Publications by authors named "An Vermeulen"

109 Publications

Identification of novel inhibitors of rat Mrp3.

Eur J Pharm Sci 2021 Jul 19;162:105813. Epub 2021 Mar 19.

Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Campus Gasthuisberg, O&N2, Herestraat 49 box 921, B-3000 Leuven, Belgium; BioNotus GCV, Wetenschapspark Universiteit Antwerpen, Galileilaan 15, B-2845 Niel, Belgium. Electronic address:

Multidrug resistance-associated protein (MRP; ABCC gene family) mediated efflux transport plays an important role in the systemic and tissue exposure profiles of many drugs and their metabolites, and also of endogenous compounds like bile acids and bilirubin conjugates. However, potent and isoform-selective inhibitors of the MRP subfamily are currently lacking. Therefore, the purpose of the present work was to identify novel rat Mrp3 inhibitors. Using 5(6)-carboxy-2',7'-dichlorofluorescein diacetate (CDFDA) as a model-(pro)substrate for Mrp3 in an oil-spin assay with primary rat hepatocytes, the extent of inhibition of CDF efflux was determined for 1584 compounds, yielding 59 hits (excluding the reference inhibitor) that were identified as new Mrp3 inhibitors. A naive Bayesian prediction model was constructed in Pipeline Pilot to elucidate physicochemical and structural features of compounds causing Mrp3 inhibition. The final Bayesian model generated common physicochemical properties of Mrp3 inhibitors. For instance, more than half of the hits contain a phenolic structure. The identified compounds have an AlogP between 2 and 4.5, between 5 to 8 hydrogen bond acceptor atoms, a molecular weight between 260 and 400, and 2 or more aromatic rings. Compared to the depleted dataset (i.e. 90% remaining compounds), the Mrp3 hit rate in the enriched set was 7.5-fold higher (i.e. 17.2% versus 2.3%). Several hits from this first screening approach were confirmed in an additional study using Mrp3 transfected inside-out membrane vesicles. In conclusion, several new and potent inhibitors of Mrp3 mediated efflux were identified in an optimized in vitro rat hepatocyte assay and confirmed using Mrp3 transfected inside-out membrane vesicles. A final naive Bayesian model was developed in an iterative way to reveal common physicochemical and structural features for Mrp3 inhibitors. The final Bayesian model will enable in silico screening of larger libraries and in vitro identification of more potent Mrp3 inhibitors.
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http://dx.doi.org/10.1016/j.ejps.2021.105813DOI Listing
July 2021

Linking Intrinsic Dissolution Rate and Thermodynamic Solubility with Pharmacokinetic Profiles of Bedaquiline Long-Acting Aqueous Microsuspensions in Rats.

Mol Pharm 2021 03 5;18(3):952-965. Epub 2021 Jan 5.

Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent B-9000, Belgium.

Pharmacokinetic (PK) profiles of a range of bedaquiline (BDQ) long-acting injectable (LAI) microsuspensions in rats after parenteral (, intramuscular and subcutaneous) administration were correlated with the intrinsic dissolution rate (IDR) and thermodynamic solubility of BDQ in media varying in surfactant type and concentration to better understand the impact of different nonionic surfactants on the performance of BDQ LAI microsuspensions. All LAI formulations had a similar particle size distribution. The investigated surfactants were d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), poloxamer 338, and poloxamer 188. Furthermore, the relevance of medium complexity by using a biorelevant setup to perform measurements was assessed by comparing IDR and thermodynamic solubility results obtained in biorelevant media and formulation vehicle containing different surfactants in varying concentrations. In the presence of a surfactant, both media could be applied to obtain representative dissolution and solubility data because the difference between the biorelevant medium and formulation vehicle was predominantly nonsignificant. Therefore, a more simplistic medium in the presence of a surfactant was preferred to obtain measurements to predict the PK performance of LAI aqueous suspensions. The type of surfactant influenced the PK profiles of BDQ microsuspensions in rats, which could be the result of a surfactant effect on the IDR and/or thermodynamic solubility of BDQ. Overall, two surfactant groups could be differentiated: TPGS and poloxamers. Most differences between the PK profiles (, maximum concentration observed, time of maximum concentration observed, and area under the curve) were observed during the first 21 days postdose, the time period during which particles in the aqueous suspension are expected to dissolve.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00948DOI Listing
March 2021

A recycler's perspective on the implications of REACH and food contact material (FCM) regulations for the mechanical recycling of FCM plastics.

Waste Manag 2021 Jan 22;119:315-329. Epub 2020 Oct 22.

CAPTURE - Centre for Polymer and Material Technologies, Faculty of Engineering & Architecture, Ghent University, Technologiepark 130, 9000 Ghent, Belgium. Electronic address:

This manuscript provides an overview of the legislative requirements for the use of mechanical recycled plastics in articles placed on the EU market, as seen from the perspective of a plastics recycler. The first part reviews the main principles included in the overarching legislation on Registration, Evaluation, Authorisation and Restrictions of Chemicals (REACH) and to what extent these are applicable for mechanical recyclers of plastics. The interactions between REACH and the Waste Framework Directive (WFD) is discussed, as well as the difficulties for recyclers to comply with certain REACH requirements. In a second part, the focus is moved to the use of recycled plastics as Food Contact Material (FCM). The scope of the different applicable EU FCM regulations is inventorised as well as the key legislative principles involved. A final section is dedicated to the discussion on the authorisation of recycling processes under the FCM regulation and the practical challenges involved for the effective introduction of FCMs containing recycled plastics. Altogether it could be concluded that the complexity of the different legal perspectives, a lack of communication and transparency within the plastic value chain together with technical challenges related to recycling processes have been hindering the effective uptake of recycled plastic FCM (with the exception for bottle PET). The development of targeted solutions across the entire value-chain, taking into account different perspectives in terms of legislation and health protection, economic growth and technical innovations, will be crucial in achieving a circular economy for plastics, including recycled plastics for FCM.
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http://dx.doi.org/10.1016/j.wasman.2020.10.012DOI Listing
January 2021

Migration of surrogate contaminants from paperboard to foods: Effect of food and surrogate properties.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2020 Dec 24;37(12):2165-2183. Epub 2020 Sep 24.

Research Group Food Chemistry and Human Nutrition (nutriFOODchem), Department of Food Technology, Safety and Health, Ghent University , Ghent, Belgium.

