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16 pages, 1244 KiB

Open AccessFeature PaperArticle

Profiling Docetaxel in Plasma and Urine Samples from a Pediatric Cancer Patient Using Ultrasound-Assisted Dispersive Liquid–Liquid Microextraction Combined with LC–MS/MS

by Olga Maliszewska, Anna Roszkowska, Marcin Lipiński, Natalia Treder, Ilona Olędzka, Piotr Kowalski, Tomasz Bączek, Ewa Bień, Małgorzata Anna Krawczyk and Alina Plenis

Pharmaceutics 2023, 15(4), 1255; https://doi.org/10.3390/pharmaceutics15041255 - 17 Apr 2023

Cited by 1 | Viewed by 1499

Abstract

In recent years, therapeutic drug monitoring (TDM) has been applied in docetaxel (DOC)-based anticancer therapy to precisely control various pharmacokinetic parameters, including the concentration of DOC in biofluids (e.g., plasma or urine), its clearance, and its area under the curve (AUC). The ability [...] Read more.

In recent years, therapeutic drug monitoring (TDM) has been applied in docetaxel (DOC)-based anticancer therapy to precisely control various pharmacokinetic parameters, including the concentration of DOC in biofluids (e.g., plasma or urine), its clearance, and its area under the curve (AUC). The ability to determine these values and to monitor DOC levels in biological samples depends on the availability of precise and accurate analytical methods that both enable fast and sensitive analysis and can be implemented in routine clinical practice. This paper presents a new method for isolating DOC from plasma and urine samples based on the coupling of microextraction and advanced liquid chromatography with tandem mass spectrometry (LC-MS/MS). In the proposed method, biological samples are prepared via ultrasound-assisted dispersive liquid–liquid microextraction (UA-DLLME) using ethanol (EtOH) and chloroform (Chl) as the desorption and extraction solvents, respectively. The proposed protocol was fully validated according to the Food and Drug Administration (FDA) and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) requirements. The developed method was then applied to monitor the DOC profile in plasma and urine samples collected from a pediatric patient suffering from cardiac angiosarcoma (AS) with metastasis to lungs and mediastinal lymph nodes, who was receiving treatment with DOC at a dose of 30 mg/m² body surface area. Due to the rarity of this disease, TDM was carried out to determine the exact levels of DOC at particular time points to ascertain which levels were conducive to maximizing the treatment’s effectiveness while minimizing the drug’s toxicity. To this end, the concentration-time profiles of DOC in the plasma and urine samples were determined, and the levels of DOC at specific time intervals up to 3 days after administration were measured. The results showed that DOC was present at higher concentrations in the plasma than in the urine samples, which is due to the fact that this drug is primarily metabolized in the liver and then eliminated with the bile. The obtained data provided information about the pharmacokinetic profile of DOC in pediatric patients with cardiac AS, which enabled the dose to be adjusted to achieve the optimal therapeutic regimen. The findings of this work demonstrate that the optimized method can be applied for the routine monitoring of DOC levels in plasma and urine samples as a part of pharmacotherapy in oncological patients. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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15 pages, 2207 KiB

Open AccessArticle

Fast and Simple Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry Method for Therapeutic Drug Monitoring of Dalbavancin in Long-Term Treatment of Subacute and/or Chronic Infections

by Rossella Barone, Matteo Conti, Pier Giorgio Cojutti, Milo Gatti, Pierluigi Viale and Federico Pea

Pharmaceutics 2023, 15(2), 480; https://doi.org/10.3390/pharmaceutics15020480 - 01 Feb 2023

Cited by 6 | Viewed by 1231

Abstract

Dalbavancin (DBV) is a long-acting antistaphylococcal lypoglycopeptide that is being increasingly used for long-term treatment of a wide range of subacute and/or chronic infections, mainly osteo-articular infections (OAI). Population pharmacokinetic studies showed that two 1500 mg doses 1 week apart can ensure effective [...] Read more.

