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Natalie D Eddington - One of the best experts on this subject based on the ideXlab platform.
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the influence of first pass metabolism on the development and validation of an IVIVC for metoprolol extended release tablets
European Journal of Pharmaceutics and Biopharmaceutics, 2002Co-Authors: Nattee Sirisuth, Natalie D EddingtonAbstract:Abstract To investigate the influence of α-hydroxymetoprolol (AHM) and 4-(2-hydroxy-3-isopropylaminopropoxy)-phenylacetic acid (ACMB), both derived from its first pass metabolism of metoprolol, an in vitro in vivo correlation incorporating first pass metabolite data for metoprolol extended release formulations was developed. Three different releasing formulations (slow (S), moderate (M) and fast (F), 100 mg) of metoprolol were evaluated in a previously reported clinical study. The non-first pass effect (Non-FPE) in vitro in vivo correlation (IVIVC) was developed using a fraction of metoprolol dissolved and a fraction of total drug (metoprolol+metabolites) as the absorption data for various combinations of formulations (S/M/F, M/F, S/M, and S/F). Direct convolution approaches predicting metoprolol concentrations and indirect convolution predicting total drug concentrations (metoprolol+metabolites) were used to determine in vivo behavior. The Non-FPE IVIVC using the S/M/F formulations displayed the strongest relationship ( r 2 >0.92). The IVIVC using the indirect approach was predictive of both the C max (prediction errors (PE) 4.77, 3.94 and 6.14%) and AUC (10.7, 11.0 and 11.3%) for metoprolol, AHM and ACMB. Poor predictability (PE>40% for C max and AUC) was observed for metoprolol when using the direct methods. The predictability of the IVIVC using the indirect approach as compared to the direct method displays the influence of first pass metabolism on the development and evaluation of an IVIVC for a drug that displays a high extraction ratio. In addition, the indirect IVIVC allows for not only predicting the in vivo performance of the parent drug but also the metabolites formed via the first pass effect.
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development and validation of a non linear IVIVC model for a diltiazem extended release formulation
Biopharmaceutics & Drug Disposition, 2002Co-Authors: Nattee Sirisuth, Larry L Augsburger, Natalie D EddingtonAbstract:To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a diltiazem multi-particulate bead extended release formulation. In vitro dissolution of diltiazem capsules was examined using the following methods: USP Apparatus II (paddle) at 100 rpm and USP Apparatus III at 30 dpm. Seven healthy subjects received three diltiazem formulations (90 mg): slow (S), moderate (M), fast (F) releasing and an oral solution (90 mg). Serial blood samples were collected over 48 h and analyzed by a validated HPLC assay using ultraviolet detection. The f(2) metric (similarity factor) was used to analyze the dissolution data. Linear and non-linear (quadratic, cubic, and sigmoid functions) correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted diltiazem concentrations were obtained by convolution of the in vivo dissolution rates. Prediction errors were estimated for C(max) and AUC to determine the validity of the correlation. Apparatus II using purified water was found to be the most discriminating dissolution method. Significant intersubject (CV%>50) was observed for C(max) and AUC. The quadratic M/F IVIVC model provided a significant relationship between FRD and FRA when using either two or three of the formulations. An average percent prediction error for C(max) and AUC for all formulations was 12.4% and 9.2%, respectively. The prediction errors observed for C(max) and AUC suggest that the predictability of the quadratic IVIVC model is inconclusive, as such, external validation studies are required.
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evaluation of external predictability of an in vitro in vivo correlation for an extended release formulation containing metoprolol tartrate
Journal of Pharmaceutical Sciences, 2000Co-Authors: H Mahayni, Gurvinder Singh Rekhi, Ramana S Uppoor, Patrick J Marroum, Ajaz S Hussain, L L Augsburger, Natalie D EddingtonAbstract:The purpose of this study was to examine the external predictability of an in vitro-in vivo correlation (IVIVC) for a metoprolol hydrophilic matrix extended-release formulation, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. In addition, this report evaluated the predictability of the IVIVC for another formulation of metoprolol tartrate differing in its release mechanism. Study 1 examined the scale up of a matrix extended-release tablet from a 3-kg small batch (I) to a 50-kg large batch (II). The second study examined the influence of scale and processing changes [3-kg small batch with fluid bed granulation and drying (III); 80-kg large batch with high shear granulation and microwave drying (IV), and a formulation with an alternate release mechanism formulated as a multiparticulate capsule (V)]. In vitro dissolution of all formulations (I-V) was conducted with a USP apparatus I at pH 6.8 and 150 rpm. Subjects received the metoprolol formulations, and serial blood samples were collected over 48 h and analyzed by a validated HPLC assay using fluorescence detection. A previously developed IVIVC was used to predict plasma profiles. Prediction errors (PE) were 20% and an AUC within 5% of observed values. The low PEs for C(max) and AUC observed for I-IV strongly suggest that the metoprolol IVIVC is externally valid, predictive of alternate processing methods (IV), scale-up (II, III), and allows the in vitro dissolution data to be used as a surrogate for validation studies. However, the lack of predictability for V supports the contention that IVIVCs are formulation specific.
