16 ±â€¯04.85%) indicated that the gum-PVP polymers are antioxidant. The results of biocompatibility, antioxidant activity, mucoadhesion and drug release properties of the polymers inferred the use of this drug carrier for colonic drug delivery.

Nanogels of a Succinylated Glycol Chitosan-Succinyl Prednisolone Conjugate: Release Behavior, Gastrointestinal Distribution, and Systemic Absorption.

Recently, the potential of nanoparticles (NPs) in ulcerative colitis (UC) therapy has been increasingly demonstrated. Namely, anionic NPs have been found to be accumulated efficiently to the UC damaged area due to epithelial enhanced permeability and retention (eEPR) effect. Previously, a novel anionic nanogel system (NG(S)) was prepared, and evaluated for the efficacy and toxicity. In the present study, release behaviors and biodistribution were investigated in detail to elucidate the functional mechanisms. Rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced ulcerative colitis (UC) were used as biomodels. In vitro release was examined with or without the contents of the cecum or distal colon. Gastrointestinal distribution and plasma concentrations were investigated after the intragastric administration of 10 mg prednisolone (PD) eq./kg. At pH 1.2 and 6.8, release behaviors were slow, but controlled. Overall release was not markedly different irrespective of coexistence of intestinal contents. In in vivo studies, a large amount of PD was distributed in the lower parts of the gastrointestinal tract 6 and 12 h after administration with NG(S). PD accumulated well in the colonic parts, and prolonged release was noted. The systemic absorption of PD with NG(S) was hardly found. NG(S) concentrated the drug in the colon and showed controlled release. These behaviors were considered to lead to the previously reported good results, promotion of effectiveness and suppression of toxic side effects.

Free prednisolone pharmacokinetics predicted from total concentrations in patients with inflammatory - immunonologic conditions.

Prednisone is an anti-inflammatory drug widely used in internal medicine and rheumatology, but dosing remains empirical. The active metabolite of prednisone is free prednisolone. The aim of this work was to build a population pharmacokinetic (PK) model that can predict free prednisolone concentrations in patients with inflammatory/immunologic conditions.A total of 107 patients from the department of internal medicine of Cochin hospital provided 343 observations. Blood samples drawn for biological analyses were used for drug determination. Total plasma prednisolone concentrations were measured by liquid chromatography-mass spectrometry, and the data were modelled using Monolix. The pharmacokinetics was ascribed a one-compartment open model with three transit compartments standing for the absorption and metabolism process. The model used predicts free concentrations that served to derive total concentrations given published binding constants. Only size parameters influenced the pharmacokinetics. Free prednisolone CLU /F and VU /F, scaled allometrically on lean body weight, were, respectively, 26.7 L/h and 94.3 L for 50 kg LBW. CLU /F interindividual variability was 0.20. The additive and proportional residual variabilities were, respectively, 4.3 µg/L and 0.20. The results point out some dosing issues, that is the possibility of under- or over-dosage in thin or overweight patients respectively.

Prednisolone Concentrations in Plasma (Total and Unbound) and Saliva of Adult Kidney Transplant Recipients.

BACKGROUND: Prednisolone displays significant pharmacokinetic variability and exposure-outcome relationships in renal transplant recipients, suggesting a role for drug monitoring in some scenarios. It is highly protein-bound, and the free form is pharmacologically active but cumbersome to measure. Saliva concentrations might reflect free plasma prednisolone and present an alternative measurement. The aim of this study was to examine the correlation between total and free plasma and saliva prednisolone in adult renal transplant recipients. METHODS: Total and free plasma and saliva prednisolone concentrations were measured in 20 patients receiving oral prednisolone 1-2 months after transplant, between pre-dose and 12 hours post-dose. Prednisolone was determined using high-performance liquid chromatography mass spectrometric detection. The Pearson coefficient was used to assess the association between plasma and salivary prednisolone concentrations and area under the concentration-time curves (AUC0-12). RESULTS: When considering all time points, the total and free plasma prednisolone concentrations correlated well (r = 0.81), but there was poor correlation between saliva and free (r = 0.003) and total (r = 0.01) plasma concentrations. When concentrations before the maximum free prednisolone plasma value were excluded, the correlation between free plasma and saliva concentrations improved (r = 0.57). There was a moderate correlation between free and total plasma prednisolone AUC0-12 (r = 0.62) using all time points, but a poor correlation between free and total plasma prednisolone AUC0-12 and saliva AUC0-12 (r = 0.07; r = 0.17). CONCLUSIONS: Total and free plasma prednisolone measurements correlated poorly with saliva measurements; however, correlation improved when concentrations early in the dosing interval were excluded.

