Publications by authors named "J Daniel Debord"

118 Publications

Masked Multiplexed Separations to Enhance Duty Cycle for Structures for Lossless Ion Manipulations.

Anal Chem 2021 Apr 2;93(14):5727-5734. Epub 2021 Apr 2.

MOBILion Systems Inc., Chadds Ford, Pennsylvania 19317, United States.

The experimental paradigm of one ion packet release per spectrum severely hinders throughput in broadband ion mobility spectrometry (IMS) systems (e.g., drift tube and traveling wave systems). Ion trapping marginally mitigates this problem, but the duty cycle deficit is amplified when moving to high resolution, long pathlength systems. As a consequence, new multiplexing strategies that maximize throughput while preserving peak fidelity are essential for high-resolution IMS separations [e.g., structures for lossless ion manipulations (SLIMs) and multi-pass technologies]. Currently, broadly applicable deconvolution strategies for Hadamard-based ion multiplexing are limited to a narrow range of modulation sequences and do not fully maximize the ion signal generated during separation across an extended path length. Compared to prior Hadamard deconvolution errors that rely upon peak picking or discrete error classification, the masked deconvolution matrix technique exploits the knowledge that Hadamard transform artifacts are reflected about the central, primary signal [i.e., the true arrival time distribution (ATD)]. By randomly inducing mathematical artifacts, it is possible to identify spectral artifacts simply by their high degree of variability relative to the core ATD. It is important to note that the deweighting approach using the masked deconvolution matrix does not make any assumptions about the underlying transform and is applicable to any multiplexing strategy employing binary sequences. In addition to demonstrating a 100-fold increase in the total number of ions detected, the effective deconvolution of data from 5, 6, 7, and 8-bit pseudo-random sequences expands the utility and efficiency of the SLIM platform.
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http://dx.doi.org/10.1021/acs.analchem.0c04799DOI Listing
April 2021

Mycophenolic Acid Exposure Prediction Using Machine Learning.

Clin Pharmacol Ther 2021 Feb 24. Epub 2021 Feb 24.

Pharmacology and Transplantation, UMR1248, INSERM, Université de Limoges, Limoges, France.

Therapeutic drug monitoring of mycophenolic acid (MPA) based on area under the curve (AUC) is well-established and machine learning (ML) approaches could help to estimate AUC. The aim of this work is to estimate the AUC of MPA in organ transplant patients using extreme gradient boosting (Xgboost R package) ML models. A total of 12,877 MPA AUC from 0 to 12 hours (AUC ) requests from 6,884 patients sent to our Immunosuppressant Bayesian Dose Adjustment expert system (https://abis.chu-limoges.fr) for AUC estimation and dose recommendation based on MPA concentrations measured at least at three sampling times (~ 20 minutes, 1 and 3 hours after dosing) were used to develop two ML models based on two or three concentrations. Data were split into a training set (75%) and a test set (25%) and the Xgboost models in the training set with the lowest root mean squared error (RMSE) in a 10-fold cross-validation experiment were evaluated in the test set and in 4 independent full-pharmacokinetic (PK) datasets from renal or heart transplant recipients. ML models based on two or three concentrations, differences between these concentrations, relative deviations from theoretical times of sampling, presence of a delayed absorption peak, and five covariates (dose, type of transplantation, associated immunosuppressant, age, and time between transplantation and sampling) yielded accurate AUC estimation performances in the test datasets (relative bias < 5% and relative RMSE < 20%) and better performance than MAP Bayesian estimation in the four independent full-PK datasets. The Xgboost ML models described allow accurate estimation of MPA AUC and can be used for routine exposure estimation and dose adjustment and will soon be implemented in a dedicated web interface.
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http://dx.doi.org/10.1002/cpt.2216DOI Listing
February 2021

Tacrolimus Exposure Prediction Using Machine Learning.

Clin Pharmacol Ther 2020 Nov 30. Epub 2020 Nov 30.

University of Limoges, IPPRITT, Limoges, France.

The aim of this work is to estimate the area-under the blood concentration curve of tacrolimus (TAC) following b.i.d. or q.d. dosing in organ transplant patients, using Xgboost machine learning (ML) models. A total of 4,997 and 1,452 TAC interdose area under the curves (AUCs) from patients on b.i.d. and q.d. TAC, sent to our Immunosuppressant Bayesian Dose Adjustment expert system (www.pharmaco.chu-limoges.fr/) for AUC estimation and dose recommendation based on TAC concentrations measured at least at 3 sampling times (predose, ~ 1 and 3 hours after dosing) were used to develop 4 ML models based on 2 or 3 concentrations. For each model, data splitting was performed to obtain a training set (75%) and a test set (25%). The Xgboost models in the training set with the lowest root mean square error (RMSE) in a 10-fold cross-validation experiment were evaluated in the test set and in 6 independent full-pharmacokinetic (PK) datasets from renal, liver, and heart transplant patients. ML models based on two or three concentrations, differences between these concentrations, relative deviations from theoretical times of sampling, and four covariates (dose, type of transplantation, age, and time between transplantation and sampling) yielded excellent AUC estimation performance in the test datasets (relative bias < 5% and relative RMSE < 10%) and better performance than maximum a posteriori Bayesian estimation in the six independent full-PK datasets. The Xgboost ML models described allow accurate estimation of TAC interdose AUC and can be used for routine TAC exposure estimation and dose adjustment. They will soon be implemented in a dedicated web interface.
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http://dx.doi.org/10.1002/cpt.2123DOI Listing
November 2020

Clinical Pharmacokinetics and Bayesian Estimators for the Individual Dose Adjustment of a Generic Formulation of Tacrolimus in Adult Kidney Transplant Recipients.