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influence of stereoselective pharmacokinetics in the development and predictability of an IVIVC for the enantiomers of metoprolol tartrate
Pharmaceutical Research, 2000Co-Authors: Nattee Sirisuth, Natalie D EddingtonAbstract:Purpose. To investigate the ability of an IVIVC developedwith a racemate drug as well as each enantiomer in predicting the invivo enantiomer drug performance.
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development and internal validation of an in vitro in vivo correlation for a hydrophilic metoprolol tartrate extended release tablet formulation
Pharmaceutical Research, 1998Co-Authors: Natalie D Eddington, Ramana S Uppoor, Patrick J Marroum, Ajaz S Hussain, L L AugsburgerAbstract:Purpose. To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a hydrophilic matrix extended release metoprolol tablet.
Amin Rostamihodjegan - One of the best experts on this subject based on the ideXlab platform.
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physiologically based pharmacokinetics joined with in vitro in vivo extrapolation of adme a marriage under the arch of systems pharmacology
Clinical Pharmacology & Therapeutics, 2012Co-Authors: Amin RostamihodjeganAbstract:Classic pharmacokinetics (PK) rarely takes into account the full knowledge of physiology and biology of the human body. However, physiologically based PK (PBPK) is built mainly from drug-independent "system" information. PBPK is not a new concept, but it has shown a very rapid rise in recent years. This has been attributed to a greater connectivity to in vitro-in vivo extrapolation (IVIVE) techniques for predicting drug absorption, distribution, metabolism, and excretion (ADME) and their variability in humans. The marriage between PBPK and IVIVE under the overarching umbrella of "systems biology" has removed many constraints related to cutoff approaches on prediction of ADME. PBPK-IVIVE linked models have repeatedly shown their value in guiding decisions when predicting the effects of intrinsic and extrinsic factors on PK of drugs. A review of the achievements and shortcomings of the models might suggest better strategies in extending the success of PBPK-IVIVE to pharmacodynamics (PD) and drug safety.
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establishing an in vitro in vivo correlation IVIVC for tramadol extended release tablets conventional vs physiologically based IVIVC
2012Co-Authors: Shriram M Pathak, Nikunjkumar Patel, David B Turner, Masoud Jamei, Amin RostamihodjeganAbstract:2 . Oral solution data were used to estimate disposition parameters and gut permeability. For each ER formulation in vivo dissolution profiles were deconvoluted from the corresponding Cp profile using the IVIVC module of the Simcyp Simulator (V13 R2). An IVIVC between deconvoluted in vivo dissolution profiles and in vitro dissolution profiles was established and validated internally using three formulations and externally using two ER formulations. Results Simple linear correlation was sufficient to establish an IVIVC (r2 = 0.99). The mean absolute %prediction errors were 5.65 (Cmax) and 7.70 (AUC) for internal and 1.71 (Cmax) and 6.84 (AUC) for external validation. The predicted Cp profiles corresponding to upper and lower limit of dissolution specifications resulted in less than 20% difference for Cmax and AUC vs. 25.00% (Cmax) and 23.35% (AUC) of the reported values using the conventional IVIVC. The conventional approach with a linear IVIVC model failed to predict the lower bioavailability of the slower formulation of tramadol until corrected for GI residence time (time scaling). Conclusion The PBPK IVIVC approach improved the predictive performance of the IVIVC and resulted in a simpler linear IVIVC model unlike the conventional approach that required time scaling.