Preparation of Chondroitin Sulfate-Glycyl-Prednisolone Conjugate Nanogel and Its Efficacy in Rats with Ulcerative Colitis.

A conjugate between chondroitin sulfate (CS) and glycyl-prednisolone (GP), named CS-GP, was produced by carbodiimide coupling at a high GP/CS ratio. CS-GP was not water-soluble and gave a nanogel (NG) in aqueous solution. Two types of nanogels, NG(I) and NG(II), with prednisolone (PD) contents of 5.5 and 21.1% (w/w), respectively, were obtained. They had particle sizes of approximately 280 and 570 nm, respectively, and showed negative ζ-potentials of approximately -40 mV. The PD release rate was slower in the nanogels than in a solution of CS-GP with a PD content of 1.4% (w/w). The PD release rate was slower in NG(II) than in NG(I), and was elevated at pH 7.4 than at pH 6.8. NG(II) was applied in vivo to rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis, and its therapeutic efficacy and pharmacokinetic features were investigated. The therapeutic efficacy of NG(II) was slightly better than that of PD alone. Drug delivery to the lower intestines was enhanced with NG(II). The CS-GP nanogel has potential as a potent DDS for the treatment of ulcerative colitis.

[Prednisolone in phospholipid nanoparticles: prolonged circulation and increased antiinflammatory effect]. / Prednizolon v fosfolipidnykh nanochastitsakh: prolongirovannaia tsirkuliatsiia i povyshennoe protivovospalitel'noe deistvie.

Along with modern new drugs, many therapeutic schemes also include known effective drugs, particularly, glucocorticoids. One of the most distributed of them is prednisolone that has pronounced anti-inflammatory properties. Its disadvantage is short-term circulation, resulting in a number of side effects. For this reason the development of its more effective and safe formulations is carried out. We have obtained the formulation of prednisolone included in nanoparticles from soy phosphatidylcholine with an average diameter of 20 nm. With oral administration to rats and analysis by HPLC an increase in prednisolone maximal concentration in of plasma and the duration of circulation as compared with free drug administration were shown. The experiment with mice with conconavalin A induced inflammation was also carried out: conconavalin A was injected subplantary in an hour after oral administration of both prednisolone formulations in several doses. The index of the inflammatory reaction (determined by the edema degree) was suppressed more effectively in the case of prednisolone in nanoparticles. Maximal suppression (62.2% as compared with 49.6% for free prednisolone) was observed even at a minimal dose (2.5 mg/kg), at which the free drug did not act at all. The results indicate an increase in the efficiency of prednisolone included in phospholipid nanoparticles, that makes it possible to diminish its administered doses and thereby reduce the risk of side effects.

Folate Conjugated Double Liposomes Bearing Prednisolone and Methotrexate for Targeting Rheumatoid Arthritis.

PURPOSE: This investigation was aimed to explore the targeting potential of folate conjugated double liposomes (fDLs) bearing combination of synergistic drugs (Prednisolone and Methotrexate) for effective management of the rheumatoid arthritis (RA). METHODS: To overcome the drawbacks of monotherapy, a combination of prednisolone (PRD) (an anti-inflammatory agent) and methotrexate (MTX) (a disease modifying anti-rheumatoid agent, DMARDs) was chosen for dual targeting approach. fDLs were prepared in two steps i.e. development of inner liposomes (ILs) using thin film casting method followed by encapsulation of ILs within folate conjugated outer liposomes (double liposomes; fDLs). Developed liposomes were characterized for various physicochemical parameters and in vivo performance. RESULTS: fDLs were prepared using FA-PEG-4000-NH-DSPE conjugate. These double liposomes were having 429.3 ± 3.6 nm in size with 0.109 PDI, 8.01 ± 0.3 mV zeta potential (ζ) and 66.7 ± 3.9% and 45.3 ± 1.7% entrapments of PRD and MTX, respectively. After 24 h, the concentrations of PRD in blood were observed to be 8.66 ± 3.11 (ILs) and 15.13 ± 0.81% (DLs) while concentration of MTX were found to be 10.89 ± 0.69 and 2.34 ± 3.15% when given as ILs and fDLs, respectively. The concentration of both drugs in inflamed joint was observed to be higher than that in the non-inflamed joints. CONCLUSIONS: The folate conjugated double liposomes possess superior targeting efficiency than conjugated and unconjugated single liposomes.