The current research describes an alternative test method to evaluate the impact of food properties and compound characteristics on migration from paperboard to food. Tightly sealed bottles containing paperboard spiked with surrogate components as a donor, together with modified polyphenylene oxide (MPPO or Tenax®) or one of the nine considered foods as a receptor, were stored at 22°C. Instead of analysing the receptor, migration from donor to receptor was followed up by evaluating the recovery of surrogates from the donor over time, thus avoiding challenges in the analysis of the foods as such. Free fat content affected the migration more than the specific surface area of the food, reaching a plateau at fat contents >8.1%. The highest migration was observed to fatty foods such as biscuits (8% to 25% fat) and chocolate (40% fat). Intermediate migration occurred to starchy and particulate foods such as egg-based wheat pasta (2.6% fat), wheat flour (1% fat) and rice flour (0.5% fat). Low migration occurred in the case of paperboard in contact with wheat pasta (0.4% fat). Native starch was found to be more sensitive to migration than gelatinised starch. Volatility was identified as the most important characteristic of the migrating compounds. MPPO was considered as a suitable surrogate for dry foods as it did not underestimate migration in any case. However, for low-fat foods such as wheat pasta, clear overestimations could occur, but only for volatile surrogates with vapour pressure over 1.45 mTorr.
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http://dx.doi.org/10.1080/19440049.2020.1778184DOI Listing
December 2020

Pharmacokinetics in Patients with Cystic Fibrosis: A Systematic Review of Data Published Between 1999 and 2019.

Clin Pharmacokinet 2020 12;59(12):1551-1573

Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.

Background: Cystic fibrosis is a lethal inherited disease that affects multiple organs. To provide optimal pharmacological treatment of comorbidities associated with cystic fibrosis, relevant alterations in pharmacokinetics must be known.

Objective: The objective of this study was to compare the pharmacokinetics of drugs between patients with cystic fibrosis and controls, based on clinical study reports published from 1999 to 2019.

Methods: Clinical studies were considered if patients with cystic fibrosis and patients without cystic fibrosis/healthy volunteers were included, a drug was administered orally/intravenously and pharmacokinetic parameters were compared.

Results: In total, 32 clinical studies were included. Twenty-one studies reported absorption parameters. For multiple drugs, speed and/or extent of oral absorption were lower in cystic fibrosis. This phenomenon is possibly related to pathophysiological changes in the gastrointestinal tract associated with cystic fibrosis. However, a large proportion of drugs had comparable absorption kinetics. Twenty-one studies discussed volume of distribution, which was comparable between groups for most drugs. Initial differences became smaller when scaled to body composition. For some highly protein-bound drugs, inflammation-related changes in plasma proteins helped explain residual variability between cystic fibrosis and controls. Twenty-four studies elaborated on clearance, whereby higher clearances were observed in cystic fibrosis. In contrast with previously published reviews, no evidence was found for increased activities of drug-metabolising enzymes nor for up-regulation of active transport processes involved in drug disposition. In most cases, scaling clearance parameters to body composition and/or incorporating differences in plasma protein concentration accounted for these larger clearances.

Implications: There is no evidence that genetic defects causing cystic fibrosis directly lead to altered pharmacokinetics. However, co-morbidities can have a potential impact on drug absorption and disposition. Because of gastrointestinal complications, it is not advisable to extrapolate drug absorption parameters from healthy volunteers to patients with cystic fibrosis. Differences observed in the volume of distribution and clearance in patients with cystic fibrosis can potentially be explained by correcting for lean body mass.
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http://dx.doi.org/10.1007/s40262-020-00932-9DOI Listing
December 2020

Desmopressin oral lyophilisate in young children: new insights in pharmacokinetics and pharmacodynamics.

Arch Dis Child 2021 Jun 31;106(6):597-602. Epub 2020 Jul 31.

Department of Internal Medicine and Paediatrics, Faculty of Medicine and Health Sciences, Ghent University, Gent, Belgium.

Objective: To study the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of desmopressin (dDAVP) oral lyophilisate in children below the age of 8 years with special emphasis on age-related and size-related differences in bioavailability.

Design: Open label, non-randomised, interventional PK and PD trial.

Setting: Single-centre study.

Patients: Children (age: 6 months to 8 years) with nocturnal polyuria, including both children with uropathy or nephropathy (glomerular filtration rate >60 mL/min/1.73 m²) and children (age: 5-8 years) with severe monosymptomatic nocturnal enuresis, who were unresponsive to treatment with 400 µg of the dDAVP tablet for at least 1 month.

Interventions: After a water load, dDAVP was administered sublingually as a single dose of oral lyophilisate. Subsequently, blood and urine samples were collected until 7 hours post-administration.

Main Outcome Measures: Non-compartmental analysis of PK parameters was performed based on dDAVP concentrations in both plasma and urine. To evaluate the effect of dDAVP lyophilisate (PD parameters), the urinary concentration capacity (urine osmolality (mOsm/kg)) and antidiuretic effect (diuresis rate (mL/kg/h)) were calculated.

Results: The PK data support the need for size-dependent dosing in children. Body weight was shown to be a significant covariate for apparent clearance (CL/F) and apparent volume of distribution (V/F). A double absorption peak of dDAVP lyophilisate in the first 2 hours post-administration was demonstrated.

Conclusions: For the first time, a double absorption profile of dDAVP lyophilisate was found in children, questioning extrapolation of bioequivalence from adults towards children. Moreover, the need for size-adapted dosing regimens of dDAVP lyophilisate in young children is indicated.

Trial Registration Number: NTC02584231.
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http://dx.doi.org/10.1136/archdischild-2019-318225DOI Listing
June 2021

A Time-to-Event Model Relating Integrated Craving to Risk of Smoking Relapse Across Different Nicotine Replacement Therapy Formulations.

Clin Pharmacol Ther 2021 02 19;109(2):416-423. Epub 2020 Sep 19.

Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.

Smoking increases the risk of cancer and other diseases, causing an estimated 7 million deaths per year. Nicotine replacement therapy (NRT) reduces craving for smoking, therefore, increasing an individual's probability to remain abstinent. In this work, we for the first time quantitatively described the relationship between craving and smoking abstinence, using retrospectively collected data from 19 studies, including 3 NRT formulations (inhaler, mouth spray, and patch) and a combination of inhaler and patch. Smokers motivated to quit were included in the NRT or placebo arms. Integrated craving (i.e., craving over a period of time) was assessed with 4-category, 5-category, or 100-mm visual analogue scale. The bounded integer model was used to assess latent craving from all scales. A time-to-event model linked predicted integrated craving to the hazard of smoking relapse. Available data included 9,323 adult subjects, observed for 3 weeks up to 2 years. At the study end, 9% (11% for NRT and 5% for placebo), on average, remained abstinent according to the protocol definition. A Gompertz-Makeham hazard best described the data, with a hazard of smoking relapse decreasing over time. Latent integrated craving was positively related to the hazard of smoking relapse, through a sigmoidal maximum effect function. For the same craving, being on NRT was found to reduce the hazard of relapse by an additional 30% compared with placebo. This work confirmed that low craving is associated with a high probability of remaining smoking abstinent and that NRT, in addition to reducing craving, increases the probability of remaining smoking abstinent.
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http://dx.doi.org/10.1002/cpt.2000DOI Listing
February 2021

PKPD Modeling and Dosing Considerations in Advanced Ovarian Cancer Patients Treated with Cisplatin-Based Intraoperative Intraperitoneal Chemotherapy.