Clin Pharmacokinet 2020 Nov 24. Epub 2020 Nov 24.

Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, University Hospital of Limoges, CBRS, Limoges, France.

Background: Tacrolimus has a narrow therapeutic range and requires dose adjustment, usually based on the trough blood concentration but preferably on the area under the concentration-time curve over 12 h post-dose (AUC). The single-arm, multicentre, clinical study IMPAKT aimed: (i) to develop, in de novo kidney transplant recipients, pharmacokinetic models and maximum a-posteriori Bayesian estimators for a generic, immediate-release, oral formulation of tacrolimus to estimate tacrolimus AUC at different post-transplant periods using a limited sampling strategy, and considering the CYP3A5*3 polymorphism as a covariate and (ii) to compare the performance of these Bayesian estimators to those previously developed for the original formulation.

Methods: Thirty patients were enrolled and 29 provided nine blood samples over 9 h at day 7 and months 1 and 3 post-transplant. Tacrolimus blood profiles measured with liquid chromatography-tandem mass spectrometry were modelled using one-compartment, double gamma absorption, linear elimination models developed in-house. Different limited sampling strategies of three time-points within 4 h post-dose were tested for the maximum a-posteriori Bayesian estimator of tacrolimus AUC. The models and estimators were validated internally and their performance compared to that of models previously developed for the original formulation.

Results: The concentration-time curves, AUC/dose and trough blood concentration/dose exhibited wide inter-individual variability. The covariate-free pharmacokinetic models developed for the three post-transplant periods closely fitted the individual profiles. Maximum a-posteriori Bayesian estimators based on three different limited sampling strategies and no covariate yielded accurate AUC estimates, including for the five cytochrome P450 3A5 expressers and for the four patients without corticosteroids. The 0-1 h-3 h strategy finally chosen had very low bias (- 4.0 to - 2.5%) and imprecision (root mean square error 5.5-9.2%). The maximum a-posteriori Bayesian estimators previously developed for the reference product fitted the generic profiles with similar performance.

Conclusions: We developed original pharmacokinetic models and accurate maximum a-posteriori Bayesian estimators to estimate patient exposure and adjust the dose of generic tacrolimus, and confirmed that the robust tools previously developed for the original formulation can be applied to this generic.
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http://dx.doi.org/10.1007/s40262-020-00959-yDOI Listing
November 2020

Tacrolimus Bayesian dose adjustment in pediatric renal transplant recipients.

Ther Drug Monit 2020 Oct 30. Epub 2020 Oct 30.

Department of Pharmacology and Toxicology, CHU Limoges, Limoges, France.

Background: Immunosuppressant Bayesian Dose Adjustment (ISBA) is an online expert system that estimates the area under the curve (AUC) of immunosuppressive drugs through pharmacokinetic modelling and Bayesian estimation to propose dose adjustments to reach predefined exposure targets. The ISBA database was retrospectively analyzed to describe tacrolimus pharmacokinetics and exposure, evaluate the efficiency of ISBA dose recommendations, and propose tacrolimus AUC0-12h target ranges for pediatric renal allograft recipients treated with immediate release tacrolimus.

Methods: The database included 1935 tacrolimus dose adjustment requests from 419 patients <19 years old who were treated with immediate-release tacrolimus and followed in 21 French hospitals. The tacrolimus exposure evolution with patient age and post-transplantation time, the correlation between trough tacrolimus concentration (C0) and AUC0-12h at different periods post-transplantation, the efficiency of dose recommendations to avoid underexposure and overexposure and to decrease between-patient AUC variability were investigated.

Results: Tacrolimus AUC showed large between-patient variability (CV%=40%) but moderate within-patient variability (median=24.3% over a three-month time period). Dose-standardized exposure but not the AUC/C0 ratio significantly decreased with time post-transplantation and patient age. We derived AUC0-12h ranges from the consensual C0 ranges using linear regression equations. When the ISBA recommended dose was applied, the AUC distribution was narrower and a significantly higher proportion was within the targets (p<0.0001).

Conclusion: ISBA efficiently reduced tacrolimus under- and overexposure. The AUC0-12h target ranges for pediatric patients derived from the database were similar to those previously reported for adults. Estimating the AUC/C0 ratio could help determine personalized C0 targets.
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http://dx.doi.org/10.1097/FTD.0000000000000828DOI Listing
October 2020

SiGe microelectronic thermoelectric generators with high power and voltage densities.

Nat Commun 2020 Aug 31;11(1):4362. Epub 2020 Aug 31.

