14 results on '"Laurent A. Décosterd"'
Search Results
2. Real-Life Therapeutic Concentration Monitoring of Long-Acting Cabotegravir and Rilpivirine: Preliminary Results of an Ongoing Prospective Observational Study in Switzerland
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Paul Thoueille, Susana Alves Saldanha, Fabian Schaller, Aline Munting, Matthias Cavassini, Dominique Braun, Huldrych F. Günthard, Katharina Kusejko, Bernard Surial, Hansjakob Furrer, Andri Rauch, Pilar Ustero, Alexandra Calmy, Marcel Stoeckle, Manuel Battegay, Catia Marzolini, Pascal Andre, Monia Guidi, Thierry Buclin, Laurent A. Decosterd, and on behalf of the Swiss HIV Cohort Study
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long-acting antiretroviral therapy ,cabotegravir ,rilpivirine ,therapeutic drug monitoring ,pharmacokinetics ,population pharmacokinetic modeling ,Pharmacy and materia medica ,RS1-441 - Abstract
SHCS#879 is an ongoing Switzerland-wide multicenter observational study conducted within the Swiss HIV Cohort Study (SHCS) for the prospective follow-up of people living with HIV (PLWH) receiving long-acting injectable cabotegravir-rilpivirine (LAI-CAB/RPV). All adults under LAI-CAB/RPV and part of SHCS are enrolled in the project. The study addresses an integrated strategy of treatment monitoring outside the stringent frame of controlled clinical trials, based on relevant patient characteristics, clinical factors, potential drug-drug interactions, and measurement of circulating blood concentrations. So far, 91 blood samples from 46 PLWH have been collected. Most individuals are less than 50 years old, with relatively few comorbidities and comedications. The observed concentrations are globally in accordance with the available values reported in the randomized clinical trials. Yet, low RPV concentrations not exceeding twice the reported protein-adjusted 90% inhibitory concentration have been observed. Data available at present confirm a considerable between-patient variability overall. Based on the growing amount of PK data accumulated during this ongoing study, population pharmacokinetic analysis will characterize individual concentration-time profiles of LAI-CAB/RPV along with their variability in a real-life setting and their association with treatment response and tolerability, thus bringing key data for therapeutic monitoring and precision dosage adjustment of this novel long-acting therapy.
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- 2022
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3. Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy
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Elinam Gayi, Laurence A. Neff, Xènia Massana Muñoz, Hesham M. Ismail, Marta Sierra, Thomas Mercier, Laurent A. Décosterd, Jocelyn Laporte, Belinda S. Cowling, Olivier M. Dorchies, and Leonardo Scapozza
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Science - Abstract
X-linked myotubular myopathy (XLMTM) is a severe muscle disease with no effective treatment. Here, the authors show that tamoxifen, a drug used to treat breast cancer, rescues the pathology in a mouse model of the disease, at least in part by normalizing expression of the disease modifier proteins DNM2 and BIN1
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- 2018
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4. Real-world trough concentrations and effectiveness of long-acting cabotegravir and rilpivirine: a multicenter prospective observational study in SwitzerlandResearch in context
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Paul Thoueille, Susana Alves Saldanha, Fabian Schaller, Eva Choong, Aline Munting, Matthias Cavassini, Dominique Braun, Huldrych F. Günthard, Katharina Kusejko, Bernard Surial, Hansjakob Furrer, Andri Rauch, Mathieu Rougemont, Pilar Ustero, Alexandra Calmy, Marcel Stöckle, Catia Marzolini, Caroline Di Benedetto, Enos Bernasconi, Patrick Schmid, Rein Jan Piso, Pascal Andre, François R. Girardin, Monia Guidi, Thierry Buclin, and Laurent A. Decosterd
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Long-acting cabotegravir and rilpivirine ,Real-world ,Drug concentration monitoring ,Public aspects of medicine ,RA1-1270 - Abstract