AAPS J 2020 07 24;22(5):96. Epub 2020 Jul 24.

Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.

Intraperitoneal chemoperfusion (IPEC) of cisplatin is a popular treatment for advanced ovarian cancer, typically under hyperthermia (HIPEC). The use of cisplatin under (H)IPEC is off-label, and the role of hyperthermia is unknown. The aim of this study was to characterize the pharmacokinetic/pharmacodynamic (PKPD) properties of cisplatin under (H)IPEC and to predict the optimal treatment regimen. Using a randomized design, data on intact cisplatin perfusate and plasma concentrations, leukocyte counts-a hematotoxicity marker-and serum creatinine-a nephrotoxicity marker-were collected from 50 patients treated with a combination of cytoreductive surgery (CRS) and either normothermic or hyperthermic IPEC of cisplatin dosed at 75, 100, and 120 mg/m. The non-linear mixed effects modeling technique was used to construct the PKPD models. The PK of intact cisplatin was characterized by a two-compartment model. A semi-physiological myelosuppression model for the leukopenia was modified to account for the CRS-induced leukocytosis and the residual myelosuppression effect of neoadjuvant chemotherapy. The incidence and severity of nephrotoxicity were described by a discrete-time Markov model. Hyperthermia increased the absorption rate of cisplatin by 16.3% but did not show a clinically relevant impact on the investigated toxicities compared with normothermia. Leukopenia was not severe, but nephrotoxicity can become severe or life-threatening and was affected by the dose and IPEC duration. The model predicted that nephrotoxicity is minimal at a cisplatin dose of 75 mg/m with an IPEC duration of 1-2 h and an 1-h duration is favored for doses between 100 and 120 mg/m. Graphical abstract.
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http://dx.doi.org/10.1208/s12248-020-00489-2DOI Listing
July 2020

Physiologically based pharmacokinetic modelling of lisinopril in children: A case story of angiotensin converting enzyme inhibitors.

Br J Clin Pharmacol 2021 03 3;87(3):1203-1214. Epub 2020 Aug 3.

Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.

Aims: Lisinopril is an angiotensin converting enzyme inhibitor to treat hypertension. It shows complex pharmacokinetics (PK), and its PK behaviour in paediatric populations is not well characterized. The aim of this study was to develop a physiologically based PK (PBPK) model for lisinopril to describe the drug's PK in children.

Methods: The PBPK model development was performed in a step-wise manner. An adult model was initially developed to characterize lisinopril's disposition and absorption and verified using literature data. Subsequently, the adult PBPK model was extrapolated to the paediatric population (0.5-18 years old) by accounting for age-dependent physiological and anatomical changes. Model performance was evaluated by comparing the PK profiles and drug exposures of observed vs predicted data.

Results: The disposition of lisinopril was well described by a minimal PBPK model-an effective strategy to capture the biphasic elimination of the drug. The absorption of lisinopril was described by the intestinal peptide transporter-mediated uptake. The adult model adequately described the literature data with predictions within a twofold range of clinical observations. Good model predictivity was also observed in children older than 6 years of age. The model overpredicted the drug exposure in children under 6 years, probably due to not incorporating the actual, unknown ontogeny of the intestinal peptide transporter.

Conclusions: The PBPK model predicted the PK of lisinopril in adults and children above 6 years of age well. Model refinement in children under 6 years warrants future informative ontogeny data of the intestinal peptide transporter.
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http://dx.doi.org/10.1111/bcp.14492DOI Listing
March 2021

Pediatric Pharmacology of Desmopressin in Children with Enuresis: A Comprehensive Review.

Paediatr Drugs 2020 Aug;22(4):369-383

Department of Pediatric Nephrology, Faculty of Medicine and Health Sciences, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium.

Desmopressin is a synthetic analogue of the natural antidiuretic hormone arginine vasopressin. Over the years, it has been clinically used to manage nocturnal polyuria in children with enuresis. Various pharmaceutical formulations of desmopressin have been commercialized for this indication-nasal spray, nasal drops, oral tablet and oral lyophilizate. Despite the fact that desmopressin is a frequently prescribed drug in children, its use and posology is based on limited pediatric data. This review provides an overview of the current pediatric pharmacological data related to the different desmopressin formulations, including their pharmacokinetics, pharmacodynamics and adverse events. Regarding the pharmacokinetics, a profound food effect on the oral bioavailability was demonstrated as well as different plasma concentration-time profiles (double absorption peak) of the desmopressin lyophilizate between adults and children. Literature about maturational differences in distribution, metabolism and excretion of desmopressin is rather limited. Regarding the pharmacodynamics, formulation/dose/food effect and predictors of response were evaluated. The lyophilizate is the preferred formulation, but the claimed bioequivalence in adults (200 µg tablet and 120 µg lyophilizate), could not be readily extrapolated to children. Prescribing the standard flat-dose regimen to the entire pediatric population might be insufficient to attain response to desmopressin treatment, whereby dosing schemes based on age and weight were proposed. Moreover, response to desmopressin is variable, whereby complete-, partial- and non-responders are reported. Different reasons were enumerated that might explain the difference in response rate to desmopressin observed: different pathophysiological mechanisms, bladder capacity and other predictive factors (i.e. breast feeding, familial history, compliance, sex, etc.). Also, the relapse rate of desmopressin treatment was high, rendering it necessary to use a pragmatic approach for the treatment of enuresis, whereby careful consideration of the position of desmopressin within this treatment is required. Regarding the safety of the different desmopressin formulations, the use of desmopressin was generally considered safe, but additional measures should be taken to prevent severe hyponatremia. To conclude the review, to date, major knowledge gaps in pediatric pharmacological aspects of the different desmopressin formulations still remain. Additional information should be collected about the clinical relevance of the double absorption peak, the food effect, the bioequivalence/therapeutic equivalence, the pediatric adapted dosing regimens, the study endpoints and the difference between performing studies at daytime or at nighttime. To fill in these gaps, additional well designed pharmacokinetic and pharmacodynamic studies in children should be performed.
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http://dx.doi.org/10.1007/s40272-020-00401-7DOI Listing
August 2020

High-dose etoposide formulations do not saturate intestinal P-glycoprotein: Development, stability, and pharmacokinetics in Sprague-Dawley rats.

Int J Pharm 2020 Jun 4;583:119399. Epub 2020 May 4.

Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark. Electronic address:

It has been suggested that oral absorption of low-permeable P-glycoprotein (P-gp) substrates can be increased through saturation of P-gp. For BCS class IV drug substances, saturating P-gp is challenging due to low aqueous solubility. The present study investigated if the BCS IV drug substance etoposide could be solubilized to a concentration saturating P-gp after oral administration. A formulation consisting of 10% (w/v) of pluronic® F-127 and polyvinylpyrrolidone/vinyl acetate (PVP/VA), and 57% (v/v) ethanol enhanced etoposide's solubility approximately 100 times (16 mg mL) compared to its aqueous solubility. In vitro, this formulation was stable upon dilution in simulated intestinal fluid. In male Sprague-Dawley rats, oral administration of increasing solubilized etoposide doses using the formulation matrix increased the AUC of etoposide dose-proportionally but resulted in a lower absolute oral bioavailability (F) and rate of absorption as compared to control. At the highest investigated dose (100 mg kg), AUC and C were significantly increased by 2.9- and 1.4-fold, respectively, compared to control dosed at 20 mg kg. A single oral dose of 20 mg kg zosuquidar followed by 20 mg kg oral etoposide increased F 8.6-fold. In conclusion, a stable formulation with improved etoposide solubility was developed, yet the formulation did not result in increased oral bioavailability of etoposide.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119399DOI Listing
June 2020

Bioinspired hyaluronic acid and polyarginine nanoparticles for DACHPt delivery.

Eur J Pharm Biopharm 2020 May 28;150:1-13. Epub 2020 Feb 28.

Micro et Nanomédecines Translationnelles, MINT, UNIV Angers, UMR INSERM 1066, UMR CNRS 6021, Angers, France; CHU Angers, Département Pharmacie, 4 rue Larrey, 49933 Angers cedex 9, France. Electronic address:

This work here presented provides insights over a novel biodegradable polymeric nanosystem made of hyaluronic acid and polyarginine for diaminocyclohexane-platinum (DACHPt) encapsulation. Using mild conditions based on ionic gelation technique, monodispersed blank and DACHPt-loaded nanoparticles (NP) with a size of around 200 nm and negative ζ potential (-35 mV) were obtained. The freeze-drying process was optimized to improve the stability and shelf-life of the developed nanoparticles. After reconstitution, nanoparticles maintained their size showing an association efficiency of around 70% and a high drug loading (8%). In vitro cytotoxicity studies revealed that DACHPt-loaded nanoparticles had a superior anticancer activity compared with oxaliplatin solution. The IC50 was reduced by a factor of two in HT-29 cells (IC50 39 µM vs 74 µM, respectively), and resulted almost 1.3 fold lower in B6KPC3 cells (18 µM vs 23 µM respectively). Whereas toxic effects of both drug and DACHPt-loaded nanoparticles were comparable in the A549 cell line (IC50 11 µM vs 12 µM). DACHPt-loaded nanoparticles were also able to modulate immunogenic cell death (ICD) in vitro. After incubation with B6KPC3 cells, an increase in HMGB1 (high-mobility group box 1) production associated with ATP release occurred. Then, in vivo pharmacokinetic studies were performed after intravenous injection (IV) of DACHPt-loaded nanoparticles and oxaliplatin solution in healthy mice (35.9 µg of platinum equivalent/mouse). An AUC six times higher (24 h * mg/L) than the value obtained following the administration of oxaliplatin solution (3.76 h * mg/L) was found. C was almost five times higher than the control (11.4 mg/L for NP vs 2.48 mg/L). Moreover, the reduction in volume of distribution and clearance clearly indicated a more limited tissue distribution. A simulated repeated IV regimen was performed in silico and showed no accumulation of platinum from the nanoparticles. Overall, the proposed approach discloses a novel nano-oncological treatment based on platinum derivative with improved antitumor activity in vitro and in vivo stability as compared to the free drug.
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http://dx.doi.org/10.1016/j.ejpb.2020.02.008DOI Listing
May 2020

Modelling and validation of the antifungal activity of DL-3-phenyllactic acid and acetic acid on bread spoilage moulds.

Food Microbiol 2020 Jun 19;88:103407. Epub 2019 Dec 19.

Laboratory of Applied Mycology (MYCOLAB), Department of Food Technology, Safety and Health, Faculty of Bioscience Engineering, Ghent University, Valentin Vaerwyckweg 1, 9000 Ghent, Belgium; Research Unit of Food Microbiology and Food Preservation, Department of Food Technology, Safety and Health, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.

Most interesting antifungal compounds from sourdough fermentation are acetic acid (AA) and DL-3-phenyllactic acid (PLA). Although the role of pH on the activity of organic acids has been established long time ago, no information is available on the importance of undissociated acid (HA) expressed on the aqueous phase of bread (C, mmole/L). Mostly, concentrations (mmole/kg dough or bread, C) and pH are given side by side. The aim of this study was to show the importance of C for adequate comparison of in-vitro growth data with bread shelf-life. Growth of Penicillium paneum and Aspergillus niger was recorded using a micro-dilution assay with optical density measurements. Parameters such as a (0.94-0.98), pH (4.6-6.0), temperature (10-30 °C), time (0-8 days) and C (0-300 mM) were varied. Growth/no-growth models were developed and shelf-life tests of par-baked breads of 45 days at 20 °C were conducted. The modelled inhibitory concentrations of undissociated acid were comparable with the shelf-life test of bread: (PLA) 50 versus 39-84 mmol/L; (AA) 110 versus 110-169 mmol/L. This study showed the applicability of G/NG models for bread shelf-life prediction and highlighted the importance of CHA. Moreover, it was found that naturally present PLA in sourdough bread is insufficient to increase bread shelf-life.
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http://dx.doi.org/10.1016/j.fm.2019.103407DOI Listing
June 2020

Effect of storage temperature, water activity, oxygen headspace concentration and pasteurization intensity on the time to growth of Aspergillus fischerianus (teleomorph Neosartorya fischeri).

Food Microbiol 2020 Jun 19;88:103406. Epub 2019 Dec 19.

Research Unit Food Microbiology and Food Preservation, Department of Food Technology, Safety and Health, Member of Food2Know, Faculty of Bioscience Engineering, Ghent University, Belgium.