Department of Physics, The University of Texas at Dallas, Richardson, TX, 75080, USA.

Microelectronic thermoelectric generators are one potential solution to energizing energy autonomous electronics, such as internet-of-things sensors, that must carry their own power source. However, thermoelectric generators with the mm footprint area necessary for on-chip integration made from high thermoelectric figure-of-merit materials have been unable to produce the voltage and power levels required to run Si electronics using common temperature differences. We present microelectronic thermoelectric generators using SiGe, made by standard Si processing, with high voltage and power generation densities that are comparable to or better than generators using high figure-of-merit materials. These Si-based thermoelectric generators have <1 mm areas and can energize off-the-shelf sensor integrated circuits using temperature differences ≤25 K near room temperature. These generators can be directly integrated with Si circuits and scaled up in area to generate voltages and powers competitive with existing thermoelectric technologies, but in what should be a far more cost-effective manner.
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http://dx.doi.org/10.1038/s41467-020-18122-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458905PMC
August 2020

Fasting Status and Circadian Variation Must be Considered When Performing AUC-based Therapeutic Drug Monitoring of Tacrolimus in Renal Transplant Recipients.

Clin Transl Sci 2020 11 11;13(6):1327-1335. Epub 2020 Jul 11.

Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.

Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC-guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice-daily tacrolimus in a real-life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting-state and under real-life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting-conditions: 45% higher peak-concentration and 20% higher AUC following the morning dose. In the real-life nonfasting setting, the PK-profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting-state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real-life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting-state, whereas flatter PK-profiles and no circadian variation was present in a real-life, nonfasting setting.
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http://dx.doi.org/10.1111/cts.12833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719361PMC
November 2020

Pharmacogenetic-Whole blood and intracellular pharmacokinetic-Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients.

PLoS One 2020 12;15(3):e0230195. Epub 2020 Mar 12.

Rennes 1 University, Rennes University Hospital, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, Rennes, France.

Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation. A non-parametric population pharmacokinetic model was applied to explore TAC pharmacokinetics in blood and PBMC. Concurrently, calcineurin activity was measured in PBMC. Influence of donor and recipient genetic polymorphisms of ABCB1, CYP3A4 and CYP3A5 on TAC exposure was assessed. Recipient ABCB1 polymorphisms 1199G>A could influence TAC whole blood and intracellular exposure (p<0.05). No association was found between CYP3A4 or CYP3A5 genotypes and TAC whole blood or intracellular concentrations. Finally, intra-PBMC calcineurin activity appeared incompletely inhibited by TAC and less than 50% of patients were expected to achieve intracellular IC50 concentration (100 pg/millions of cells) at therapeutic whole blood concentration (i.e.: 4-10 ng/mL). Together, these data suggest that personalized medicine regarding TAC therapy might be optimized by ABCB1 pharmacogenetic biomarkers and by monitoring intracellular concentration whereas the relationship between intracellular TAC exposure and pharmacodynamics biomarkers more specific than calcineurin activity should be further investigated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230195PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067455PMC
June 2020

Population pharmacokinetics and Bayesian estimators for intravenous mycophenolate mofetil in haematopoietic stem cell transplant patients.

Br J Clin Pharmacol 2020 08 28;86(8):1550-1559. Epub 2020 Feb 28.

Department of Pharmacology and Toxicology, CHU Dupuytren, Limoges, France.

Aims: Intravenous mycophenolate mofetil (IV MMF), a prodrug of mycophenolic acid (MPA), is used during nonmyeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease. The aims of this study were to develop population pharmacokinetic models and Bayesian estimators based on limited sampling strategies to allow for individual dose adjustment of intravenous mycophenolate mofetil administered by infusion in haematopoietic stem cell transplant patients.

Methods: Sixty-three MPA concentration-time profiles (median [min-max] = 6 [4-7] samples) were collected from 34 HCT recipients transplanted for 14 (1-45) days and administered IV MMF every 8 hours, concomitantly with cyclosporine. The database was split into development (75%) and validation (25%) datasets. Pharmacokinetic models characterized by a single compartment with first-order elimination, combined with two gamma distributions to describe the transformation of MMF into mycophenolic acid, were developed using in parallel nonparametric (Pmetrics) and parametric (ITSIM) approaches. The performances of the models and the derived Bayesian estimators were evaluated in the validation set.

Results: The best limited sampling strategy led to a bias (min, max), root mean square error between observed and modeled interdose areas under the curve in the validation dataset of -11.72% (-31.08%, 5.00%), 14.9% for ITSIM and -2.21% (-23.40%, 30.01%), 12.4% for Pmetrics with three samples collected at 0.33, 2 and 3 hours post dosing.

Conclusion: Population pharmacokinetic models and Bayesian estimators for IV MMF in HCT have been developed and are now available online (https://pharmaco.chu-limoges.fr) for individual dose adjustment based on the interdose area under the curve.
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http://dx.doi.org/10.1111/bcp.14261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373706PMC
August 2020

Perforated diverticulosis within an inguinal hernia.

Hernia 2019 12 23;23(6):1297-1298. Epub 2019 Aug 23.