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a new rapidly absorbed paracetamol tablet containing sodium bicarbonate ii dissolution studies and in vitro in vivo correlation
Drug Development and Industrial Pharmacy, 2002Co-Authors: Amin Rostamihodjegan, M R Shiran, G T Tucker, Barbara R Conway, W J Irwin, Lance R Shaw, Tim J GrattanAbstract:The objective of this study was to compare the in vitro dissolution profile of a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with that of a conventional paracetamol tablet (P), and to relate these by deconvolution and mapping to in vivo release. The dissolution methods used include the standard procedure described in the USP monograph for paracetamol tablets, employing buffer at pH5.8 or 0.05 M HCl at stirrer speeds between 10 and 50 rpm. The mapping process was developed and implemented in Microsoft Excel® worksheets that iteratively calculated the optimal values of scale and shape factors which linked in vivo time to in vitro time. The in vitro-in vivo correlation (IVIVC) was carried out simultaneously for both formulations to produce common mapping factors. The USP method, using buffer at pH5.8, demonstrated no difference between the two products. However, using an acidic medium the rate of dissolution of P but not of PS decreased with decreasing stirrer speed. A significant correlation (r=0.773; p<.00001) was established between in vivo release and in vitro dissolution using the profiles obtained with 0.05 M HCl and a stirrer speed of 30 rpm. The scale factor for optimal simultaneous IVIVC in the fasting state was 2.54 and the shape factor was 0.16; corresponding values for mapping in the fed state were 3.37 and 0.13 (implying a larger in vitro-in vivo time difference but reduced shape difference in the fed state). The current IVIVC explains, in part, the observed in vivo variability of the two products. The approach to mapping may also be extended to different batches of these products, to predict the impact of any changes of in vitro dissolution on in vivo release and plasma drug concentration-time profiles.
Filippos Kesisoglou - One of the best experts on this subject based on the ideXlab platform.
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a survey on IVIVC ivivr development in the pharmaceutical industry past experience and current perspectives
European Journal of Pharmaceutical Sciences, 2017Co-Authors: Mai Anh Nguyen, Filippos Kesisoglou, Talia Flanagan, Marcus E Brewster, Stefania Beato, Jeike Biewenga, John R Crison, Rene Holm, Erik Mannaert, Mark McallisterAbstract:The present work aimed to describe the current status of IVIVC/IVIVR development in the pharmaceutical industry, focusing on the use and perception of specific approaches as well as successful and failed case studies. Two questionnaires have been distributed to 13 EFPIA partners of the Oral Biopharmaceutics Tools Initiative and to the Pharmacokinetics Working Party of the European Medicines Agency in order to capture the perspectives and experiences of industry scientists and agency members, respectively. Responses from ten companies and three European Agencies were received between May 21st 2014 and January 19th 2016. The majority of the companies acknowledged the importance of IVIVC/IVIVR throughout the drug development stages and a well-balanced rate of return on investment. However, the IVIVC/IVIVR approach seemed to be underutilized in regulatory submissions. Four of the ten companies stated to have an internal guidance related to IVIVC/IVIVR modelling, whereas three felt that an overall strategy is not necessary. Successful models mainly served to support formulation development and to provide a better mechanistic understanding. There was not yet much experience with safe-space IVIVRs as well as the use of physiologically based modelling in the field of IVIVC. At the same time, the responses from both industry and agencies indicated that there might be a need for a regulatory framework to guide the application of these novel approaches. The relevance of IVIVC/IVIVR for oral IR drug products was recognized by most of the companies. For IR formulations, relationships other than Level A correlation were more common outcomes among the provided case studies, such as multiple Level C correlation or safe-space IVIVR, which could be successfully used for requesting regulatory flexibility. Compared to the responses from industry scientists, there was a trend towards a higher appreciation of the BCS among the regulators, but a less positive attitude towards the utility of non-compendial dissolution methods for establishing a successful IVIVC/IVIVR. The lack of appropriate in vivo data and regulatory uncertainty were considered the major difficulties in IVIVC/IVIVR development. The results of this survey provide unique insights into current IVIVC/IVIVR practices in the pharmaceutical industry. Pursuing an IVIVC/IVIVR should be generally encouraged, considering its high value from both industry and regulators' perspective.