Dalbavancin (DBV) is a long-acting antistaphylococcal lypoglycopeptide that is being increasingly used for long-term treatment of a wide range of subacute and/or chronic infections, mainly osteo-articular infections (OAI). Population pharmacokinetic studies showed that two 1500 mg doses 1 week apart can ensure effective treatment for several weeks. In this scenario, therapeutic drug monitoring (TDM) can be a helpful tool for providing clinicians with real-time feedback on the duration of optimal treatment by measuring drug concentrations over time in each single patient. The aim of this study was to develop and validate a fast and simple analytical method based on the Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry (ITD LC-MS/MS) technique for measuring DBV concentrations in human plasma microsamples. It will allow an innovative, very convenient and minimally invasive way of sampling. Analysis was performed by simple single-step sample preparation and very short instrumental run time (4 min). Analytical performance met all criteria in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, dilution integrity and stability under different conditions set by the European Medicines Agency (EMA) for drug quantification by means of bioanalytical methods. The method was successfully applied for measuring DBV concentrations (range = 2.0–77.0 mg/L) in a cohort of patients receiving long-term DBV treatment of subacute and/or chronic infections. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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15 pages, 807 KiB

Open AccessArticle

Impact of Guidelines Regarding Dihydropyrimidine Dehydrogenase (DPD) Deficiency Screening Using Uracil-Based Phenotyping on the Reduction of Severe Side Effect of 5-Fluorouracil-Based Chemotherapy: A Propension Score Analysis

by Nicolas Laures, Céline Konecki, Mathias Brugel, Anne-Lise Giffard, Naceur Abdelli, Damien Botsen, Claire Carlier, Claire Gozalo, Catherine Feliu, Florian Slimano, Zoubir Djerada and Olivier Bouché

Pharmaceutics 2022, 14(10), 2119; https://doi.org/10.3390/pharmaceutics14102119 - 06 Oct 2022

Cited by 7 | Viewed by 1600

Abstract

Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with severe fluoropyrimidines-induced toxicity. As of September 2018, French recommendations call for screening for DPD deficiency by plasma uracil quantification prior to all fluoropyrimidine-based chemotherapy. A dose reduction of fluoropyrimidine is recommended when uracil concentration is equal [...] Read more.

Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with severe fluoropyrimidines-induced toxicity. As of September 2018, French recommendations call for screening for DPD deficiency by plasma uracil quantification prior to all fluoropyrimidine-based chemotherapy. A dose reduction of fluoropyrimidine is recommended when uracil concentration is equal to or greater than 16 ng/mL. This matched retrospective study assessed the impact of DPD screening on the reduction of severe side effects and on the management of DPD-deficient patients. Using a propensity score, we balanced the factors influencing 5-Fluorouracil (5-FU) toxicity. Then, the severity scores (G3 and G4 severity as well as their frequency) of patients who did not benefit from DPD screening were compared with those of patients who benefited from DPD screening for each treatment cycle (from 1 to 4). Among 349 screened patients, 198 treated patients were included. Among them, 31 (15.7%) had DPD deficiency (median uracilemia 19.8 ng/mL (range: 16.1–172.3)). The median toxicity severity score was higher in the unscreened group for each treatment cycle (0 vs. 1, p < 0.001 at each cycle from 1 to 4) as well as the cumulative score during all courses of treatment (p = 0.028). DPD-deficient patients received a significantly lower dose of 5-FU (p < 0.001). This study suggests that pretherapeutic plasmatic uracil assessment, along with 5-FU dosage adjustment, may be beneficial in reducing 5-FU toxicity in real-life patients. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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7 pages, 1134 KiB

Open AccessCommunication

Therapeutic Drug Monitoring of Sputum Voriconazole in Pulmonary Aspergillosis

by Sacha Sarfati, Julien Wils, Timothée Lambert, Céline Mory, Laurent Imbert, Gilles Gargala, Hélène Morisse-Pradier and Fabien Lamoureux

Pharmaceutics 2022, 14(8), 1598; https://doi.org/10.3390/pharmaceutics14081598 - 30 Jul 2022

Cited by 4 | Viewed by 1278

Abstract

Voriconazole is one of the most used antifungal azoles against pulmonary aspergillosis. Therapeutic drug monitoring (TDM) of the voriconazole concentration in plasma is recommended in clinical practice guidelines to prevent treatment failure and toxicity. The aim of this study was to evaluate the [...] Read more.