Department of Surgery, University of Illinois College of Medicine Peoria, 624 NE Glen Oak, Room 2670, Peoria, IL, 61603, USA.

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http://dx.doi.org/10.1007/s10029-019-02022-7DOI Listing
December 2019

SSI, SSO, SSE, SSOPI: the elusive language of complications in hernia surgery.

Hernia 2018 10 10;22(5):737-738. Epub 2018 Sep 10.

University Hospital Lund, Lund, Sweden.

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http://dx.doi.org/10.1007/s10029-018-1813-1DOI Listing
October 2018

Comment on "Population Pharmacokinetics of Mycophenolic Acid: An Update".

Clin Pharmacokinet 2018 09;57(9):1211-1213

Université Limoges, IPPRITT, 87000, Limoges, France.

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http://dx.doi.org/10.1007/s40262-018-0687-9DOI Listing
September 2018

A Limited Sampling Strategy to Estimate Exposure of Everolimus in Whole Blood and Peripheral Blood Mononuclear Cells in Renal Transplant Recipients Using Population Pharmacokinetic Modeling and Bayesian Estimators.

Clin Pharmacokinet 2018 11;57(11):1459-1469

Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France.

Background And Objective: Intracellular exposure of everolimus may be a better marker of therapeutic effect than trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators based on a limited sampling strategy for estimation of dose interval exposures of everolimus in whole blood and peripheral blood mononuclear cells (PBMCs) in renal transplant recipients.

Methods: Full whole blood and PBMC concentration-time profiles of everolimus were obtained from 12 stable renal transplant recipients on two different occasions, 4 weeks apart. The dataset was treated as 24 individual profiles and split into a development dataset (n = 20) and a validation dataset (n = 4). The pharmacokinetic model was developed using non-parametric modeling and its performances and those of the derived Bayesian estimator were evaluated in the validation set.

Results: A structural two-compartment model with first-order elimination and two absorption phases described by a sum of two gamma distributions were developed. None of the tested covariates (age, sex, albumin, hematocrit, fat-free mass and genetic variants such as CYP3A5*1, ABCB1 haplotype, PPARA*42, PPARA*48, and POR*28) were retained in the final model. A limited sampling schedule of two whole blood samples at 0 and 1.5 h and one PBMC sample at 1.5 h post dose provided accurate estimates of the area under the plasma concentration-time curve (AUC) in comparison with the trapezoidal reference AUC (relative bias ± standard deviation = - 3.9 ± 10.6 and 4.1 ± 12.3% for whole blood and PBMC concentrations, respectively).

Conclusion: The developed model allows simultaneous and accurate prediction of everolimus exposure in whole blood and PBMCs, and supplies a base for a feasible exploration of the relationships between intracellular exposure and therapeutic effects in prospective trials.
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http://dx.doi.org/10.1007/s40262-018-0646-5DOI Listing
November 2018

Pharmacokinetic models to assist the prescriber in choosing the best tacrolimus dose.

Pharmacol Res 2018 04 13;130:316-321. Epub 2018 Feb 13.

Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; School of Pharmacy, University of Oslo, Norway.

Due to a high inter-individual variability in its pharmacokinetics, tacrolimus dose individualization is mandatory. Even though the expert opinion has defined the area under the curve (AUC) as the best marker to use when performing dose adjustment of tacrolimus, most centres only use trough levels. Multiple targets have been proposed for this parameter and physicians rely largely on their personal experience when making a decision about dose adjustment. Several population pharmacokinetics models (POPPK) allowing AUC determination have been developed, but only a few are actually used in routine practice for dose individualization. These POPPK models can also be used to perform Monte Carlo simulations that help to establish different dosing rules or to anticipate the pharmacokinetics of tacrolimus in particular populations, without conducting clinical trials. Various available applications of POPPK models to assist the prescriber in choosing the best tacrolimus dose are discussed in this paper as well as the difficulties in introducing them into routine therapeutic drug monitoring.
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http://dx.doi.org/10.1016/j.phrs.2018.02.016DOI Listing
April 2018

Population Pharmacokinetics and Bayesian Estimators for Refined Dose Adjustment of a New Tacrolimus Formulation in Kidney and Liver Transplant Patients.

Clin Pharmacokinet 2017 12;56(12):1491-1498

Department of Pharmacology and Toxicology, CHU Limoges, Limoges University Hospital, Limoges Cedex, 87042, France.

Background And Objectives: A new once-daily formulation of tacrolimus (Envarsus) has recently been developed, with alleged different pharmacokinetics from previous tacrolimus formulations. The objectives of this study were to develop population pharmacokinetic models and Bayesian estimators based on limited sampling strategies for Envarsus in kidney and liver transplant recipients.

Materials And Methods: Full tacrolimus concentration-time profiles (13 samples) were drawn from 57 liver (113 profiles) and 49 kidney (97 profiles) graft recipients transplanted for at least 6 months and switched from Prograf to Envarsus. The two databases were split into a development (75%) and a validation (25%) dataset. Pharmacokinetic models characterised by a single compartment with first-order elimination and absorption in two phases described by a sum of two gamma distributions were developed using non-parametric (Pmetrics) and parametric (ITSIM) approaches in parallel. The best limited sampling strategy for each patient group was determined using the multiple model optimal algorithm. The performance of the models and derived Bayesian estimators was evaluated in the validation set.

