scholarly journals Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors

2020 ◽  
Vol 94 (8) ◽  
pp. 2637-2661 ◽  
Author(s):  
E. E. J. Kasteel ◽  
K. Darney ◽  
N. I. Kramer ◽  
J. L. C. M. Dorne ◽  
L. S. Lautz
Keyword(s):  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Extensive Literature ◽  
Interindividual Differences ◽  
Uncertainty Factors ◽  
Chemical Risk Assessment ◽  
Acute And Chronic Exposure

Abstract UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposure. Using this database, UGT-related uncertainty factors were derived and compared to the default factor (i.e. 3.16) allowing for interindividual differences in kinetics. Overall, results show that pharmacokinetic data are predominantly available for Caucasian populations and scarce for other populations of different geographical ancestry. Furthermore, the relationships between UGT polymorphisms and pharmacokinetic parameters are rarely addressed in the included studies. The data show that UGT-related uncertainty factors were mostly below the default toxicokinetic uncertainty factor of 3.16, with the exception of five probe substrates (1-OH-midazolam, ezetimibe, raltegravir, SN38 and trifluoperazine), with three of these substrates being metabolised by the polymorphic isoform 1A1. Data gaps and future work to integrate UGT-related variability distributions with in vitro data to develop quantitative in vitro–in vivo extrapolations in chemical risk assessment are discussed.

scholarly journals Pharmacokinetic and Pharmacodynamic Study of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir after Multiple Oral Dosing

2001 ◽  
Vol 45 (1) ◽  
pp. 30-37 ◽  
Author(s):  
Brian M. Sadler ◽  
Catherine Gillotin ◽  
Yu Lou ◽  
Daniel S. Stein
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Dose Range ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Protease Enzyme ◽  
Immunodeficiency Virus

ABSTRACT In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily (b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected adults, 59 of whom had pharmacokinetic data. Log-log regression analysis (the power model) revealed that the steady-state area under the curve (AUCss) and the maximum, minimum, and average concentrations at steady state (C max,ss,C min,ss, and C avg,ss, respectively) increased in a dose-proportional manner over the 300- to 1,200-mg dose range. Steady-state clearance was dose independent. AUCss/AUC0→∞ decreased linearly with dose and correlated significantly with treatment-associated decreases in α1-acid glycoprotein. After 3 weeks, the dose of 1,200 mg b.i.d. provided a median amprenavir Cmin,ss (0.280 μg/ml) that was higher than the median in vitro 50% inhibitory concentration for clinical HIV isolates (0.023 μg/ml), even after adjustment for protein binding. The median amprenavir C min,sswas also greater than the estimated in vivo trough concentration calculated to yield 90% of the maximum antiviral effect (0.228 μg/ml) over 4 weeks. A pharmacodynamic analysis of the relationship between steady-state pharmacokinetic parameters and safety revealed headache and oral numbness to be the only side effects significantly associated with C max. The pharmacodynamic relationship defined in this study supports the use of 1,200 mg b.i.d. as the approved dose of amprenavir.

scholarly journals Predicting absorption and pharmacokinetic profile of carbamazepine from controlled-release tablet formulation in humans using rabbit model

2011 ◽  
Vol 65 (1-2) ◽  
pp. 71-81
Author(s):  
Irena Homsek ◽  
Dragica Popadic ◽  
Slobodanka Simic ◽  
Slavica Ristic ◽  
Katarina Vucicevic ◽  
...  
Keyword(s):  
Controlled Release ◽  
Rabbit Model ◽  
Tablet Formulation ◽  
Human Model ◽  
In Vitro Dissolution ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Drug Concentrations