Voriconazole is one of the most used antifungal azoles against pulmonary aspergillosis. Therapeutic drug monitoring (TDM) of the voriconazole concentration in plasma is recommended in clinical practice guidelines to prevent treatment failure and toxicity. The aim of this study was to evaluate the feasibility and utility of TDM of the voriconazole concentration in the sputum of patients treated for pulmonary aspergillosis. Fifty sputum and 31 plasma samples were analysed with high-performance tandem mass spectrometry (HPLC-MS/MS) in 24 patients included in the study. The voriconazole concentration was simultaneously assessed in the plasma and sputum in 22 samples. The correlation between the sputum and plasma levels was estimated with a univariate linear regression model, and the observed R² was 0.86. We determined the following equation, C_sputum = 0.45 (C_plasma) + 0.21, which could predict the voriconazole concentration in plasma from sputum. TDM of the voriconazole concentration in sputum is an easy, non-invasive and accurate method with which to evaluate voriconazole exposure in patients with pulmonary aspergillosis. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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15 pages, 1619 KiB

Open AccessArticle

Impaired Pharmacokinetics of Amiodarone under Veno-Venous Extracorporeal Membrane Oxygenation: From Bench to Bedside

by Mickaël Lescroart, Claire Pressiat, Benjamin Péquignot, N’Guyen Tran, Jean-Louis Hébert, Nassib Alsagheer, Nicolas Gambier, Bijan Ghaleh, Julien Scala-Bertola and Bruno Levy

Pharmaceutics 2022, 14(5), 974; https://doi.org/10.3390/pharmaceutics14050974 - 30 Apr 2022

Cited by 1 | Viewed by 1919

Abstract

Background: Adjusting drug therapy under veno-venous extracorporeal membrane oxygenation (VV ECMO) is challenging. Although impaired pharmacokinetics (PK) under VV ECMO have been reported for sedative drugs and antibiotics, data about amiodarone are lacking. We evaluated the pharmacokinetics of amiodarone under VV ECMO both [...] Read more.

Background: Adjusting drug therapy under veno-venous extracorporeal membrane oxygenation (VV ECMO) is challenging. Although impaired pharmacokinetics (PK) under VV ECMO have been reported for sedative drugs and antibiotics, data about amiodarone are lacking. We evaluated the pharmacokinetics of amiodarone under VV ECMO both in vitro and in vivo. Methods: In vitro: Amiodarone concentration decays were compared between closed-loop ECMO and control stirring containers over a 24 h period. In vivo: Potassium-induced cardiac arrest in 10 pigs with ARDS, assigned to either control or VV ECMO groups, was treated with 300 mg amiodarone injection under continuous cardiopulmonary resuscitation. Pharmacokinetic parameters C_max, T_max AUC and F were determined from both direct amiodarone plasma concentrations observation and non-linear mixed effects modeling estimation. Results: An in vitro study revealed a rapid and significant decrease in amiodarone concentrations in the closed-loop ECMO circuitry whereas it remained stable in control experiment. In vivo study revealed a 32% decrease in the AUC and a significant 42% drop of C_max in the VV ECMO group as compared to controls. No difference in T_max was observed. VV ECMO significantly modified both central distribution volume and amiodarone clearance. Monte Carlo simulations predicted that a 600 mg bolus of amiodarone under VV ECMO would achieve the amiodarone bioavailability observed in the control group. Conclusions: This is the first study to report decreased amiodarone bioavailability under VV ECMO. Higher doses of amiodarone should be considered for effective amiodarone exposure under VV ECMO. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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15 pages, 1770 KiB