Results: The best limited sampling strategy was 0, 8 and 12 h post-dose, leading to a relative bias ± standard deviation (root-mean-square error) between observed and modelled inter-dose area under the curve in the validation dataset of: 0.32 ± 6.86% (6.87%) for ITSIM and 3.4 ± 13.4% (13.2%) for Pmetrics in kidney transplantation; and 0.89 ± 7.32% (7.38%) for ITSIM and -2.62 ± 8.65% (8.89%) for Pmetrics in liver transplantation.

Conclusion: Population pharmacokinetic models and Bayesian estimators for Envarsus in kidney and liver transplantation were developed and are now available online for area under the curve-based tacrolimus dose adjustment.
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http://dx.doi.org/10.1007/s40262-017-0533-5DOI Listing
December 2017

A Time-Dependent Model Describes Methotrexate Elimination and Supports Dynamic Modification of MRP2/ABCC2 Activity.

Ther Drug Monit 2017 04;39(2):145-156

*Department of Pharmacology and Toxicology, CHU Limoges; †INSERM UMR 850, University of Limoges, Limoges, France; ‡Laboratory of Biochemistry and Molecular Biology, CHU Tours, Tours, France; §Department of Clinical Hematology, CHU Limoges, Limoges; and ¶Department of Clinical Hematology, La Pitié Salpetrière Hospital, APHP, Paris, France.

Background: Multidrug resistance protein-2 encoded by the ABCC2 gene (MRP2/ABCC2), an efflux transporter expressed at the proximal renal tubule, is rate-limiting for urine excretion of coproporphyrin (UCP) isomers I and III, translating in high UCP [I/(I + III)] ratio in MRP2-deficient patients presenting with the Dubin-Johnson Syndrome. MRP2 is also a major contributor to methotrexate (MTX) clearance. As MTX is both a substrate and an inhibitor of MRP2, time course of the concentrations of MTX in blood could induce functional modification of MRP2 over time, which in turn can modify its own elimination rate.

Methods: A 3-parameter time-dependent MTX population pharmacokinetic (PK) model based on a power function accounting for nonlinearity in its clearance was developed using Pmetrics in a first cohort of 41 patients (76 PK profiles) and compared with a previously published 2-compartment model developed with NONMEM and a 3-compartment model developed with ITSIM. In a second cohort (62 patients and 62 PK profiles), the association between the UCP [I/(I + III)] ratio at 3 periods [before MTX administration (P1), at the end of infusion (P2), and at hospital discharge (P3)] and the time-dependent PK parameters of MTX was investigated. Effects of genetic polymorphisms and of coadministered drugs were also studied.

Results: The model developed tightly fitted the data in both cohorts. A significant inverse correlation was found between log (k1) (ie, the rate constant explaining MTX concentration decrease) and the difference in UCP [I/(I + III)] ratio between P3 and P2 (DP3) (β ± SD = -0.025 ± 0.008, P = 0.00443).

Conclusions: Self-inhibition of the MRP2-dependent secretion of MTX is a plausible explanation for the time-dependent PKs of this drug. Additional studies specifically designed to evaluate this hypothesis are required.
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http://dx.doi.org/10.1097/FTD.0000000000000381DOI Listing
April 2017

Lipid specific molecular ion emission as a function of the primary ion characteristics in TOF-SIMS.

J Vac Sci Technol B Nanotechnol Microelectron 2016 Sep 24;34(5):051804. Epub 2016 Aug 24.

Department of Chemistry and Biochemistry, Florida International University , Miami, Florida 33199 and Biomolecular Science Institute, Florida International University , Miami, Florida 33199.

In the present work, the emission characteristics of lipids as a function of the primary ion cluster size and energy were studied using time-of-flight secondary ion mass spectrometry (TOF-SIMS). Characteristic fragmentation patterns for common lipids are described, and changes in secondary ion (SI) yields using various primary ion beams are reported. In particular, emission characteristics were studied for pairs of small polyatomic and nanoparticle primary ion beams (e.g., Bi versus Ar and Au versus Au) based on the secondary ion yield of characteristic fragment and intact molecular ions as a function of the lipid class. Detailed descriptions of the fragmentation patterns are shown for positive and negative mode TOF-SIMS. Results demonstrate that the lipid structure largely dictates the spectral presence of molecular and/or fragment ions in each ionization mode due to the localization of the charge carrier (head group or fatty acid chain). Our results suggest that the larger the energy per atom for small polyatomic projectiles (Bi and Au), the larger the SI yield; in the case of nanoparticle projectiles, the SI increase with primary ion energy (200-500 keV range) for Au and with the decrease of the energy per atom (10-40 eV/atom range) for Ar clusters. The secondary ion yield of the molecular ion of lipids from a single standard or from a mixture of lipids does not significantly change with the primary ion identity in the positive ion mode TOF-SIMS and slightly decreases in the negative ion mode TOF-SIMS.
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http://dx.doi.org/10.1116/1.4961461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001976PMC
September 2016

Modeling of Tacrolimus Exposure in Kidney Transplant According to Posttransplant Time Based on Routine Trough Concentration Data.