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Comparison of Deconvolution-Based and Absorption Modeling IVIVC for Extended Release Formulations of a BCS III Drug Development Candidate
The AAPS Journal, 2015Co-Authors: Filippos Kesisoglou, Binfeng Xia, Nancy G. B. AgrawalAbstract:In vitro – in vivo correlations (IVIVC) are predictive mathematical models describing the relationship between dissolution and plasma concentration for a given drug compound. The traditional deconvolution/convolution-based approach is the most common methodology to establish a level A IVIVC that provides point to point relationship between the in vitro dissolution and the in vivo input rate. The increasing application of absorption physiologically based pharmacokinetic model (PBPK) has provided an alternative IVIVC approach. The current work established and compared two IVIVC models, via the traditional deconvolution/convolution method and via absorption PBPK modeling, for two types of modified release (MR) formulations (matrix and multi-particulate tablets) of MK-0941, a BCS III drug development candidate. Three batches with distinct release rates were studied for each formulation technology. A two-stage linear regression model was used for the deconvolution/convolution approach while optimization of the absorption scaling factors (a model parameter that relates permeability and input rate) in Gastroplus^TM Advanced Compartmental Absorption and Transit model was used for the absorption PBPK approach. For both types of IVIVC models established, and for either the matrix or the multiparticulate formulations, the average absolute prediction errors for AUC and C _max were below 10% and 15%, respectively. Both the traditional deconvolution/convolution-based and the absorption/PBPK-based level A IVIVC model adequately described the compound pharmacokinetics to guide future formulation development. This case study highlights the potential utility of absorption PBPK model to complement the traditional IVIVC approaches for MR products.
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development of in vitro in vivo correlation for amorphous solid dispersion immediate release suvorexant tablets and application to clinically relevant dissolution specifications and in process controls
Journal of Pharmaceutical Sciences, 2015Co-Authors: Filippos Kesisoglou, Andre Hermans, Colleen Neu, Ka Lai Yee, John Palcza, Jessica MillerAbstract:Although in vitro-in vivo correlations (IVIVCs) are commonly pursued for modified-release products, there are limited reports of successful IVIVCs for immediate-release (IR) formulations. This manuscript details the development of a Multiple Level C IVIVC for the amorphous solid dispersion formulation of suvorexant, a BCS class II compound, and its application to establishing dissolution specifications and in-process controls. Four different 40 mg batches were manufactured at different tablet hardnesses to produce distinct dissolution profiles. These batches were evaluated in a relative bioavailability clinical study in healthy volunteers. Although no differences were observed for the total exposure (AUC) of the different batches, a clear relationship between dissolution and Cmax was observed. A validated Multiple Level C IVIVC against Cmax was developed for the 10, 15, 20, 30, and 45 min dissolution time points and the tablet disintegration time. The relationship established between tablet tensile strength and dissolution was subsequently used to inform suitable tablet hardness ranges within acceptable Cmax limits. This is the first published report for a validated Multiple Level C IVIVC for an IR solid dispersion formulation demonstrating how this approach can facilitate Quality by Design in formulation development and help toward clinically relevant specifications and in-process controls.
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development of in vitro in vivo correlation for extended release niacin after administration of hypromellose based matrix formulations to healthy volunteers
Journal of Pharmaceutical Sciences, 2014Co-Authors: Filippos Kesisoglou, Stefaan Rossenu, Colm Farrell, Michiel W Van Den Heuvel, Marita Prohn, Shaun Fitzpatrick, Pieterjan De Kam, Ryan C VargoAbstract:ABSTRACT Development of in vitro – in vivo correlations (IVIVCs) for extended‐release (ER) products is commonly pursued during pharmaceutical development to increase product understanding, set release specifications, and support biowaivers. This manuscript details the development of Level C and Level A IVIVCs for ER formulations of niacin, a highly variable and extensively metabolized compound. Three ER formulations were screened in a cross‐over study against immediate‐release niacin. A Multiple Level C IVIVC was established for both niacin and its primary metabolite nicotinuric acid (NUA) as well as total niacin metabolites urinary excretion. For NUA, but not for niacin, Level A IVIVC models with acceptable prediction errors were achievable via a modified IVIVC rather than a traditional deconvolution/convolution approach. Hence, this is in contradiction with current regulatory guidelines that suggest that when a Multiple Level C IVIVC is established, Level A models should also be readily achievable. We demonstrate that for a highly variable, highly metabolized compound such as niacin, development of a Level A IVIVC model fully validated according to agency guidelines may be challenging. However, Multiple Level C models are achievable and could be used to guide release specifications and formulation/manufacturing changes. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3713–3723, 2014
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survey results for in vitro in vivo correlations IVIVC critical variables for success
Dissolution Technologies, 2013Co-Authors: Nikoletta Fotaki, Filippos Kesisoglou, Vivian A Gray, Steve Mayock, Tahseen Mirza, Alger Salt, Arzu SelenAbstract:This report summarizes the results of the "In Vitro-In Vivo Correlations (IVIVC): Critical Variables for Success" survey orga- nized by the In Vitro Release and Dissolution Testing (IVRDT) and the QbD and Product Performance AAPS Focus Groups. This was a web-based survey conducted over a 26-day period from Wednesday, June 29, 2011, to Sunday, July 24, 2011, and results were initially presented at the 2011 AAPS Annual Meeting and Exposition. The goal was to describe the current views from scientists across academia, industry, and regulatory agencies on the adoption, utility, and benefits of IVIVCs and to begin identifying potentially critical variables for their success. Questions in the survey cover their development, use, and success.