Open AccessArticle

Ciprofloxacin in Patients Undergoing Extracorporeal Membrane Oxygenation (ECMO): A Population Pharmacokinetic Study

by Dzenefa Alihodzic, Sebastian G. Wicha, Otto R. Frey, Christina König, Michael Baehr, Dominik Jarczak, Stefan Kluge and Claudia Langebrake

Pharmaceutics 2022, 14(5), 965; https://doi.org/10.3390/pharmaceutics14050965 - 29 Apr 2022

Cited by 4 | Viewed by 1933

Abstract

Extracorporeal membrane oxygenation (ECMO) is utilized to temporarily sustain respiratory and/or cardiac function in critically ill patients. Ciprofloxacin is used to treat nosocomial infections, but data describing the effect of ECMO on its pharmacokinetics is lacking. Therefore, a prospective, observational trial including critically [...] Read more.

Extracorporeal membrane oxygenation (ECMO) is utilized to temporarily sustain respiratory and/or cardiac function in critically ill patients. Ciprofloxacin is used to treat nosocomial infections, but data describing the effect of ECMO on its pharmacokinetics is lacking. Therefore, a prospective, observational trial including critically ill adults (n = 17), treated with ciprofloxacin (400 mg 8–12 hourly) during ECMO, was performed. Serial blood samples were collected to determine ciprofloxacin concentrations to assess their pharmacokinetics. The pharmacometric modeling was performed (NONMEM^®) and utilized for simulations to evaluate the probability of target attainment (PTA) to achieve an AUC_0–24/MIC of 125 mg·h/L for ciprofloxacin. A two-compartment model most adequately described the concentration-time data of ciprofloxacin. Significant covariates on ciprofloxacin clearance (CL) were plasma bicarbonate and the estimated glomerular filtration rate (eGFR). For pathogens with an MIC of ≤0.25 mg/L, a PTA of ≥90% was attained. However, for pathogens with an MIC of ≥0.5 mg/L, plasma bicarbonate ≥ 22 mmol/L or eGFR ≥ 10 mL/min PTA decreased below 90%, steadily declining to 7.3% (plasma bicarbonate 39 mmol/L) and 21.4% (eGFR 150 mL/min), respectively. To reach PTAs of ≥90% for pathogens with MICs ≥ 0.5 mg/L, optimized dosing regimens may be required. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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12 pages, 1578 KiB

Open AccessArticle

Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial

by Guillaume Drevin, Marie Briet, Caroline Bazzoli, Emmanuel Gyan, Aline Schmidt, Hervé Dombret, Corentin Orvain, Aurelien Giltat, Christian Recher, Norbert Ifrah, Philippe Guardiola, Mathilde Hunault-Berger and Chadi Abbara

Pharmaceutics 2022, 14(4), 792; https://doi.org/10.3390/pharmaceutics14040792 - 05 Apr 2022

Viewed by 1750

Abstract

Daunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optimal population [...] Read more.

Daunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optimal population PK study design. Fourteen patients were enrolled in the PK ancillary study of the BIG-1 trial and 6–8 samples were taken up to 24 h after administration of the first dose of daunorubicin (90 mg/m²/day). Daunorubicin and daunorubicinol quantifications were assessed using a validated liquid chromatography technique coupled with a fluorescence detector method. Data were analysed using a non-compartmental approach and non-linear mixed effects modelling. Optimal sampling strategy was proposed using the R function PFIM. The median daunorubicin and daunorubicinol AUC0-tlast were 577 ng/mL·hr (Range: 375–1167) and 2200 ng/mL·hr (range: 933–4683), respectively. The median metabolic ratio was 0.32 (range: 0.1–0.44). Daunorubicin PK was best described by a three-compartment parent, two-compartment metabolite model, with a double first-order transformation of daunorubicin to metabolite. Body surface area and plasma creatinine had a significant impact on the daunorubicin and daunorubicinol PK. A practical optimal population design has been derived from this model with five sampling times per subject (0.5, 0.75, 2, 9, 24 h) and this can be used for a future population PK study. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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9 pages, 1128 KiB

