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Guiastrennec, Benjamin
Publications (6 of 6) Show all publications
Stage, T. B., Wellhagen, G., Christensen, M. M., Guiastrennec, B., Brosen, K. & Kjellsson, M. C. (2019). Using a semi-mechanistic model to identify the main sources of variability of metformin pharmacokinetics. Basic & Clinical Pharmacology & Toxicology, 124(1), 105-114
Open this publication in new window or tab >>Using a semi-mechanistic model to identify the main sources of variability of metformin pharmacokinetics
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2019 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 124, no 1, p. 105-114Article in journal (Refereed) Published
Abstract [en]

Metformin pharmacokinetics (PK) is highly variable, and researchers have for years tried to shed light on determinants of inter-individual (IIV) and inter-occasion variability (IOV) of metformin PK. We set out to identify the main sources of PK variability using a semi-mechanistic model. We assessed the influence of subject characteristics, including seven genetic variants. Data from three studies of healthy individuals with PK measurements of plasma and urine after single dose or at steady-state were used in this study. In total, 87 subjects were included (16 crossover subjects). Single nucleotide polymorphisms in ATM, OCT1, OCT2, MATE1 and MATE2-K were investigated as dominant, recessive or additive. A three-compartment model with transit absorption and renal elimination with a proportional error was fitted to the data using NONMEM 7.3. Oral parameters were separated from disposition parameters as dose-dependent absolute bioavailability was determined with support from urine data. Clearance was expressed as net renal secretion and filtration, assuming full fraction unbound and fraction excreted. Mean transit time and peripheral volume of distribution were identified as the main sources of variability according to estimates, with 94% IOV and 95% IIV, respectively. Clearance contributed only with 16% IIV. Glomerular filtration rate and body-weight were the only covariates found to affect metformin net secretion, reducing IIV to 14%. None of the genetic variants were found to affect metformin PK. Based on our analysis, finding covariates explaining absorption of metformin is much more valuable in understanding variability and avoiding toxicity than elimination.

National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-374110 (URN)10.1111/bcpt.13139 (DOI)000454711300012 ()30267605 (PubMedID)
Available from: 2019-01-21 Created: 2019-01-21 Last updated: 2019-01-21Bibliographically approved
Guiastrennec, B., Sonne, D. P., Bergstrand, M., Vilsbøll, T., Knop, F. K. & Karlsson, M. O. (2018). Model-based prediction of plasma concentration and enterohepatic circulation of total bile acids in humans. CPT: pharmacometrics and systems pharmacology, 7(9), 603-612
Open this publication in new window or tab >>Model-based prediction of plasma concentration and enterohepatic circulation of total bile acids in humans
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2018 (English)In: CPT: pharmacometrics and systems pharmacology, E-ISSN 2163-8306, Vol. 7, no 9, p. 603-612Article in journal (Refereed) Published
Abstract [en]

Bile acids released postprandially can modify the rate and extent of lipophilic compounds’ absorption. This study aimed to predict the enterohepatic circulation (EHC) of total bile acids (TBAs) in response to caloric intake from their spillover in plasma. A model for TBA EHC was combined with a previously developed gastric emptying (GE) model. Longitudinal gallbladder volumes and TBA plasma concentration data from 30 subjects studied after ingestion of four different test drinks were supplemented with literature data. Postprandial gallbladder refilling periods were implemented to improve model predictions. The TBA hepatic extraction was reduced with the high‐fat drink. Basal and nutrient‐induced gallbladder emptying rates were altered by type 2 diabetes (T2D). The model was predictive of the central trend and the variability of gallbladder volume and TBA plasma concentration for all test drinks. Integration of this model within physiological pharmacokinetic modeling frameworks could improve the predictions for lipophilic compounds’ absorption considerably.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-340234 (URN)10.1002/psp4.12325 (DOI)000445602000009 ()
Funder
EU, FP7, Seventh Framework Programme, 115369
Available from: 2018-01-28 Created: 2018-01-28 Last updated: 2018-10-25Bibliographically approved
Guiastrennec, B., Ramachandran, G., Karlsson, M. O., Kumar, A. H., Bhavani, P. K., Gangadevi, N. P., . . . Savic, R. M. (2018). Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications. Clinical Pharmacology and Therapeutics, 104(4), 733-741
Open this publication in new window or tab >>Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications
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2018 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 104, no 4, p. 733-741Article in journal (Refereed) Published
Abstract [en]