This study aims to assess, by means of a full factorial design, the effect of storage temperature (10-30 °C), water activity (a, 0.87-0.89), headspace oxygen (O) level (0.15-0.80%) and pasteurization intensity (95 °C-105 °C/15sec) on the time to visible growth (t, days) of Aspergillus fischerianus on acidified Potato Dextrose Agar (aPDA, pH 3.6) for up to 90 days. Moreover, in order to validate the results obtained on aPDA, 12 conditions were selected and assessed in concentrate strawberry-puree based medium. Overall, storage temperature had the greatest effect on the t of A. fischerianus on the evaluated conditions. At 10 °C, no visible growth was observed over the 90 day incubation period, whilst visible mycelia (diameter ≥ 2 mm) were present in 37% and 89% of the conditions at 22 °C and 30 °C, respectively. Pasteurization intensity had only a minor effect on the outgrowth of A. fischerianus. Growth inhibition was observed when a was reduced to 0.870 ± 0.005 in combination with very low headspace O levels (0.15% ± 0.10) in both, aPDA and concentrate strawberry-based media, regardless of the incubation temperature and heat pasteurization intensity. Overall, longer t's were required when incubation was done at 22 °C compared to 30 °C. Ultimately, the effect of O (0.05 and 1%) and pasteurization intensity (95 °C and 105 °C/15sec) were evaluated on totally 22 fruit purees (un-concentrates and concentrates) over a 60 day storage period. None of the concentrates purees (a ≤0.860) evaluated in this study supported the growth of A. fischerianus. On the other hand, A. fischerianus growth inhibition was only observed when the O levels were ≤0.05% on un-concentrates fruit purees (a ≥ 0.980) stored at ambient temperature (22 °C). Combination of multiple stress factors effectively inhibited growth of A. fischerianus. In general, storage of fruit purees at low temperatures (<10 °C) or distribution in the form of concentrates can be considered as important strategies to prevent the growth of spoilage associated heat-resistant moulds.
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http://dx.doi.org/10.1016/j.fm.2019.103406DOI Listing
June 2020

Corrigendum to "Physiologically-Based Pharmacokinetic model for Ciprofloxacin in children with complicated Urinary Tract Infection" [European Journal of Pharmaceutical Sciences 128 (2019) 171-179].

Eur J Pharm Sci 2020 02 20;143:105182. Epub 2019 Dec 20.

Ghent University, Faculty of Pharmaceutical Sciences, Laboratory of Medical Biochemistry and Clinical Analysis, Ghent, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.ejps.2019.105182DOI Listing
February 2020

Preclinical evaluation of local prolonged release of paclitaxel from gelatin microspheres for the prevention of recurrence of peritoneal carcinomatosis in advanced ovarian cancer.

Sci Rep 2019 10 16;9(1):14881. Epub 2019 Oct 16.

Laboratory of Pharmaceutical Technology, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.

Patients with advanced ovarian cancer develop recurrence despite initial treatment response to standard treatment of surgery and intravenous/intraperitoneal (IP) chemotherapy, partly due to a limited peritoneal exposure time of chemotherapeutics. Paclitaxel-loaded genipin-crosslinked gelatin microspheres (PTX-GP-MS) are evaluated for the treatment of microscopic peritoneal carcinomatosis and prevention of recurrent disease. The highest drug load (39.2 µg PTX/mg MS) was obtained by immersion of GP-MS in aqueous PTX nanosuspension (PTX-GP-MS) instead of ethanolic PTX solution (PTX-GP-MS). PTX release from PTX-GP-MS was prolonged. PTX-GP-MS displayed a more controlled release compared to a biphasic release from PTX-GP-MS. Anticancer efficacy of IP PTX-GP-MS (PTX-GP-MS, D = 7.5 mg PTX/kg; PTX-GP-MS D = 7.5 and 35 mg PTX/kg), IP nanoparticular albumin-bound PTX (D = 35 mg PTX/kg) and controls (0.9% NaCl, blank GP-MS) was evaluated in a microscopic peritoneal carcinomatosis xenograft mouse model. PTX-GP-MS showed superior anticancer efficacy with significant increased survival time, decreased peritoneal carcinomatosis index score and ascites incidence. However, prolonged PTX release over 14 days from PTX-GP-MS caused drug-related toxicity in 27% of high-dosed PTX-GP-MS-treated mice. Dose simulations for PTX-GP-MS demonstrated an optimal survival without drug-induced toxicity in a range of 7.5-15 mg PTX/kg. Low-dosed PTX-GP-MS can be a promising IP drug delivery system to prevent recurrent ovarian cancer.
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http://dx.doi.org/10.1038/s41598-019-51419-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795903PMC
October 2019

Relating Nicotine Plasma Concentration to Momentary Craving Across Four Nicotine Replacement Therapy Formulations.

Clin Pharmacol Ther 2020 01 3;107(1):238-245. Epub 2019 Sep 3.

Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.

Tobacco use is a major health concern. To assist smoking cessation, nicotine replacement therapy (NRT) is used to reduce nicotine craving. We quantitatively described the relationship between nicotine pharmacokinetics (PKs) from NRTs and momentary craving, linking two different pharmacodynamic (PD) scales for measuring craving. The dataset comprised retrospective data from 17 clinical studies and included 1,077 adult smokers with 39,802 craving observations from four formulations: lozenge, gum, mouth spray, and patch. A PK/PD model was developed that linked individual predicted nicotine concentrations with the categorical and visual analogue PD scales through a joint bounded integer model. A maximum effect model, accounting for acute tolerance development, successfully related nicotine concentrations to momentary craving. Results showed that all formulations were similarly effective in reducing craving, albeit with a fourfold lower potency for the patch. Women were found to have a higher maximal effect of nicotine to reduce craving, compared with men.
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http://dx.doi.org/10.1002/cpt.1595DOI Listing
January 2020

An Integrated Paediatric Population PK/PD Analysis of dDAVP: How do PK Differences Translate to Clinical Outcomes?

Clin Pharmacokinet 2020 01;59(1):81-96

Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.

Introduction: The bioequivalence of two formulations of desmopressin (dDAVP), a vasopressin analogue prescribed for nocturnal enuresis treatment in children, has been previously confirmed in adults but not in children. In this study, we aimed to study the pharmacokinetics (PK) and pharmacodynamics (PD) of these two formulations, in both fasted and fed children, including patients younger than 6 years of age.

Methods: Previously published data from one PK study and one PK/PD study in children aged between 6 and 16 years were combined with a new PK/PD study in children aged between 6 months and 8 years, and analysed using population PK/PD modelling. Simulations were performed to further explore the relative bioavailability of both formulations and evaluate current dosing strategies.

Results: The complex absorption behaviour of the lyophilizate was modelled using a double input, linked to a one-compartmental model with linear elimination and an indirect response model linking dDAVP concentration to produced urine volume and osmolality. The final model described the observed data well and elucidated the complexity of bioequivalence and therapeutic equivalence of the two formulations. Simulations showed that current dosing regimens using a fixed dose of lyophilizate 120 μg is not adequate for children, assuming children to be in the fed state when taking dDAVP. A new age- and weight-based dosing regimen was suggested and was shown to lead to improved, better tailored effects.

Conclusions: Bioequivalence and therapeutic equivalence data of two formulations of the same drug in adults cannot be readily extrapolated to children. This study shows the importance of well-designed paediatric clinical trials and how they can be analysed using mixed-effects modelling to make clinically relevant inferences. A follow-up clinical trial testing the proposed dDAVP dosing regimen should be performed.

Clinical Trial Registration: This trial has been registered at www.clinicaltrials.gov (identifier NCT02584231; EudraCT 2014-005200-13).
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http://dx.doi.org/10.1007/s40262-019-00798-6DOI Listing
January 2020

Model-based analysis of treatment effects of paclitaxel microspheres in a microscopic peritoneal carcinomatosis model in mice.