Open AccessArticle

Local Anesthetic Plasma Concentrations as a Valuable Tool to Confirm the Diagnosis of Local Anesthetic Systemic Toxicity? A Report of 10 Years of Experience

by Camille Riff, Axel Le Caloch, Julien Dupouey, Laurent Allanioux, Marc Leone, Olivier Blin, Aurélie Bourgoin and Romain Guilhaumou

Pharmaceutics 2022, 14(4), 708; https://doi.org/10.3390/pharmaceutics14040708 - 26 Mar 2022

Cited by 7 | Viewed by 2121

Abstract

Background: Local anesthetic systemic toxicity (LAST) has been reported as a serious complication of local anesthetic (LA) peripheral injection. The signs and symptoms of LAST are highly variable, and the challenge remains to confirm its diagnosis. In this context, the determination of LA [...] Read more.

Background: Local anesthetic systemic toxicity (LAST) has been reported as a serious complication of local anesthetic (LA) peripheral injection. The signs and symptoms of LAST are highly variable, and the challenge remains to confirm its diagnosis. In this context, the determination of LA plasma concentration appears as a valuable tool to confirm LAST diagnosis. The aims of this study were to describe observed LA concentrations in patients suspected with LAST and their contribution to diagnostic confirmation. Methods: We retrospectively reported suspected LAST in patients for which at least one plasma LA concentration was determined to confirm diagnosis of LAST. Data collection came from our pharmacological laboratory’s database. Clinical signs and symptoms of toxicity, their onset time and observed LA concentrations were used to confirm LAST diagnosis. Results: 33 patients who presented with suspected LAST after ropivacaine and/or lidocaine administration were included. Prodromal symptoms were observed in 13 patients. Isolated central nervous system (CNS) toxicity occurred in 11 patients, and combined CNS and cardiovascular toxicity occurred in 12. One, two or three venous plasma samples were performed in 11, 3 and 19 patients, respectively. Toxic plasma LA concentrations were observed in three patients, receiving peripheral LA injection using lidocaine (16.1 µg/mL) and ropivacaine (4.2 and 4.8 µg/mL). Conclusion: This study presents an important biological and clinical dataset of patients who presented with suspected LAST. Plasma LA concentrations could bring valuable information in the diagnosis of LAST but requires rigorous sample protocols. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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13 pages, 4107 KiB

Open AccessArticle

Population Pharmacokinetics of Amikacin in Patients on Veno-Arterial Extracorporeal Membrane Oxygenation

by Claire Pressiat, Agathe Kudela, Quentin De Roux, Nihel Khoudour, Claire Alessandri, Hakim Haouache, Dominique Vodovar, Paul-Louis Woerther, Alice Hutin, Bijan Ghaleh, Anne Hulin and Nicolas Mongardon

Pharmaceutics 2022, 14(2), 289; https://doi.org/10.3390/pharmaceutics14020289 - 26 Jan 2022

Cited by 2 | Viewed by 2147

Abstract

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) support leads to complex pharmacokinetic alterations, whereas adequate drug dosing is paramount for efficacy and absence of toxicity in critically ill patients. Amikacin is a major antibiotic used in nosocomial sepsis, especially for these patients. We aimed [...] Read more.