Controlled-release (CR) pharmaceutical formulations offer several advantages over the conventional, immediate release dosage forms of the same drug, including reduced dosing frequency, decreased incidence and/or intensity of adverse effects, greater selectivity of pharmacological activity, reduced drug plasma fluctuation, and better compliance. After a drug product has been registered, and is already on market, minor changes in formulation might be needed. At the same time, the product has to remain effective and safe for patients that could be confirmed via plasma drug concentrations and pharmacokinetic characteristics. It is challenging to predict human absorption and pharmacokinetic characteristics of a drug based on the in vitro dissolution test and the animal pharmacokinetic data. Therefore, the objective of this study was to establish correlation of the pharmacokinetic parameters of carbamazepine (CBZ) CR tablet formulation between the rabbit and the human model, and to establish in vitro in vivo correlation (IVIVC) based on the predicted fractions of absorbed CBZ. Although differences in mean plasma concentration profiles were notified, the data concerning the predicted fraction of drug absorbed were almost superimposable. Accordingly, it can be concluded that rabbits may be representative as an in vivo model for predicting the pharmacokinetics of the CR formulation of CBZ in humans.

scholarly journals Proof-of-Concept Study of Drug Brain Permeability Between in Vivo Human Brain and an in Vitro iPSCs-Human Blood-Brain Barrier Model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gwenaëlle Le Roux ◽  
Rafika Jarray ◽  
Anne-Cécile Guyot ◽  
Serena Pavoni ◽  
Narciso Costa ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Apparent Permeability ◽  
Clinical Drug Development ◽  
Blood Brain

Abstract The development of effective central nervous system (CNS) drugs has been hampered by the lack of robust strategies to mimic the blood-brain barrier (BBB) and cerebrovascular impairments in vitro. Recent technological advancements in BBB modeling using induced pluripotent stem cells (iPSCs) allowed to overcome some of these obstacles, nonetheless the pertinence for their use in drug permeation study remains to be established. This mandatory information requires a cross comparison of in vitro and in vivo pharmacokinetic data in the same species to avoid failure in late clinical drug development. Here, we measured the BBB permeabilities of 8 clinical positron emission tomography (PET) radioligands with known pharmacokinetic parameters in human brain in vivo with a newly developed in vitro iPSC-based human BBB (iPSC-hBBB) model. Our findings showed a good correlation between in vitro and in vivo drug brain permeability (R2 = 0.83; P = 0.008) which contrasted with the limited correlation between in vitro apparent permeability for a set of 18 CNS/non-CNS compounds using the in vitro iPSCs-hBBB model and drug physicochemical properties. Our data suggest that the iPSC-hBBB model can be integrated in a flow scheme of CNS drug screening and potentially used to study species differences in BBB permeation.

scholarly journals Celecoxib Loaded In-Situ Provesicular Powder and Its In-Vitro Cytotoxic Effect for Cancer Therapy: Fabrication, Characterization, Optimization and Pharmacokinetic Evaluation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1157
Author(s):  
Ali M. Nasr ◽  
Sameh S. Elhady ◽  
Shady A. Swidan ◽  
Noha M. Badawi
Keyword(s):  
Fatty Alcohol ◽  
Desirability Function ◽  
Area Under The Curve ◽  
Free Form ◽  
Pharmacokinetic Parameters ◽  
Anticancer Efficacy ◽  
Cox 2

Introduction: Several recent studies have shown that the role of cyclooxygenase 2 (COX-2) in carcinogenesis has become more evident. It affects angiogenesis, apoptosis, and invasion, and plays a key role in the production of carcinogens. It has also been reported that COX-2 inhibitors such as celecoxib (CLX) might play an effective role in preventing cancer formation and progression. Formulation of CLX into nanovesicles is a promising technique to improve its bioavailability and anticancer efficacy. Aim: The aim of this study is to optimize and evaluate the anticancer efficacy of CLX-loaded in-situ provesicular powder composed of surfactants and fatty alcohol-based novel nanovesicles in-vitro and determine its pharmacokinetic parameters in-vivo. Methods: The novel provesicular powders were prepared by the slurry method and optimized by 32 full factorial design using the desirability function. Results: Small mean particle size was achieved by the formed vesicles with value of 351.7 ± 1.76 nm and high entrapment efficacy of CLX in the formed vesicles of 97.53 ± 0.84%. Solid state characterization of the optimized formulation showed that the powder was free flowing, showed no incompatibilities between drug and excipients and showed smooth texture. The cytotoxic study of the optimized formula on HCT-116, HepG-2, A-549, PC-3 and MCF-7 cell lines showed significant increase in activity of CLX compared to its free form. The pharmacokinetic study on albino rabbits after oral administration showed significant increase in the area under the curve (AUC)0–24 h and significantly higher oral relative bioavailability of the optimized formulation compared to Celebrex® 100 mg market product (p < 0.05). Conclusion: All findings of this study suggest the potential improvement of efficacy and bioavailability of CLX when formulated in the form of in-situ provesicular powder composed of surfactants and fatty alcohol-based novel nanovesicles for its repositioned use as an anticancer agent.