The IGF system in patients with inflammatory bowel disease treated with prednisolone or infliximab: potential role of the stanniocalcin-2 / PAPP-A / IGFBP-4 axis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) present with reduced serum insulin-like growth factor I (IGF-I). Anti-inflammatory treatment with prednisolone or infliximab ameliorates symptoms and increases circulating IGF-I, but prednisolone induces catabolism, whereas infliximab may promote protein synthesis. Recently, stanniocalcin-2 (STC2) was discovered as a novel inhibitor of the enzyme pregnancy-associated plasma protein-A (PAPP-A), which modulates IGF-I activity. PAPP-A can cleave IGF binding protein-4 (IGFBP-4), upon which IGF-I is liberated. We hypothesized that prednisolone and infliximab exert different effects on levels of STC2, PAPP-A, and IGFBP-4, thereby explaining the distinct metabolic effects of prednisolone and infliximab. METHODS: Thirty-eight patients with active IBD treated with either prednisolone (n = 17) or infliximab (n = 21) were examined before and after 7 days of treatment. Circulating levels of IGF-I, IGF-II, IGFBP-3, PAPP-A, and STC2 were measured by immunoassays. Intact IGFBP-4 and two IGFBP-4 fragments were determined by a novel immunoassay. Bioactive IGF was assessed by cell-based IGF receptor activation assay. Concentrations of IGFBP-4, PAPP-A, and STC2 on day 0 and 7 were compared to healthy control subjects. RESULTS: Following seven days of prednisolone treatment, total and bioactive IGF-I were increased (p < 0.001 and p < 0.05, respectively). Upon infliximab treatment, total IGF-I levels were augmented (p < 0.05), yet IGF bioactivity remained unaltered. Intact IGFBP-4 and the two IGFBP-4 fragments generated upon cleavage by PAPP-A were all decreased following treatment with either prednisolone or infliximab (all p < 0.05). PAPP-A levels were only increased by infliximab (p = 0.005), whereas the inhibitor STC2 did not respond to any of the treatments. CONCLUSION: IGF-I and IGFBP-4 concentrations were markedly altered in patients with IBD and near-normalized with disease remission following treatment with prednisolone or infliximab. Thus, IGFBP-4 may modulate IGF bioavailability in IBD. The effect of immunosuppression did not appear to extend beyond the regulation of IGF and IGFBP-4, as neither PAPP-A nor STC2 were discernibly affected. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00955123 . Date of registration: August 7, 2009 (retrospectively registered).

Tear Fluid Pharmacokinetics Following Oral Prednisone Administration in Dogs With and Without Conjunctivitis.

Purpose: To describe the pharmacokinetics (PK) of prednisone and prednisolone in tear fluid of dogs receiving oral prednisone at anti-inflammatory to immunosuppressive doses and to assess the impact of induced conjunctivitis on lacrimal drug levels. Methods: Six healthy Beagle dogs were administered 4 courses of prednisone at 0.5, 1.0, 2.0, and 4.0 mg/kg given orally once a day for 5 days. At steady state, topical histamine was applied to induce mild (1 mg/mL) or severe (375 mg/mL) conjunctivitis in 1 eye of each dog and tear samples were collected from both eyes at selected times. Prednisone and prednisolone were quantified in tears by liquid chromatography-mass spectrometry. Results: Lacrimal prednisone and prednisolone concentrations ranged from 2 to 523 ng/mL and 5 to 191 ng/mL, respectively. Drug concentrations were overall greater in dogs receiving higher doses of prednisone, but were not correlated with tear flow rate. Eyes with conjunctivitis often had larger amounts of prednisone and prednisolone in tear fluid compared to control eyes (up to +64%), but differences were not statistically significant. Significantly greater, but clinically insignificant, levels of prednisolone were found in eyes with severe versus mild conjunctivitis for oral prednisone doses ≥1.0 mg/kg. Conclusions: Disruption of the blood-tear barrier with conjunctivitis did not significantly affect drug levels in tears. Based on drug PK in tears, oral prednisone is likely safe for the management of reflex uveitis and ocular surface diseases. However, further prospective trials using systemic corticotherapy in diseased animals are warranted to confirm findings from this preclinical study.

Influence of PDLA nanoparticles size on drug release and interaction with cells.