Pharm Res 2019 Jun 24;36(9):127. Epub 2019 Jun 24.

Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.

Purpose: Paclitaxel (PTX)-loaded genipin-crosslinked gelatin microspheres (GP-MS) are a prolonged IP delivery system under development for the treatment of peritoneal minimal residual disease (pMRD). Here, we show the use of a pharmacokinetic-pharmacodynamic (PKPD) modelling approach to inform the formulation development of PTX-GP-MS in a mice pMRD model.

Methods: PTX blood concentrations and survival data were obtained in Balb/c Nu mice receiving different single IP doses (7.5 and/or 35 mg/kg) of PTX-ethanolic loaded GP-MS (PTX-GP-MS), PTX-nanosuspension loaded GP-MS (PTX-GP-MS), and immediate release formulation Abraxane®. A population PK model was developed to characterize the PTX blood concentration pattern and to predict PTX concentrations in peritoneum. Afterwards, PKPD relationships between the predicted peritoneal or blood concentrations and survival were explored using time-to-event modelling.

Results: A PKPD model was developed that simultaneously describes the competing effects of treatment efficacy (driven by peritoneal concentration) and toxicity (driven by blood concentration) of PTX on survival. Clear survival advantages of PTX-GP-MS over PTX-GP-MS and Abraxane® were found. Simulations of different doses of PTX-GP-MS demonstrated that drug-induced toxicity is high at doses between 20 and 35 mg/kg.

Conclusions: The model predicts that the dose range of 7.5-15 mg/kg of PTX-GP-MS provides an optimal balance between efficacy and safety.
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http://dx.doi.org/10.1007/s11095-019-2660-1DOI Listing
June 2019

Growth/no-growth models of in-vitro growth of Penicillium paneum as a function of thyme essential oil, pH, a, temperature.

Food Microbiol 2019 Oct 8;83:9-17. Epub 2019 Apr 8.

Laboratory of Applied Mycology (MYCOLAB), Department of Food Technology, Safety and Health, Faculty of Bioscience Engineering, Ghent University, Valentin Vaerwyckweg 1, 9000 Ghent, Belgium; Research Unit Food Microbiology and Food Preservation, Department of Food Technology, Safety and Health, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.

The aims of this study were (i) screening of antifungal activity of thyme essential oil on Penicillium paneum; (ii) development of growth/no-growth models (G/NG); and (iii) validation of the G/NG models by performing bread baking trials. The screening method was based on the measurement of fungal growth in a semi-solid medium through optical density. The combined influence of a (0.88-0.97), pH (4.8-7.0), temperature (22 and 30 °C), time (0-144 h) and varying concentrations of thyme oil (0-2 μL/mL YES) were assessed. Growth of P. paneum at a 0.88 was significantly reduced compared to a 0.93-0.97. A slight pH effect was observed at a 0.93; growth was delayed at pH 6 compared to pH 4.8. The lowest concentration of thyme oil preventing growth during 144 h of incubation was 1 μL/mL medium. According to the results of the shelf-life test of par-baked bread, fungal growth was inhibited for more than 45 days using 0.3 mL thyme oil/100 g dough. To conclude, this study recognized the potential of using G/NG models to develop better product formulations and to facilitate product innovation.
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http://dx.doi.org/10.1016/j.fm.2019.04.003DOI Listing
October 2019

Population Pharmacokinetic Modeling in the Presence of Missing Time-Dependent Covariates: Impact of Body Weight on Pharmacokinetics of Paracetamol in Neonates.

AAPS J 2019 05 28;21(4):68. Epub 2019 May 28.

Division of Clinical Pharmacology, Children's National Health System, Washington, District of Columbia, USA.

Body weight is the primary covariate in pharmacokinetics of many drugs and dramatically changes during the first weeks of life of neonates. The objective of this study is to determine if missing body weights in preterm and term neonates affect estimates of model parameters and which methods can be used to improve performance of a population pharmacokinetic model of paracetamol. Data for our analysis were obtained from previously published studies on the pharmacokinetics of intravenous paracetamol in neonates. We adopted a population model of body weight change in neonates to implement three previously introduced methods of handling missing covariates based on data imputation, likelihood function modification, and full random effects modeling. All models were implemented in NONMEM 7.4, and population parameters were estimated using the FOCE method. Our major finding was that missing body weights minimally affect population estimates of pharmacokinetic parameters but do affect the covariate relationship parameters, particularly the one describing dependence of clearance on body weight. None of the tested methods changed estimates of between-subject variability nor impacted the predictive performance of the model. Our analysis shows that a modeling approach towards handling missing covariates allows borrowing information gathered in various studies as long as they target the same population. This approach is particularly useful for handling time-dependent missing covariates.
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http://dx.doi.org/10.1208/s12248-019-0331-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820681PMC
May 2019

A Receiver Operating Characteristic Framework for Non-adherence Detection Using Drug Concentration Thresholds-Application to Simulated Risperidone Data in Schizophrenic Patients.

AAPS J 2019 03 14;21(3):40. Epub 2019 Mar 14.

Janssen Research & Development, Quantitative Sciences Consulting, Beerse, Belgium.

Non-adherence to antipsychotic medication is a primary factor in disease relapse in schizophrenic patients. We sought to evaluate if plasma concentrations of the antipsychotic risperidone can be used as a predictor of treatment adherence and to identify the optimal plasma concentration threshold to reliably distinguish between adherent and non-adherent patients. A population pharmacokinetic model was used to simulate plasma risperidone steady-state trough concentrations in 1000 virtual patients, where 60% of the patients were 100% adherent to their medication, while 40% of the patients were non-adherent to their medication. The probability of adherence was assessed by receiver operating characteristic (ROC) analysis on C. The area under the ROC curve (AUC) was used to identify the optimal C threshold. Single vs multiple C at steady state was also evaluated. After a single risperidone C measurement, the AUC (95% CI) was estimated to be 0.71 (0.69-0.72) and the optimal C threshold accounting for the lowest number of adherent and non-adherent misclassifications was estimated to be 11.9 ng/mL. After multiple C measurements, the AUC (95% CI) increased up to 0.85 (0.84-0.87) for three C measurements. The optimal probability threshold to reliably discriminate between adherent and non-adherent patients was estimated to be 0.51. Using this model which is reflective of typical adherence to antipsychotic medication, we found that three consecutive steady-state C measurements are needed for an accurate and precise diagnostic test to discriminate between patients who are adherent or non-adherent to treatment.
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http://dx.doi.org/10.1208/s12248-019-0299-9DOI Listing
March 2019

A semiphysiological population pharmacokinetic model of agomelatine and its metabolites in Chinese healthy volunteers.

Br J Clin Pharmacol 2019 05 21;85(5):1003-1014. Epub 2019 Mar 21.

Research Institute of Drug Metabolism and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.