scholarly journals Nano-sized Droplets of Self-Emulsifying System for Enhancing Oral Bioavailability of Chemotherapeutic Agent VP-16 in Rats: A Nano Lipid Carrier for BCS Class IV Drugs

2018 ◽  
Vol 21 ◽  
pp. 398-408 ◽  
Author(s):  
Nayab Khalid ◽  
Muhammad Sarfraz ◽  
Mosab Arafat ◽  
Muhammad Akhtar ◽  
Raimar Löbenberg ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Chemotherapeutic Agent ◽  
Ternary Phase Diagram ◽  
In Vitro Dissolution ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
The Mean ◽  
Class Iv

PURPOSE: The purpose of this study was to investigate the ability of a self-nano-emulsifying drug delivery system (SNEDDS) to enhance the oral bioavailability of a BCS class IV drug, etoposide (VP-16). METHOD: A series of SNEDDS formulations with VP-16 were prepared consisting of medium chain triglycerides, polysorbate 80, diethylene glycol monoethyl ether and propylene glycol monolaurate type-1.  Based on an obtained ternary phase diagram, an optimum formulation was selected and characterized in terms of size, zeta potential, loading, morphology and in vitro drug release. The pharmacokinetic parameters and oral bioavailability of VP-16 suspension and VP-16 in SNEDDS was assessed using 30 Male Sprague–Dawley rats and compared with the commercial product (VePesid®). RESULTS: Pharmacokinetic data showed that the mean values for AUC0-t of VP-16 in SNEDDS was 6.4 fold higher compared to a drug suspension and 2.4-folds higher than VePesid®. Similarly, the mean value for Cmax of VP-16 in SNEDDS (1.13± 0.07 µg/ml µg.h/mL) was higher than VePesid® (0.62± 0.09 µg/mL) and drug suspension (0.13± 0.07 µg/mL). CONCLUSION: The SNEDDS formulation was able to enhance the oral bioavailability of the BCS Class IV chemotherapeutic agent VP-16 by increasing the dissolution and absorption of the drug. A good in vitro in vivo correlation was found between the in vitro dissolution and in vivo absorption data of VP-16 SNEDDS preparation. Therefore, SNEDDS formulations might be a very promising approach for BCS Class IV drugs.

scholarly journals Pharmacokinetics (PK), Pharmacodynamics (PD), and PK-PD Integration of Danofloxacin in Sheep Biological Fluids

2003 ◽  
Vol 47 (2) ◽  
pp. 626-635 ◽  
Author(s):  
F. Shojaee Aliabadi ◽  
M. F. Landoni ◽  
P. Lees
Keyword(s):  
Rational Design ◽  
Ex Vivo ◽  
Biological Fluids ◽  
Area Under The Curve ◽  
Pharmacokinetic Data ◽  
Mean Values ◽  
Novel Approach ◽  
Pharmacokinetic Properties