This work aimed to evaluate the once‐daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration–time profiles and treatment outcome were obtained from 161 Indian children with drug‐sensitive tuberculosis undergoing thrice‐weekly dosing as per previous Indian pediatric guidelines. The exposure–response relationships were established using a population pharmacokinetic‐pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4–7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (Punfavorable). Model‐based simulation of optimized (Punfavorable ≤ 5%) rifampin once‐daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose‐exposure–response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-340236 (URN)10.1002/cpt.987 (DOI)000444673500018 ()29247506 (PubMedID)
Funder
Swedish Research Council, 521-2011-3442
Available from: 2018-01-28 Created: 2018-01-28 Last updated: 2018-11-27Bibliographically approved
Guiastrennec, B., Soderlind, E., Richardson, S., Peric, A. & Bergstrand, M. (2017). In Vitro and In Vivo Modeling of Hydroxypropyl Methylcellulose (HPMC) Matrix Tablet Erosion Under Fasting and Postprandial Status. Pharmaceutical research, 34(4), 847-859
Open this publication in new window or tab >>In Vitro and In Vivo Modeling of Hydroxypropyl Methylcellulose (HPMC) Matrix Tablet Erosion Under Fasting and Postprandial Status
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2017 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 4, p. 847-859Article in journal (Refereed) Published
Abstract [en]

To develop a model linking in vitro and in vivo erosion of extended release tablets under fasting and postprandial status. A nonlinear mixed-effects model was developed from the in vitro erosion profiles of four hydroxypropyl methylcellulose (HPMC) matrix tablets studied under a range of experimental conditions. The model was used to predict in vivo erosion of the HPMC matrix tablets in different locations of the gastrointestinal tract, determined by magnetic marker monitoring. In each gastrointestinal segment the pH was set to physiological values and mechanical stress was estimated in USP2 apparatus rotation speed equivalent. Erosion was best described by a Michaelis-Menten type model. The maximal HPMC release rate (V-MAX) was affected by pH, mechanical stress, HPMC and calcium hydrogen phosphate content. The amount of HPMC left at which the release rate is half of V-MAX depended on pH and calcium hydrogen phosphate. Mechanical stress was estimated for stomach (39.5 rpm), proximal (93.3 rpm) and distal (31.1 rpm) small intestine and colon (9.99 rpm). The in silico model accurately predicted the erosion profiles of HPMC matrix tablets under fasting and postprandial status and can be used to facilitate future development of extended release tablets.

Keywords
food effect, hydroxypropyl methylcellulose, in vitro in vivo correlation, magnetic marker monitoring, NONMEM
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-321446 (URN)10.1007/s11095-017-2113-7 (DOI)000396065400016 ()28155077 (PubMedID)
Available from: 2017-05-05 Created: 2017-05-05 Last updated: 2018-01-29
Guiastrennec, B., Sonne, D. P., Hansen, M., Bagger, J. I., Lund, A., Rehfeld, J. F., . . . Bergstrand, M. (2016). Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, 5(12), 692-700
Open this publication in new window or tab >>Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake
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2016 (English)In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 5, no 12, p. 692-700Article in journal (Refereed) Published
Abstract [en]

Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-314421 (URN)10.1002/psp4.12152 (DOI)000390923300006 ()
Funder
EU, FP7, Seventh Framework Programme
Available from: 2017-02-06 Created: 2017-02-02 Last updated: 2018-01-29Bibliographically approved
Guiastrennec, B., Keizer, R. J. & Karlsson, M. O. (2015). Quantitative Model Diagrams (QMD): A New Perspective in Model Evaluation. Paper presented at The American Conference on Pharmacometrics 2015 (ACoP6), October 3 to 8, 2015, Virginia, USA. Journal of Pharmacokinetics and Pharmacodynamics, 42(S1), S53-S53
Open this publication in new window or tab >>Quantitative Model Diagrams (QMD): A New Perspective in Model Evaluation
2015 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 42, no S1, p. S53-S53Article in journal, Meeting abstract (Other academic) Published
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-280820 (URN)000367842000094 ()
Conference
The American Conference on Pharmacometrics 2015 (ACoP6), October 3 to 8, 2015, Virginia, USA
Note

Meeting Abstract: T-24

Available from: 2016-03-30 Created: 2016-03-15 Last updated: 2018-01-10Bibliographically approved
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