Aims: Agomelatine is an antidepressant for major depressive disorders. It undergoes extensive first-pass hepatic metabolism and displays irregular absorption profiles and large interindividual variability (IIV) and interoccasion variability of pharmacokinetics. The objective of this study was to characterize the complex pharmacokinetics of agomelatine and its metabolites in healthy subjects.

Methods: Plasma concentration-time data of agomelatine and its metabolites were collected from a 4-period, cross-over bioequivalence study, in which 44 healthy subjects received 25 mg agomelatine tablets orally. Nonlinear mixed effects modelling was used to characterize the pharmacokinetics and variability of agomelatine and its metabolites. Deterministic simulations were carried out to investigate the influence of pathological changes due to liver disease on agomelatine pharmacokinetics.

Results: A semiphysiological pharmacokinetic model with parallel first-order absorption and a well-stirred liver compartment adequately described the data. The estimated IIV and interoccasion variability of the intrinsic clearance of agomelatine were 130.8% and 28.5%, respectively. The IIV of the intrinsic clearance turned out to be the main cause of the variability of area under the curve-based agomelatine exposure. Simulations demonstrated that a reduction in intrinsic clearance or liver blood flow, and an increase in free drug fraction had a rather modest influence on agomelatine exposures (range: -50 to 200%). Portosystemic shunting, however, substantially elevated agomelatine exposure by 12.6-109.1-fold.

Conclusions: A semiphysiological pharmacokinetic model incorporating first-pass hepatic extraction was developed for agomelatine and its main metabolites. The portosystemic shunting associated with liver disease might lead to significant alterations of agomelatine pharmacokinetics, and lead to substantially increased exposure.
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http://dx.doi.org/10.1111/bcp.13902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475681PMC
May 2019

Physiologically based pharmacokinetic (PBPK) modeling and simulation in neonatal drug development: how clinicians can contribute.

Expert Opin Drug Metab Toxicol 2019 Jan 17;15(1):25-34. Epub 2018 Dec 17.

b Department of Development and Regeneration , KU Leuven , Leuven , Belgium.

: Legal initiatives to stimulate neonatal drug development should be accompanied by development of valid research tools. Physiologically based (PB)-pharmacokinetic (PK) modeling and simulation are established tools, accepted by regulatory authorities. Consequently, PBPK holds promise to be a strong research tool to support neonatal drug development. : The currently available PBPK models still have poor predictive performance in neonates. Using an illustrative approach on distinct PK processes of absorption, distribution, metabolism, excretion, and real-world data in neonates, we provide evidence on the need to further refine available PBPK system parameters through generation and integration of new knowledge. This necessitates cross talk between clinicians and modelers to integrate knowledge (PK datasets, system knowledge, maturational physiology) or test and refine PBPK models. : Besides refining these models for 'small molecules', PBPK model development should also be more widely applied for therapeutic proteins and to determine exposure through breastfeeding. Researchers should also be aware that PBPK modeling in combination with clinical observations can also be used to elucidate age-related changes that are almost impossible to study based on or data. This approach has been explored for hepatic biliary excretion, renal tubular activity, and central nervous system exposure.
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http://dx.doi.org/10.1080/17425255.2019.1558205DOI Listing
January 2019

Physiologically-Based Pharmacokinetic model for Ciprofloxacin in children with complicated Urinary Tract Infection.

Eur J Pharm Sci 2019 Feb 29;128:171-179. Epub 2018 Nov 29.

Ghent University, Faculty of Pharmaceutical Sciences, Laboratory of Medical Biochemistry and Clinical Analysis, Ghent, Belgium. Electronic address:

In a recent multicenter population pharmacokinetic study of ciprofloxacin administered to children suffering from complicated urinary tract infection (cUTI), the apparent volume of distribution (V) and total plasma clearance (CL) were decreased by 83.6% and 41.5% respectively, compared to healthy children. To understand these differences, a physiologically-based pharmacokinetic model (PBPK) for ciprofloxacin was developed for cUTI children. First, a PBPK model in adults was developed, modified incorporating age-dependent functions and evaluated with paediatric data generated from a published model in healthy children. Then, the model was then adapted to a cUTI paediatric population according to the degree of renal impairment (KF) affecting renal clearance (CL) and CYP1A2 clearance (CL). Serum and urine samples obtained from 22 cUTI children were used for model evaluation. Lastly, a parameter sensitivity analysis identified the most influential parameters on V and CL. The PBPK model predicted the ciprofloxacin exposure in adults and children, capturing age-related pharmacokinetic changes. Plasma concentrations and fraction excreted unchanged in urine (f) predictions improved in paediatric cUTI patients once CL and CL were corrected by KF. The presented PBPK model for ciprofloxacin demonstrates its adequacy to simulate different dosing scenarios to obtain PK predictions in a healthy population from 3 months old onwards. Model adaptation of CL and CL according to KF explained partially the differences seen in the plasma drug concentrations and f vs time profiles between healthy and cUTI children. Nevertheless, it is necessary to further investigate the disease-related changes in cUTI to improve model predictions.
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http://dx.doi.org/10.1016/j.ejps.2018.11.033DOI Listing
February 2019

PBPK and its Virtual Populations: the Impact of Physiology on Pediatric Pharmacokinetic Predictions of Tramadol.

AAPS J 2018 11 29;21(1). Epub 2018 Nov 29.

Faculty of Pharmaceutical Sciences, Laboratory of Medical Biochemistry and Clinical Analysis, Ottergemsesteenweg 460, 9000, Ghent, Belgium.

In pediatric PBPK models, age-related changes in the body are known to occur. Given the sparsity of and the variability associated with relevant physiological parameters, different PBPK software providers may vary in their system's data. In this work, three commercially available PBPK software packages (PK-Sim®, Simcyp®, and Gastroplus®) were investigated regarding their differences in system-related information, possibly affecting clearance prediction. Three retrograde PBPK clearance models were set up to enable prediction of pediatric tramadol clearance. These models were qualified in terms of total, CYP2D6, and renal clearance in adults. Tramadol pediatric clearance predictions from PBPK were compared with a pooled popPK model covering clearance ranging from neonates to adults. Fold prediction errors were used to evaluate the results. Marked differences in liver clearance prediction between PBPK models were observed. In general, the prediction bias of total clearance was greatest at the youngest population and decreased with age. Regarding CYP2D6 and renal clearance, important differences exist between PBPK software tools. Interestingly, the PBPK model with the shortest CYP2D6 maturation half-life (PK-Sim) agreed best with the in vivo CYP2D6 maturation model. Marked differences in physiological data explain the observed differences in hepatic clearance prediction in early life between the various PBPK software providers tested. Consensus on the most suited pediatric data to use should harmonize and optimize pediatric clearance predictions. Moreover, the combination of bottom-up and top-down approaches, using a convenient probe substrate, has the potential to update system-related parameters in order to better represent pediatric physiology.
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http://dx.doi.org/10.1208/s12248-018-0277-7DOI Listing
November 2018

The use of PBPK modeling across the pediatric age range using propofol as a case.