Exp Clin Transplant 2016 Aug;14(4):394-400

From the Service de Pharmacologie, Faculté de Médecine, Monastir, Tunisia.

Objectives: The aim of this study was to develop a pharmacokinetics model allowing the description of the evolution of tacrolimus exposure in kidney transplant patients over the first months after transplant, using trough concentrations of routinely collected blood.

Materials And Methods: The authors performed a retrospective analysis of trough concentration data collected from adult kidney transplant recipients (from 2008 to 2013). The total data set was divided into a building data set, used to build the structural model, and a validation data set, used to validate the structural model. (C0 = 133; 26 patients). A pharmacokinetics analysis was carried out by applying a nonparametric adaptive grid approach. The structural model parameters were tacrolimus clearance and volume of distribution.

Results: In patients in the building set group, estimated clearance was 3.6 ± 0.57 L/h and estimated volume of distribution was 9.9 ± 1.14 L. No covariate was significantly associated with tacrolimus clearance or volume of distribution. The model adequately described tacrolimus dose-normalized trough concentration evolution after transplant (the plot of individual model predicted versus observed concentrations resulted in r = 0.84). The prediction performance in the validation group yielded 2.3% mean prediction error and 21.4% root mean squared error.

Conclusions: This model could be highly useful in the optimization of tacrolimus prescription at any posttransplant time in kidney transplant patients.
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August 2016

Increasing Polyaromatic Hydrocarbon (PAH) Molecular Coverage during Fossil Oil Analysis by Combining Gas Chromatography and Atmospheric-Pressure Laser Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS).

Energy Fuels 2016 Jan 14;30(1):196-203. Epub 2015 Dec 14.

Department of Chemistry and Biochemistry, Florida International University, Miami, Florida 33199, United States; Biomolecular Sciences Institute, Florida International University, Miami, Florida 33199, United States.

Thousands of chemically distinct compounds are encountered in fossil oil samples that require rapid screening and accurate identification. In the present paper, we show for the first time, the advantages of gas chromatography (GC) separation in combination with atmospheric-pressure laser ionization (APLI) and ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) for the screening of polyaromatic hydrocarbons (PAHs) in fossil oils. In particular, reference standards of organics in shale oil, petroleum crude oil, and heavy sweet crude oil were characterized by GC-APLI-FT-ICR MS and APLI-FT-ICR MS. Results showed that, while APLI increases the ionization efficiency of PAHs, when compared to other ionization sources, the complexity of the fossil oils reduces the probability of ionizing lower-concentration compounds during direct infusion. When gas chromatography precedes APLI-FT-ICR MS, an increase (more than 2-fold) in the ionization efficiency and an increase in the signal-to-noise ratio of lower-concentration fractions are observed, giving better molecular coverage in the / 100-450 range. That is, the use of GC prior to APLI-FT-ICR MS resulted in higher molecular coverage, higher sensitivity, and the ability to separate and characterize molecular isomers, while maintaining the ultrahigh resolution and mass accuracy of the FT-ICR MS separation.
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http://dx.doi.org/10.1021/acs.energyfuels.5b02292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869715PMC
January 2016

Lifetimes and stabilities of familiar explosive molecular adduct complexes during ion mobility measurements.

Analyst 2015 Aug;140(16):5692-9

Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA.

Trapped ion mobility spectrometry coupled to mass spectrometry (TIMS-MS) was utilized for the separation and identification of familiar explosives in complex mixtures. For the first time, molecular adduct complex lifetimes, relative stability, binding energies and candidate structures are reported for familiar explosives. Experimental and theoretical results showed that the adduct size and reactivity, complex binding energy and the explosive structure tailor the stability of the molecular adduct complex. The flexibility of TIMS to adapt the mobility separation as a function of the molecular adduct complex stability (i.e., short or long IMS experiments/low or high IMS resolution) permits targeted measurements of explosives in complex mixtures with high confidence levels.
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http://dx.doi.org/10.1039/c5an00527bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516649PMC
August 2015

Fast Screening of Polycyclic Aromatic Hydrocarbons using Trapped Ion Mobility Spectrometry - Mass Spectrometry.

Anal Methods 2014 Dec;6(23):9328-9332

Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA.

In the present paper, we showed the advantages of trapped ion mobility spectrometry coupled too mass spectrometry (TIMS-MS) combined with theoretical calculations for fast identification (millisecond timescale) of polycyclic aromatic hydrocarbons (PAH) compounds from complex mixtures. Accurate PAH collision cross sections (CCS, in nitrogen as a bath gas) are reported for the most commonly encountered PAH compounds and the ability to separate PAH geometric isomers is shown for three isobaric pairs with mobility resolution exceeding 150 (3-5 times higher than conventional IMS devices). Theoretical candidate structures (optimized at the DFT/B3LYP level) are proposed for the most commonly encountered PAH compounds showing good agreement with the experimental CCS values (<5%). The potential of TIMS-MS for the separation and identification of PAH compounds from complex mixtures without the need of lengthy pre-separation steps is illustrated for the case of a complex soil mixture.
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http://dx.doi.org/10.1039/C4AY01655FDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280789PMC
December 2014

A label-free aptamer-fluorophore assembly for rapid and specific detection of cocaine in biofluids.