Polymeric nanoparticles (NPs) are strong candidates for the development of systemic and targeted drug delivery applications. Their size is a determinant property since it defines the NP-cell interactions, drug loading capacity, and release kinetics. Herein, poly(d,l-lactic acid) (PDLA) NPs were produced by the nanoprecipitation method, in which the influence of type and concentration of surfactant as well as PDLA concentration were assessed. The adjustment of these parameters allowed the successful production of NPs with defined medium sizes, ranging from 80 to 460 nm. The surface charge of the different NPs populations was consistently negative. Prednisolone was effectively entrapped and released from NPs with statistically different medium sizes (i.e., 80 or 120 nm). Release profiles indicate that these systems were able to deliver appropriate amounts of drug with potential applicability in the treatment of inflammatory conditions. Both NPs populations were cytocompatible with human endothelial and fibroblastic cells, in the range of concentrations tested (0.187-0.784 mg/mL). However, confocal microscopy revealed that within the range of sizes tested in our experiments, NPs presenting a medium size of 120 nm were able to be internalized in endothelial cells. In summary, this study demonstrates the optimization of the processing conditions to obtain PDLA NPs with narrow size ranges, and with promising performance for the treatment of inflammatory diseases. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 482-493, 2019.

The availability of drug by liposomal drug delivery : Individual kinetics and tissue distribution of encapsulated and released drug in mice after administration of PEGylated liposomal prednisolone phosphate.

Lately, the usefulness of liposomal drug delivery systems has been debated. To better understand the underlying pharmacokinetics of the targeted drug delivery by liposomes, individual encapsulated and non-encapsulated drug concentrations in blood, tumor, liver, spleen and kidneys were quantified after i.v. administration of liposomal prednisolone phosphate in mice. Kinetic analysis shows that the tumor influx of encapsulated drug is not dominant compared to the uptake by the other tissues. Further, from a quantitative point of view, the availability of non-encapsulated drug in the tumor tissue after liposomal delivery is not pronounced as compared to the other tissues studied. However, drug release in the tumor seems more extended than in the other tissues and the non-encapsulated drug concentration decreases more slowly in the tumor than in the liver and spleen. The spleen shows a high affinity for the uptake of encapsulated drug as well as the release of drug from the liposomes. Subsequently, released drug in the spleen, and possibly also in other tissues, is probably quickly redistributed towards the blood and other tissues. This also impairs the drug delivery effect of the liposomes. In contrast to the released drug in the central circulation, liver and spleen, the released drug concentration in the tumor remains at a fairly constant level likely due to the extended release kinetics from the liposomes. These extended release characteristics in the tumor most probably contribute to the beneficial effect. Nevertheless, it should be noted that larger released drug concentrations are formed in healthy tissues.

Electrosprayed microparticles for intestinal delivery of prednisolone.

Single and coaxial electrospraying was used to prepare Eudragit L100-55 polymer microparticles containing prednisolone as the active pharmaceutical ingredient. Different compositions of prednisolone and Eudragit L100-55 were used to develop five different formulations with different polymer : drug ratios. The resultant microparticles had a toroidal shape with a narrow size distribution. Prednisolone was present in an amorphous physical state, as confirmed by X-ray diffraction analysis. Dissolution studies were carried out in order to investigate the feasibility of the proposed system for site-specific release of prednisolone. The release rates were interpreted in terms of diffusion-controlled release. It was shown that utilization of pH-responsive Eudragit L100-55 could minimize the release of prednisolone in the acidic conditions of the stomach, which was followed by rapid release as the pH of the release medium was adjusted to 6.8 after the first 2 h. This is especially desirable for the treatment of conditions including inflammatory bowel disease and colon cancer.

Learning pharmacokinetic models for in vivo glucocorticoid activation.

To understand trends in individual responses to medication, one can take a purely data-driven machine learning approach, or alternatively apply pharmacokinetics combined with mixed-effects statistical modelling. To take advantage of the predictive power of machine learning and the explanatory power of pharmacokinetics, we propose a latent variable mixture model for learning clusters of pharmacokinetic models demonstrated on a clinical data set investigating 11ß-hydroxysteroid dehydrogenase enzymes (11ß-HSD) activity in healthy adults. The proposed strategy automatically constructs different population models that are not based on prior knowledge or experimental design, but result naturally as mixture component models of the global latent variable mixture model. We study the parameter of the underlying multi-compartment ordinary differential equation model via identifiability analysis on the observable measurements, which reveals the model is structurally locally identifiable. Further approximation with a perturbation technique enables efficient training of the proposed probabilistic latent variable mixture clustering technique using Estimation Maximization. The training on the clinical data results in 4 clusters reflecting the prednisone conversion rate over a period of 4 h based on venous blood samples taken at 20-min intervals. The learned clusters differ in prednisone absorption as well as prednisone/prednisolone conversion. In the discussion section we include a detailed investigation of the relationship of the pharmacokinetic parameters of the trained cluster models for possible or plausible physiological explanation and correlations analysis using additional phenotypic participant measurements.