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) support leads to complex pharmacokinetic alterations, whereas adequate drug dosing is paramount for efficacy and absence of toxicity in critically ill patients. Amikacin is a major antibiotic used in nosocomial sepsis, especially for these patients. We aimed to describe amikacin pharmacokinetics on V-A ECMO support and to determine relevant variables to improve its dosing. All critically ill patients requiring empirical antimicrobial therapy, including amikacin for nosocomial sepsis supported or not by V-A ECMO, were included in a prospective population pharmacokinetic study. This population pharmacokinetic analysis was built with a dedicated software, and Monte Carlo simulations were performed to identify doses achieving therapeutic plasma concentrations. Thirty-nine patients were included (control n = 15, V-A ECMO n = 24); 215 plasma assays were performed and used for the modeling process. Patients received 29 (24–33) and 32 (30–35) mg/kg of amikacin in control and ECMO groups, respectively. Data were best described by a two-compartment model with first-order elimination. Inter-individual variabilities were observed on clearance, central compartment volume (V₁)_, and peripherical compartment volume (V₂). Three significant covariates explained these variabilities: Kidney Disease Improving Global Outcomes (KDIGO) stage on amikacin clearance, total body weight on V_1, and ECMO support on V₂. Our simulations showed that the adequate dosage of amikacin was 40 mg/kg in KDIGO stage 0 patients, while 25 mg/kg in KDIGO stage 3 patients was relevant. V-A ECMO support had only a secondary impact on amikacin pharmacokinetics, as compared to acute kidney injury. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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11 pages, 1099 KiB

Open AccessEditor’s ChoiceArticle

Implementation and Comparison of Two Pharmacometric Tools for Model-Based Therapeutic Drug Monitoring and Precision Dosing of Daptomycin

by Justine Heitzmann, Yann Thoma, Romain Bricca, Marie-Claude Gagnieu, Vincent Leclerc, Sandrine Roux, Anne Conrad, Tristan Ferry and Sylvain Goutelle

Pharmaceutics 2022, 14(1), 114; https://doi.org/10.3390/pharmaceutics14010114 - 04 Jan 2022

Cited by 9 | Viewed by 1795

Abstract

Daptomycin is a candidate for therapeutic drug monitoring (TDM). The objectives of this work were to implement and compare two pharmacometric tools for daptomycin TDM and precision dosing. A nonparametric population PK model developed from patients with bone and joint infection was implemented [...] Read more.

Daptomycin is a candidate for therapeutic drug monitoring (TDM). The objectives of this work were to implement and compare two pharmacometric tools for daptomycin TDM and precision dosing. A nonparametric population PK model developed from patients with bone and joint infection was implemented into the BestDose software. A published parametric model was imported into Tucuxi. We compared the performance of the two models in a validation dataset based on mean error (ME) and mean absolute percent error (MAPE) of individual predictions, estimated exposure and predicted doses necessary to achieve daptomycin efficacy and safety PK/PD targets. The BestDose model described the data very well in the learning dataset. In the validation dataset (94 patients, 264 concentrations), 21.3% of patients were underexposed (AUC_24h < 666 mg.h/L) and 31.9% of patients were overexposed (C_min > 24.3 mg/L) on the first TDM occasion. The BestDose model performed slightly better than the model in Tucuxi (ME = −0.13 ± 5.16 vs. −1.90 ± 6.99 mg/L, p < 0.001), but overall results were in agreement between the two models. A significant proportion of patients exhibited underexposure or overexposure to daptomycin after the initial dosage, which supports TDM. The two models may be useful for model-informed precision dosing. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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11 pages, 547 KiB

Open AccessArticle

Variability of Tacrolimus Trough Concentration in Liver Transplant Patients: Which Role of Inflammation?

by Anaelle Chavant, Xavier Fonrose, Elodie Gautier-Veyret, Marie Noelle Hilleret, Matthieu Roustit and Francoise Stanke-Labesque

Pharmaceutics 2021, 13(11), 1960; https://doi.org/10.3390/pharmaceutics13111960 - 19 Nov 2021

Cited by 3 | Viewed by 1770

Abstract

Tacrolimus presents high intra and inter-individual variability in its blood trough concentration (Cmin). Knowledge of the factors that are involved in tacrolimus Cmin variability is thus clinically important to prevent or limit it. Inflammation can affect the pharmacokinetic properties of drugs. We evaluated [...] Read more.