Anal Chem 2014 Nov 4;86(22):11100-6. Epub 2014 Nov 4.

Department of Chemistry and Biochemistry, Florida International University , 11200 SW Eighth Street, Miami, Florida 33199, United States.

We report a rapid and specific aptamer-based method for one-step cocaine detection with minimal reagent requirements. The feasibility of aptamer-based detection has been demonstrated with sensors that operate via target-induced conformational change mechanisms, but these have generally exhibited limited target sensitivity. We have discovered that the cocaine-binding aptamer MNS-4.1 can also bind the fluorescent molecule 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND) and thereby quench its fluorescence. We subsequently introduced sequence changes into MNS-4.1 to engineer a new cocaine-binding aptamer (38-GC) that exhibits higher affinity to both ligands, with reduced background signal and increased signal gain. Using this aptamer, we have developed a new sensor platform that relies on the cocaine-mediated displacement of ATMND from 38-GC as a result of competitive binding. We demonstrate that our sensor can detect cocaine within seconds at concentrations as low as 200 nM, which is 50-fold lower than existing assays based on target-induced conformational change. More importantly, our assay achieves successful cocaine detection in body fluids, with a limit of detection of 10.4, 18.4, and 36 μM in undiluted saliva, urine, and serum samples, respectively.
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http://dx.doi.org/10.1021/ac503360nDOI Listing
November 2014

Secondary ion mass spectrometry imaging of Dictyostelium discoideum aggregation streams.

PLoS One 2014 9;9(6):e99319. Epub 2014 Jun 9.

Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, United States of America.

High resolution imaging mass spectrometry could become a valuable tool for cell and developmental biology, but both, high spatial and mass spectral resolution are needed to enable this. In this report, we employed Bi3 bombardment time-of-flight (Bi3 ToF-SIMS) and C60 bombardment Fourier transform ion cyclotron resonance secondary ion mass spectrometry (C60 FTICR-SIMS) to image Dictyostelium discoideum aggregation streams. Nearly 300 lipid species were identified from the aggregation streams. High resolution mass spectrometry imaging (FTICR-SIMS) enabled the generation of multiple molecular ion maps at the nominal mass level and provided good coverage for fatty acyls, prenol lipids, and sterol lipids. The comparison of Bi3 ToF-SIMS and C60 FTICR-SIMS suggested that while the first provides fast, high spatial resolution molecular ion images, the chemical complexity of biological samples warrants the use of high resolution analyzers for accurate ion identification.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099319PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049834PMC
October 2015

Pharmacokinetic tools for the dose adjustment of ciclosporin in haematopoietic stem cell transplant patients.

Br J Clin Pharmacol 2014 Oct;78(4):836-46

Service de Pharmacologie, Toxicologie et Pharmacovigilance, CHU Limoges, Limoges, France; INSERM UMR-S850, Univ Limoges, Limoges, France.

Aims: Ciclosporin A (CsA) is used in the prophylaxis and treatment of acute and chronic graft vs. host disease after haematopoietic stem cell (HSCT) transplantation. Our objective was to build and compare three independent Bayesian estimators of CsA area under the curve (AUC) using a limited sampling strategy (LSS), to assist in dose adjustment.

Methods: The Bayesian estimators were developed using in parallel: two independent parametric modelling approaches (nonmem® and iterative two stage (ITS) Bayesian modelling) and the non-parametric adaptive grid method (Pmetrics®). Seventy-two full pharmacokinetic profiles (at pre-dose and 0.33, 0.66, 1, 2, 3, 4, 6, 8 and 12h after dosing) collected from 40 HSCT patients given CsA were used to build the pharmacokinetic models, while 15 other profiles (n = 7) were kept for validation. For each Bayesian estimator, AUCs estimated using the full profiles were compared with AUCs estimated using three samples.

Results: The pharmacokinetic profiles were well fitted using a two compartment model with first order elimination, combined with a gamma function for the absorption phase with ITS and Pmetrics or an Erlang distribution with nonmem. The derived Bayesian estimators based on a C0-C1 h-C4 h sampling schedule (best LSS) accurately estimated CsA AUC(0,12 h) in the validation group (n = 15; nonmem: bias (mean ± SD)/RMSE 2.05% ± 13.31%/13.02%; ITS: 4.61% ± 10.56%/11.20%; Pmetrics: 0.30% ± 10.12%/10.47%). The dose chosen confronting the three results led to a pertinent dose proposal.

Conclusions: The developed Bayesian estimators were all able to predict ciclosporin AUC(0,12 h) in HSCT patients using only three blood with minimal bias and may be combined to increase the reliability of CsA dose adjustment in routine.
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http://dx.doi.org/10.1111/bcp.12394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239977PMC
October 2014

Ion dynamics in a trapped ion mobility spectrometer.