L L Augsburger - One of the best experts on this subject based on the ideXlab platform.
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evaluation of external predictability of an in vitro in vivo correlation for an extended release formulation containing metoprolol tartrate
Journal of Pharmaceutical Sciences, 2000Co-Authors: H Mahayni, Gurvinder Singh Rekhi, Ramana S Uppoor, Patrick J Marroum, Ajaz S Hussain, L L Augsburger, Natalie D EddingtonAbstract:The purpose of this study was to examine the external predictability of an in vitro-in vivo correlation (IVIVC) for a metoprolol hydrophilic matrix extended-release formulation, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. In addition, this report evaluated the predictability of the IVIVC for another formulation of metoprolol tartrate differing in its release mechanism. Study 1 examined the scale up of a matrix extended-release tablet from a 3-kg small batch (I) to a 50-kg large batch (II). The second study examined the influence of scale and processing changes [3-kg small batch with fluid bed granulation and drying (III); 80-kg large batch with high shear granulation and microwave drying (IV), and a formulation with an alternate release mechanism formulated as a multiparticulate capsule (V)]. In vitro dissolution of all formulations (I-V) was conducted with a USP apparatus I at pH 6.8 and 150 rpm. Subjects received the metoprolol formulations, and serial blood samples were collected over 48 h and analyzed by a validated HPLC assay using fluorescence detection. A previously developed IVIVC was used to predict plasma profiles. Prediction errors (PE) were 20% and an AUC within 5% of observed values. The low PEs for C(max) and AUC observed for I-IV strongly suggest that the metoprolol IVIVC is externally valid, predictive of alternate processing methods (IV), scale-up (II, III), and allows the in vitro dissolution data to be used as a surrogate for validation studies. However, the lack of predictability for V supports the contention that IVIVCs are formulation specific.
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development and internal validation of an in vitro in vivo correlation for a hydrophilic metoprolol tartrate extended release tablet formulation
Pharmaceutical Research, 1998Co-Authors: Natalie D Eddington, Ramana S Uppoor, Patrick J Marroum, Ajaz S Hussain, L L AugsburgerAbstract:Purpose. To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a hydrophilic matrix extended release metoprolol tablet.
Peter Langguth - One of the best experts on this subject based on the ideXlab platform.
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A time-scaled convolution approach to construct IVIVC for enteric-coated acetylsalicylic acid tablets.
Die Pharmazie, 2018Co-Authors: Jozef Al-gousous, Peter LangguthAbstract:: A scaled convolution-based in vitro-in vivo (IVIVC) model was constructed for two enteric-coated acetylsalicylic acid tablet formulations. The in vitro data used were the results of dissolution testing performed using three different dissolution methods: the United States Pharmacopoeia (USP) method, a method employing blank Fasted State Simulated Fluid (FaSSIF), and a new method developed in house. The in vivo data were obtained from a pharmacokinetic study on human subjects in the fasted state. When the new dissolution method results were used, an average prediction error less than 10% and a maximum prediction error less than 15% were obtained for the peak plasma concentration (Cmax) and area under the curve (AUC) parameters, thus meeting the internal validation criteria of the IVIVC guidance of the US Food and Drug Administration (FDA).