J Pharmacokinet Pharmacodyn 2018 12 8;45(6):765-785. Epub 2018 Oct 8.

Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.

The project SAFEPEDRUG aims to provide guidelines for drug research in children, based on bottom-up and top-down approaches. Propofol, one of the studied model compounds, was selected because it is extensively metabolized in liver and kidney, with an important role for the glucuronidation pathway. Besides, being a lipophilic molecule, it is distributed into fat tissues, from where it redistributes into the systemic circulation. In the past, both bottom-up (Physiologically based pharmacokinetic, PBPK) and top-down approaches (population pharmacokinetic, popPK) were applied to describe its pharmacokinetics (PK). In this work, a combination of the two was used to check their performance to describe PK in children and neonates (both term and preterm) using propofol as a case compound. First, in vitro data was generated in human liver microsomes and recombinant enzymes and used to develop an adult PBPK model in Simcyp. Activity adjustment factors (AAFs) were calculated to account for differences between in vitro and in vivo enzyme activity. Clinical data were analyzed using a 3-compartment model in NONMEM. These data were used to construct a retrograde PBPK model and for qualification of the PBPK models. Once an accurate in vivo clearance was obtained accounting for the contribution of the different metabolic pathways, the resulting PBPK models were challenged with new data for qualification. After that, the constructed adult PPBK model for propofol was extrapolated to the pediatric population. Both the default built-in and in vivo derived ontogeny functions were used to do so. The models were qualified by comparing their predicted PK parameters to published values, and by comparison of predicted concentration-time profiles to available clinical data. Clearance values were predicted well, especially when compared with values obtained from trials where long-term sampling was applied, whereas volume of distribution was lower compared to the most common popPK model predictions. Concentration-time profiles were predicted well up until and including the preterm neonatal population. In this work, it was thus shown that PBPK can be used to predict the PK up to and including the preterm neonatal population without the use of pediatric in vivo data. This work adds weight to the need for further development of PBPK models, especially regarding distribution modeling and the use of in vivo derived ontogeny functions.
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http://dx.doi.org/10.1007/s10928-018-9607-8DOI Listing
December 2018

A robust simulator for physiologically structured population models.

IEEE/ACM Trans Comput Biol Bioinform 2018 Feb 27. Epub 2018 Feb 27.

A framework to simulate physiologically structured population (PSP) models on high performance compute (HPC) infrastructure is built. Based on the model of a single cell, billions of cells can be simulated in an efficient way, allowing fast simulation of the interaction of an entire organ with other body parts. Trough combination of three state-of-the-art algorithms, the simulation time is decreased with multiple orders of magnitude. First: PSP modelling exploits the fact that a lot of the cells act the same at the same time which results in multiple orders of magnitude speed-up. Secondly, speed-up is achieved by using an unconditionally stable, partial differential equation solver which allows to trade speed for precision and allows big time stepping. Third speed-up is due to the fact that the framework is designed with HPC cluster use in mind. The PSP simulator is mathematically derived to have maximal stability.Simulation results are validated and simulation speed and accuracy are measured.
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http://dx.doi.org/10.1109/TCBB.2018.2810077DOI Listing
February 2018

Results of a Multicenter Population Pharmacokinetic Study of Ciprofloxacin in Children with Complicated Urinary Tract Infection.

Antimicrob Agents Chemother 2018 09 27;62(9). Epub 2018 Aug 27.

Faculty of Pharmaceutical Sciences, Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Ghent, Belgium.

Resistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on developmental pharmacology of ciprofloxacin, the primary aim of this study was to develop a population pharmacokinetic model for ciprofloxacin in children treated for complicated urinary tract infections. Children to whom ciprofloxacin was prescribed, intravenous (10 to 15 mg/kg body weight every 12 h) or (15 to 20 mg/kg every 12 h), were enrolled. One hundred eight serum and 119 urine samples were obtained during 10 intravenous and 13 oral courses of ciprofloxacin in 22 patients (age range, 0.31 to 15.51 years). A one-compartment model best described our data. Fat-free mass and glomerular filtration rate (estimated by a formula using cystatin C and creatinine), standardized for body surface area, were significant covariates for ciprofloxacin clearance. In our population, ciprofloxacin clearance is 0.16 to 0.43 liter/h/kg of body weight, volume of distribution 0.06 to 2.88 liters/kg, and bioavailability 59.6%. All of our patients had a clinical cure of their infection. Based on target attainment simulations across doses, all children reached the pharmacodynamic target for , but on average only 53% did for and 3% for , at the 15-mg/kg oral dose. For treating urinary tract infections caused by , oral doses should be at least 20 mg/kg. Furthermore, in our population, fat-free mass and kidney function should be considered, as they prove to be significant covariates for ciprofloxacin clearance and, hence, exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT02598362.).
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http://dx.doi.org/10.1128/AAC.00517-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125553PMC
September 2018

Relationship between antipsychotic blood levels and treatment failure during the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study.

Schizophr Res 2018 11 24;201:324-328. Epub 2018 May 24.

Neurosciences, Janssen Research & Development, 1800 American Boulevard, Pennington, NJ, 08534, United States.

Objective: Antipsychotic blood levels (ABLs) may help identify patients at risk for treatment failure. Reference ranges (RR) for plasma concentrations of ABLs that account for between-patient variability were developed for risperidone and olanzapine based on population pharmacokinetic models. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) collected clinical outcomes and ABLs, allowing testing of the relationship of ABLs with outcomes.

Methods: ABLs from 694 patients who were randomized to olanzapine or risperidone were compared to the 80% RRs and were assessed as below or within/above the RR. Treatment failure was defined per any of these criteria: (1) emergency room visit for psychiatric reasons, (2) hospitalization for psychiatric reasons, (3) adverse event of completed suicide, suicidal ideation, or suicide attempt, (4) assaultive behavior, (5) arrested or jailed, (6) 2-point increase from baseline in Clinical Global Impression-Severity score, (7) 25% increase in Positive and Negative Syndrome Scale total score. Patients assessed with treatment failure within 100 days of drug concentration measurement were analyzed.

Results: Treatment failure occurred in 126 of 323 patients. The proportion of patients with ABLs below RR was 18.3% (59/323) compared to 10% expected in a fully adherent population. Among the 59 with ABLs below RR, 50.8% had treatment failure (compared to 36.4% for the 264 with ABLs within/above RR). The difference between groups was significant (odds ratio = 1.810; 95% CI = 1.025, 3.197; p = 0.0408).

Conclusions: Analysis of CATIE data showed that ABLs within the context of RRs may identify patients with higher risk of relapse.
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http://dx.doi.org/10.1016/j.schres.2018.05.028DOI Listing
November 2018