Summary: Background: The efficacy and tolerability of long-acting cabotegravir and rilpivirine were demonstrated in Phase III trials. However, low concentrations combined with other risk factors have been associated with an increased risk of virologic failure. This study aims to verify whether drug concentrations measured in a real-world setting are consistent with those previously reported. Methods: SHCS-879 is a nationwide observational study within the Swiss HIV Cohort Study for the monitoring of people with HIV (PWH) on long-acting cabotegravir plus rilpivirine. Samples were collected from March 2022 to March 2023. Findings: Overall, 725 samples were obtained from 186 PWH. Our data show a large inter-individual variability in cabotegravir and rilpivirine concentrations, with some individuals exhibiting repeatedly low concentrations. Rilpivirine trough concentrations were consistent with those from Phase III trials, while cabotegravir concentrations were lower. The first concentrations quartile was only slightly above the target of 664 ng/mL. Exploratory statistical analyses found 35% (p
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- 2024
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5. A Single-Run HPLC–MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis
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Niklas Köhler, Hande Karaköse, Hans-Peter Grobbel, Doris Hillemann, Sönke Andres, Christina König, Barbara Kalsdorf, Thomas Theo Brehm, Laura Böttcher, Inna Friesen, Harald Hoffmann, Dražen Strelec, Dagmar Schaub, Charles A. Peloquin, Stefan Schmiedel, Laurent A. Decosterd, Eva Choong, Sebastian G. Wicha, Rob E. Aarnoutse, Christoph Lange, and Patricia M. Sánchez Carballo
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TDM ,levofloxacin ,moxifloxacin ,bedaquiline ,linezolid ,clofazimine ,Pharmacy and materia medica ,RS1-441 - Abstract
The treatment of drug-resistant Mycobacterium tuberculosis relies on complex antibiotic therapy. Inadequate antibiotic exposure can lead to treatment failure, acquired drug resistance, and an increased risk of adverse events. Therapeutic drug monitoring (TDM) can be used to optimize the antibiotic exposure. Therefore, we aimed to develop a single-run multiplex assay using high-performance liquid chromatography–mass spectrometry (HPLC–MS) for TDM of patients with multidrug-resistant, pre-extensively drug-resistant and extensively drug-resistant tuberculosis. A target profile for sufficient performance, based on the intended clinical application, was established and the assay was developed accordingly. Antibiotics were analyzed on a zwitterionic hydrophilic interaction liquid chromatography column and a triple quadrupole mass spectrometer using stable isotope-labeled internal standards. The assay was sufficiently sensitive to monitor drug concentrations over five half-lives for rifampicin, rifabutin, levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, terizidone/cycloserine, ethambutol, delamanid, pyrazinamide, meropenem, prothionamide, and para-amino salicylic acid (PAS). Accuracy and precision were sufficient to support clinical decision making (≤±15% in clinical samples and ±20–25% in spiked samples, with 80% of future measured concentrations predicted to fall within ±40% of nominal concentrations). The method was applied in the TDM of two patients with complex drug-resistant tuberculosis. All relevant antibiotics from their regimens could be quantified and high-dose therapy was initiated, followed by microbiological conversion. In conclusion, we developed a multiplex assay that enables TDM of the relevant first- and second-line anti-tuberculosis medicines in a single run and was able to show its applicability in TDM of two drug-resistant tuberculosis patients.
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- 2023
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6. Elevated acute phase proteins affect pharmacokinetics in COVID‐19 trials: Lessons from the CounterCOVID ‐ imatinib study
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Imke H. Bartelink, Pierre M. Bet, Nicolas Widmer, Monia Guidi, Erik Duijvelaar, Bram Grob, Richard Honeywell, Amanda Evelo, Ivo P. E. Tielbeek, Sue D. Snape, Henrike Hamer, Laurent A. Decosterd, Harm Jan Bogaard, Jurjan Aman, and Eleonora L. Swart
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID‐19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID‐19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (Cmax) and trough concentration (Ctrough) were 2.32‐fold (95% confidence interval [CI] 1.34–3.29), 2.31‐fold (95% CI 1.33–3.29), and 2.32‐fold (95% CI 1.11–3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID‐19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1‐acid glycoprotein (AAG) concentrations measured in patients with COVID‐19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG‐PK‐Model) gave an estimated mean (SD) prediction error (PE) of −20% (31%) for total and −7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID‐19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID‐19.