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IVIVC approach based on carbamazepine bioequivalence studies combination
Die Pharmazie, 2017Co-Authors: Ignacio Gonzalezgarcia, Peter Langguth, Victor Mangassanjuan, Matilde Merinosanjuan, C Alvarezalvarez, Diazgarzon J Marco, M A Rodriguezbonnin, T Langguth, J J Torradoduran, Alfredo GarciaarietaAbstract:The aim of the present study was to explore the feasibility of obtaining an IVIVC by combination of data from two bioequivalence (BE) studies of carbamazepine (CBZ) in order to assess if the previously published dissolution media and conditions could be applicable to any other oral immediate release (IR) CBZ products with conventional excipients. Twenty-four healthy male subjects from two BE study received one IR dose of the test (test 1 or 2) or the reference formulation (Tegretol, 400 mg). Dissolution studies of the IR CBZ tablets were performed in two different laboratories. In order to develop IVIVC, individual or average data analysis were considered. A level C, level B and level A correlation have been successfully developed by combining data from different BE studies of CBZ immediate release drug products. A level A IVIVC was developed with all four datasets with a good R2 for all the combinations of in vivo and in vitro data. A dissolution medium containing 1% SLS has demonstrated its suitability as the universal biopredictive dissolution medium, even if different batches and in vivo/in vitro studies were combined.
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predicting the in vivo release from a liposomal formulation by IVIVC and non invasive positron emission tomography imaging
European Journal of Pharmaceutical Sciences, 2010Co-Authors: Eva Huhn, Hansgeorg Buchholz, Gamal A Shazly, Stephan Maus, Oliver Thews, Nicole Bausbacher, Frank Rosch, Mathias Schreckenberger, Peter LangguthAbstract:This study aimed to predict the in vivo performance from the in vitro release of a low-molecular weight model compound, [(18)F]-2-fluoro-2-deoxy-d-glucose ([(18)F]FDG), from liposomes and by means of positron emission tomography (PET). Liposomes composed of hydrogenated phosphatidylcholine (HPC) were prepared by a freeze-thaw method. Particle size distribution was measured by dynamic light scattering (DLS). In vitro release was examined with a dispersion method detecting the radioactivity of [(18)F]FDG. In vivo release of [(18)F]FDG, following i.p. injection of the liposomes in rats, was determined by using a Micro-PET scanner. Convolution was performed to predict the in vivo profiles from the in vitro data and to establish an in vitro-in vivo correlation (IVIVC). The in vivo predictions slightly underestimated the experimentally determined values. The magnitude of the prediction errors (13% and 19%) displayed a satisfactory IVIV relationship leaving yet room for further improvement. This study demonstrated for the first time the use of PET in attaining an IVIVC for a parenterally administered modified release dosage form. It is therefore possible to predict target tissue concentrations, e.g., in the brain, from in vitro release experiments. IVIVC using non-invasive PET imaging could thus be a valuable tool in drug formulation development, resulting in reduced animal testing.
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justification of biowaiver for carbamazepine a low soluble high permeable compound in solid dosage forms based on IVIVC and gastrointestinal simulation
Molecular Pharmaceutics, 2009Co-Authors: Ivan Kovacevic, Jelena Parojcic, Irena Homsek, Marija Tubicgrozdanis, Peter LangguthAbstract:The aim of the present study was to use gastrointestinal simulation technology and in vitro-in vivo correlation (IVIVC) as tools to investigate a possible extension of biowaiver criteria to BCS class II drugs using carbamazepine (CBZ) as a candidate compound. Gastrointestinal simulation based on the advanced compartmental absorption and transit model implemented in GastroPlus was used. Actual in vitro and in vivo data generated in CBZ bioequivalence studies were used for correlation purposes. The simulated plasma profile, based on the CBZ physicochemical and pharmacokinetic properties, was almost identical with that observed in vivo. Parameter sensitivity analysis (PSA) indicated that the percent of drug absorbed is relatively insensitive to the variation of the input parameters. Additionally, plasma concentration-time profiles were simulated based on dissolution profiles observed under the different experimental conditions. Regardless of the differences observed in vitro, the predicted pharmacokinetic profiles were similar in the extent of drug exposure (AUC) while there were certain differences in parameters defining the drug absorption rate (C(max)t(max)). High level A IVIVC was established for the pooled data set (r = 0.9624), indicating that 1% SLS may be considered as the universal biorelevant dissolution medium for both the IR and CR CBZ tablets. The proposed methodology involving gastrointestinal simulation technology and IVIVC suggests that there is a rationale for considering CBZ biowaiver extension and introduction of the wider dissolution specifications for CBZ immediate release tablets.