Tacrolimus presents high intra and inter-individual variability in its blood trough concentration (Cmin). Knowledge of the factors that are involved in tacrolimus Cmin variability is thus clinically important to prevent or limit it. Inflammation can affect the pharmacokinetic properties of drugs. We evaluated the contribution of acute inflammation in the pharmacokinetic variability of tacrolimus blood Cmin in a large cohort of liver transplant patients. Demographic, biological, and clinical data from 248 liver transplant patients treated with tacrolimus from January 2010 to December 2016 were retrospectively collected from medical records. In total, 1573 Cmin/dose and concomitant C-reactive protein (CRP) measurements were analysed. In multivariate analysis, the log Cmin/dose of tacrolimus was significantly and positively associated with the hematocrit, ALAT, and CRP concentrations. CRP concentrations were higher (p = 0.003) for patients with tacrolimus overexposure (i.e., tacrolimus Cmin > 15 µg/L) (median CRP (10th–90th percentiles): 27 mg/L (3–149 mg/L), n = 91) than they were for patients with a tacrolimus Cmin ≤ 15 µg/L (13 mg/mL (3–95 mg/L), n = 1482)). CRP in the fourth quartile (49 to 334 mg/L) was associated with a 2.6-fold increased risk of tacrolimus Cmin overexposure. Our study provides evidence that inflammation contributes to tacrolimus Cmin variability and suggests that inflammation should be considered for the correct interpretation of tacrolimus blood concentration. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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13 pages, 10005 KiB

Open AccessArticle

Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model

by David Ternant, Olivier Le Tilly, Laurence Picon, Driffa Moussata, Christophe Passot, Theodora Bejan-Angoulvant, Céline Desvignes, Denis Mulleman, Philippe Goupille and Gilles Paintaud

Pharmaceutics 2021, 13(11), 1821; https://doi.org/10.3390/pharmaceutics13111821 - 01 Nov 2021

Cited by 2 | Viewed by 2022

Abstract

Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment [...] Read more.

Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (R^C₀ = 3.3 nM and R^P₀ = 0.46 nM), steady-stated dissociation rates (K^C_SS = 15.4 nM and K^P_SS = 0.49 nM), and first-order elimination rates of complexes (k^C_int = 0.17 day⁻¹ and k^P_int = 0.0079 day⁻¹). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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20 pages, 3847 KiB

Open AccessArticle

External Evaluation of Population Pharmacokinetic Models and Bayes-Based Dosing of Infliximab

by Celine Konecki, Catherine Feliu, Yoann Cazaubon, Delphine Giusti, Marcelle Tonye-Libyh, Hedia Brixi, Guillaume Cadiot, Amélie Biron and Zoubir Djerada

Pharmaceutics 2021, 13(8), 1191; https://doi.org/10.3390/pharmaceutics13081191 - 03 Aug 2021

Cited by 12 | Viewed by 2516

Abstract

Despite the well-demonstrated efficacy of infliximab in inflammatory diseases, treatment failure remains frequent. Dose adjustment using Bayesian methods has shown in silico its interest in achieving target plasma concentrations. However, most of the published models have not been fully validated in accordance with [...] Read more.

Despite the well-demonstrated efficacy of infliximab in inflammatory diseases, treatment failure remains frequent. Dose adjustment using Bayesian methods has shown in silico its interest in achieving target plasma concentrations. However, most of the published models have not been fully validated in accordance with the recommendations. This study aimed to submit these models to an external evaluation and verify their predictive capabilities. Eight models were selected for external evaluation, carried out on an independent database (409 concentrations from 157 patients). Each model was evaluated based on the following parameters: goodness-of-fit (comparison of predictions to observations), residual error model (population weighted residuals (PWRES), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE)), and predictive performances (prediction-corrected visual predictive checks (pcVPC) and Bayesian simulations). The performances observed during this external evaluation varied greatly from one model to another. The eight evaluated models showed a significant bias in population predictions (from −7.19 to 7.38 mg/L). Individual predictions showed acceptable bias and precision for six of the eight models (mean error of −0.74 to −0.29 mg/L and mean percent error of −16.6 to −0.4%). Analysis of NPDE and pcVPC confirmed these results and revealed a problem with the inclusion of several covariates (weight, concomitant immunomodulatory treatment, presence of anti-drug antibodies). This external evaluation showed satisfactory results for some models, notably models A and B, and highlighted several prospects for improving the pharmacokinetic models of infliximab for clinical-biological application. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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Review