ABSTRACT The fluoroquinolone antimicrobial drug danofloxacin was administered to sheep intravenously (i.v.) and intramuscularly (i.m.) at a dose of 1.25 mg/kg of body weight in a two-period crossover study. The pharmacokinetic properties of danofloxacin in serum, inflamed tissue cage fluid (exudate), and noninflamed tissue cage fluid (transudate) were established by using a tissue cage model. The in vitro and ex vivo activities of danofloxacin in serum, exudate, and transudate against a pathogenic strain of Mannheimia haemolytica were established. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the area under the curve (AUC)/MIC for serum, exudate, and transudate of 60.5, 85.6, and 45.7 h, respectively, after i.v. dosing and 55.9, 77.9, and 49.1 h, respectively, after i.m. dosing. After i.m. dosing, the maximum concentration/MIC ratios for serum, exudate, and transudate were 10.8, 3.0, and 1.6, respectively. The ex vivo growth inhibition data after i.m. dosing were fitted to the inhibitory sigmoid E max equation to provide the values of AUC/MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria. The respective values for serum were 17.8, 20.2, and 28.7 h, and slightly higher values were obtained for transudate and exudate. It is proposed that use of these data might provide a novel approach to the rational design of dosage schedules.

scholarly journals Acetylcholinesterase inhibition in electric eel and human donor blood: an in vitro approach to investigate interspecies differences and human variability in toxicodynamics

2020 ◽  
Vol 94 (12) ◽  
pp. 4055-4065
Author(s):  
Emma E. J. Kasteel ◽  
Sandra M. Nijmeijer ◽  
Keyvin Darney ◽  
Leonie S. Lautz ◽  
Jean Lou C. M. Dorne ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Human Blood ◽  
Ache Inhibition ◽  
In Vitro Method ◽  
Interindividual Differences ◽  
Chemical Risk ◽  
Chemical Risk Assessment ◽  
Electric Eel

Abstract In chemical risk assessment, default uncertainty factors are used to account for interspecies and interindividual differences, and differences in toxicokinetics and toxicodynamics herein. However, these default factors come with little scientific support. Therefore, our aim was to develop an in vitro method, using acetylcholinesterase (AChE) inhibition as a proof of principle, to assess both interspecies and interindividual differences in toxicodynamics. Electric eel enzyme and human blood of 20 different donors (12 men/8 women) were exposed to eight different compounds (chlorpyrifos, chlorpyrifos-oxon, phosmet, phosmet-oxon, diazinon, diazinon-oxon, pirimicarb, rivastigmine) and inhibition of AChE was measured using the Ellman method. The organophosphate parent compounds, chlorpyrifos, phosmet and diazinon, did not show inhibition of AChE. All other compounds showed concentration-dependent inhibition of AChE, with IC50s in human blood ranging from 0.2–29 µM and IC20s ranging from 0.1–18 µM, indicating that AChE is inhibited at concentrations relevant to the in vivo human situation. The oxon analogues were more potent inhibitors of electric eel AChE compared to human AChE. The opposite was true for carbamates, pointing towards interspecies differences for AChE inhibition. Human interindividual variability was low and ranged from 5–25%, depending on the concentration. This study provides a reliable in vitro method for assessing human variability in AChE toxicodynamics. The data suggest that the default uncertainty factor of ~ 3.16 may overestimate human variability for this toxicity endpoint, implying that specific toxicodynamic-related adjustment factors can support quantitative in vitro to in vivo extrapolations that link kinetic and dynamic data to improve chemical risk assessment.

scholarly journals Peptide drugs for photopharmacology: how much of a safety advantage can be gained by photocontrol?

2020 ◽  
Vol 2 (1) ◽  
pp. FDD28 ◽  
Author(s):  
Oleg Babii ◽  
Sergii Afonin ◽  
Tim Schober ◽  
Liudmyla V Garmanchuk ◽  
Liudmyla I Ostapchenko ◽  
...  
Keyword(s):  
Chemotherapeutic Agent ◽  
In Vitro Cytotoxicity ◽  
Pharmacokinetic Parameters ◽  
Cancer Model ◽  
Pharmacokinetic Properties ◽  
Insight Into ◽  
Safety Advantage ◽  
Murine Cancer Model