Analyst 2014 Apr;139(8):1913-21

Department of Chemistry and Biochemistry, Florida International University, Miami, USA.

In the present paper, theoretical simulations and experimental observations are used to describe the ion dynamics in a trapped ion mobility spectrometer. In particular, the ion motion, ion transmission and mobility separation are discussed as a function of the bath gas velocity, radial confinement, analysis time and speed. Mobility analysis and calibration procedure are reported for the case of sphere-like molecules for positive and negative ion modes. Results showed that a maximal mobility resolution can be achieved by optimizing the gas velocity, radial confinement (RF amplitude) and ramp speed (voltage range and ramp time). The mobility resolution scales with the electric field and gas velocity and R = 100-250 can be routinely obtained at room temperature.
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http://dx.doi.org/10.1039/c3an02174bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144823PMC
April 2014

Massive panniculectomy results in improved functional outcome.

Am J Surg 2014 Mar 19;207(3):441-4; discussion 444. Epub 2013 Dec 19.

Department of General Surgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.

Background: Panniculus morbidus is a large abdominal apron found in morbidly obese patients. This condition creates a vicious cycle of weight gain and functional incapacity. Our study assessed the functional improvement in patients undergoing massive panniculectomy.

Methods: A retrospective review of panniculectomies performed from 1994 to 2012 was conducted. Twenty-seven patients with resections >20 lbs were selected. Data on demographics, operative details, complications, and pre- and postoperative functional capacity (using the Steinbrocker Functional Classification) were collected.

Results: The preoperative mean body mass index was 58 kg/m(2), with a mean resection weight of 33 lbs. The overall complication rate was 74%. A statistically significant improvement in functional capacity (preop mean 3.7 vs postop mean 2.0; P < .0001) was identified.

Conclusions: Panniculus morbidus is a functionally debilitating condition and massive panniculectomy is often the only treatment available. Our data suggest that massive panniculectomy is a viable option for patients functionally incapacitated by panniculus morbidus.
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http://dx.doi.org/10.1016/j.amjsurg.2013.09.010DOI Listing
March 2014

Surface characterization of biological nanodomains using NP-ToF-SIMS.

Surf Interface Anal 2013 Jan;45(1)

Department of Chemistry, Texas A&M University, College Station, TX 77843-3144, USA.

This paper describes the application of nanoparticle bombardment with time-of-flight secondary ion mass spectrometry (NP-ToF-SIMS) for the analysis of native biological surfaces for the case of sagittal sections of mammalian brain tissue. The use of high energy, single nanoparticle impacts (e.g. 520 keV Au) permits desorption of intact lipid molecular ions, with enhanced molecular ion yield and reduced fragmentation. When coupled with complementary molecular ion fragmentation and exact mass measurement analysis, high energy nanoparticle probes (e.g. 520 keV Au NP) provide a powerful tool for the analysis of the lipid components from native brain sections without the need for surface preparation and with ultimate spatial resolution limited to the desorption volume per impact (~10 nm).
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http://dx.doi.org/10.1002/sia.4901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808454PMC
January 2013

Simultaneous detection and localization of secondary ions and electrons from single large cluster impacts.

Surf Interface Anal 2013 Jan;45(1)

Department of Chemistry, Texas A&M University, College Station, TX, 77842-3012, USA.

The use of large cluster primary ions (e.g. C, Au) in secondary ion mass spectrometry has become prevalent in recent years due to their enhanced emission of secondary ions, in particular, molecular ions (MW ≤ 1500 Da). The co-emission of electrons with SIs was investigated per projectile impact. It has been found that SI and electrons yields increased with increasing projectile energy and size. The use of the emitted electrons from impacts of C for localization has been demonstrated for cholesterol deposited on a copper grid. The instrumentation, methodologies, and results from these experiments are presented.
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http://dx.doi.org/10.1002/sia.4949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807816PMC
January 2013

Characterization of individual nano-objects with nanoprojectile-SIMS.

Surf Interface Anal 2013 Jan;45(1):329-332

Department of Chemistry, Texas A&M University, College Station, TX, 77843-3255, USA.

Secondary ion mass spectrometry (SIMS) applied in the event-by-event bombardment/detection mode is uniquely suited for the characterization of individual nano-objects. In this approach, nano-objects are examined one-by-one, allowing for the detection of variations in composition. The validity of the analysis depends upon the ability to physically isolate the nano-objects on a chemically inert support. This requirement can be realized by deposition of the nano-objects on a Nano-Assisted Laser Desorption/Ionization (NALDI™) plate. The featured nanostructured surface provides a support where nano-objects can be isolated if the deposition is performed at a proper concentration. We demonstrate the characterization of individual nano-objects on a NALDI™ plate for two different types of nanometric bacteriophages: Qβ and M13. Scanning electron microscope (SEM) images verified that the integrity of the phages is preserved on the NALDI™ substrate. Mass spectrometric data show secondary ions from the phages are identified and resolved from those from the underlying substrate.
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http://dx.doi.org/10.1002/sia.5084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806210PMC
January 2013