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37 pages, 782 KiB

Open AccessReview

Solid Phase-Based Microextraction Techniques in Therapeutic Drug Monitoring

by Sofia Soares, Tiago Rosado, Mário Barroso and Eugenia Gallardo

Pharmaceutics 2023, 15(4), 1055; https://doi.org/10.3390/pharmaceutics15041055 - 24 Mar 2023

Cited by 5 | Viewed by 2132

Abstract

Therapeutic drug monitoring is an established practice for a small group of drugs, particularly those presenting narrow therapeutic windows, for which there is a direct relationship between concentration and pharmacological effects at the site of action. Drug concentrations in biological fluids are used, [...] Read more.

Therapeutic drug monitoring is an established practice for a small group of drugs, particularly those presenting narrow therapeutic windows, for which there is a direct relationship between concentration and pharmacological effects at the site of action. Drug concentrations in biological fluids are used, in addition to other clinical observation measures, to assess the patient’s status, since they are the support for therapy individualization and allow assessing adherence to therapy. Monitoring these drug classes is of great importance, as it minimizes the risk of medical interactions, as well as toxic effects. In addition, the quantification of these drugs through routine toxicological tests and the development of new monitoring methodologies are extremely relevant for public health and for the well-being of the patient, and it has implications in clinical and forensic situations. In this sense, the use of new extraction procedures that employ smaller volumes of sample and organic solvents, therefore considered miniaturized and green techniques, is of great interest in this field. From these, the use of fabric-phase extractions seems appealing. Noteworthy is the fact that SPME, which was the first of these miniaturized approaches to be used in the early ‘90s, is still the most used solventless procedure, providing solid and sound results. The main goal of this paper is to perform a critical review of sample preparation techniques based on solid-phase microextraction for drug detection in therapeutic monitoring situations. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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Open AccessReview

The Role of Intra-Patient Variability of Tacrolimus Drug Concentrations in Solid Organ Transplantation: A Focus on Liver, Heart, Lung and Pancreas

by Gwendal Coste and Florian Lemaitre

Pharmaceutics 2022, 14(2), 379; https://doi.org/10.3390/pharmaceutics14020379 - 08 Feb 2022

Cited by 12 | Viewed by 1940

Abstract

Tacrolimus, the keystone immunosuppressive drug administered after solid organ transplantation, presents a narrow therapeutic index and wide inter- and intra-patient pharmacokinetic variability (IPV). The latter has been fairly studied in kidney transplantation, where it could impact outcomes. However, literature about other transplanted organ [...] Read more.

Tacrolimus, the keystone immunosuppressive drug administered after solid organ transplantation, presents a narrow therapeutic index and wide inter- and intra-patient pharmacokinetic variability (IPV). The latter has been fairly studied in kidney transplantation, where it could impact outcomes. However, literature about other transplanted organ recipients remains inconclusive. This review aimed at summarizing the evidence about the IPV of tacrolimus concentrations outside of the scope of kidney transplantation. First, factors influencing IPV will be presented. Then, the potential of IPV as a biomarker predictive of graft outcomes will be discussed in liver, heart, lung and pancreas transplantation. Lastly, strategies to reduce IPV will be reviewed, with the ultimate objective being ready-to-implement solutions in clinical practice by transplantation professionals. Full article

(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)

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