Aim: To verify whether photocontrol of biological activity could augment safety of a chemotherapeutic agent. Materials & methods: LD50 values for gramicidin S and photoisomeric forms of its photoswitchable diarylethene-containing analogs were determined using mice. The results were compared with data obtained from cell viability measurements taken for the same compounds. Absorption, Distribution, Metabolism, and Elimination (ADME) tests using a murine cancer model were conducted to get insight into the underlying reasons for the observed in vivo toxicity. Results: While in vitro cytotoxicity values of the photoisomers differed substantially, the differences in the observed LD50 values were less pronounced due to unfavorable pharmacokinetic parameters. Conclusion: Despite unfavorable pharmacokinetic properties as in the representative case studied here, there is an overall advantage to be gained in the safety profile of a chemotherapeutic agent via photocontrol. Nevertheless, optimization of the pharmacokinetic parameters of photoisomers is an important issue to be addressed during the development of photopharmacological drugs.

scholarly journals In VitroDissolution andIn VivoBioavailability of Six Brands of Ciprofloxacin Tablets Administered in Rabbits and Their Pharmacokinetic Modeling

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Sahar Fahmy ◽  
Eman Abu-Gharbieh
Keyword(s):  
Pharmacokinetic Modeling ◽  
Pharmacokinetic Parameters ◽  
Noncompartmental Analysis ◽  
Dose Oral ◽  
Generic Products ◽  
Ensure Product Quality ◽  
Pharmacopoeial Requirements ◽  
Compartment Open Model

This study was undertaken to assess thein vitrodissolution andin vivobioavailability of six brands of ciprofloxacin oral tablets available in the UAE market using rabbits. Thein vitrodissolution profiles of the six ciprofloxacin products were determined using the USP dissolution paddle method. Pharmacokinetic modeling using compartmental and noncompartmental analysis was done to determine the pharmacokinetic parameters of ciprofloxacin after single-dose oral administration.In vitrorelease study revealed that the amount of ciprofloxacin released in 20 minutes was not less than 80% of the labeled amount which is in accordance with the pharmacopoeial requirements. All tested products are considered to be very rapid dissolving except for formulae A and D. Ciprofloxacin plasma concentration in rabbits was best fitted to a two-compartment open model. The lowest bioavailability was determined to be for product A (93.24%) while the highest bioavailability was determined to be for product E (108.01%). Postmarketing surveillance is very crucial to ensure product quality and eliminating substandard products to be distributed and, consequently, ensure better patient clinical outcome. The tested ciprofloxacin generic products distributed in the UAE market were proven to be of good quality and could be used interchangeably with the branded ciprofloxacin product.

scholarly journals Development and biopharmaceutical evaluation of extended release formulation of tramadol hydrochloride based on osmotic technology

2009 ◽  
Vol 59 (1) ◽  
pp. 15-30 ◽  
Author(s):  
Pramod Kumar ◽  
Sanjay Singh ◽  
Brahmeshwar Mishra
Keyword(s):  
Drug Release ◽  
Extended Release ◽  
Relative Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Healthy Human ◽  
Tramadol Hydrochloride ◽  
Release Formulation ◽  
Extended Release Formulation

Development and biopharmaceutical evaluation of extended release formulation of tramadol hydrochloride based on osmotic technologyExtended release formulation of tramadol hydrochloride (TRH) based on osmotic technology was developed and evaluated. Target release profile was selected and different variables were optimized to achieve it. Formulation variables such as the level of swellable polymer, plasticizer and the coat thickness of semipermeable membrane (SPM) were found to markedly affect drug release. TRH release was directly proportional to the levels of plasticizer but inversely proportional to the levels of swellable polymer and coat thickness of SPM. Drug release from developed formulations was independent of pH and agitation intensity but dependent on osmotic pressure of the release media.In vivostudy was also performed on six healthy human volunteers and various pharmacokinetic parameters (cmax,tmax,AUC0-24,MRT) and relative bioavailability were calculated. Thein vitroandin vivoresults were compared with the performance of two commercial TRH tablets. The developed formulation provided more prolonged and controlled TRH release compared to the marketed formulation.In vitro-in vivocorrelation (IVIVC) was analyzed according to the Wagner-Nelson method. The optimized formulation (batch IVB) exhibited good IVIV correlation (R= 0.9750). The manufacturing procedure was found to be reproducible and formulations were stable over 6 months of accelerated stability testing.

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