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- 2021
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7. Precision Oncology by Point-of-Care Therapeutic Drug Monitoring and Dosage Adjustment of Conventional Cytotoxic Chemotherapies: A Perspective
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Myriam Briki, Pascal André, Yann Thoma, Nicolas Widmer, Anna D. Wagner, Laurent A. Decosterd, Thierry Buclin, Monia Guidi, and Sandro Carrara
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therapeutic drug monitoring ,point-of-care ,oncology ,cytotoxics ,Pharmacy and materia medica ,RS1-441 - Abstract
Therapeutic drug monitoring (TDM) of conventional cytotoxic chemotherapies is strongly supported yet poorly implemented in daily practice in hospitals. Analytical methods for the quantification of cytotoxic drugs are instead widely presented in the scientific literature, while the use of these therapeutics is expected to keep going for longer. There are two main issues hindering the implementation of TDM: turnaround time, which is incompatible with the dosage profiles of these drugs, and exposure surrogate marker, namely total area under the curve (AUC). Therefore, this perspective article aims to define the adjustment needed from current to efficient TDM practice for cytotoxics, namely point-of-care (POC) TDM. For real-time dose adjustment, which is required for chemotherapies, such POC TDM is only achievable with analytical methods that match the sensitivity and selectivity of current methods, such as chromatography, as well as model-informed precision dosing platforms to assist the oncologist with dose fine-tuning based on quantification results and targeted intervals.
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- 2023
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8. Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies
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Paulina Biniecka, Saki Matsumoto, Axel Belotti, Jessie Joussot, Jian Fei Bai, Somi Reddy Majjigapu, Paul Thoueille, Dany Spaggiari, Vincent Desfontaine, Francesco Piacente, Santina Bruzzone, Michele Cea, Laurent A. Decosterd, Pierre Vogel, Alessio Nencioni, Michel A. Duchosal, and Aimable Nahimana
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NAMPT inhibitor ,NAD ,anticancer ,leukemia ,lymphoma ,multiple myeloma ,Organic chemistry ,QD241-441 - Abstract
Targeting cancer cells that are highly dependent on the nicotinamide adenine dinucleotide (NAD+) metabolite is a promising therapeutic strategy. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme catalyzing NAD+ production. Despite the high efficacy of several developed NAMPT inhibitors (i.e., FK866 (APO866)) in preclinical studies, their clinical activity was proven to be limited. Here, we report the synthesis of new NAMPT Inhibitors, JJ08, FEI191 and FEI199, which exhibit a broad anticancer activity in vitro. Results show that these compounds are potent NAMPT inhibitors that deplete NAD+ and NADP(H) after 24 h of drug treatment, followed by an increase in reactive oxygen species (ROS) accumulation. The latter event leads to ATP loss and mitochondrial depolarization with induction of apoptosis and necrosis. Supplementation with exogenous NAD+ precursors or catalase (ROS scavenger) abrogates the cell death induced by the new compounds. Finally, in vivo administration of the new NAMPT inhibitors in a mouse xenograft model of human Burkitt lymphoma delays tumor growth and significantly prolongs mouse survival. The most promising results are collected with JJ08, which completely eradicates tumor growth. Collectively, our findings demonstrate the efficient anticancer activity of the new NAMPT inhibitor JJ08 and highlight a strong interest for further evaluation of this compound in hematological malignancies.
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- 2023
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9. Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers
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Antonia E. Schantl, Anja Verhulst, Ellen Neven, Geert J. Behets, Patrick C. D’Haese, Marc Maillard, David Mordasini, Olivier Phan, Michel Burnier, Dany Spaggiari, Laurent A. Decosterd, Mark G. MacAskill, Carlos J. Alcaide-Corral, Adriana A. S. Tavares, David E. Newby, Victoria C. Beindl, Roberto Maj, Anne Labarre, Chrismita Hegde, Bastien Castagner, Mattias E. Ivarsson, and Jean-Christophe Leroux
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Science - Abstract
Cardiovascular calcification is a serious pathology for which effective pharmacological treatments are lacking. Here the authors show that an optimized oligo(ethylene glycol) derivative of inositol phosphate interferes with calcium phosphate crystallization and inhibits soft tissue calcification in vivo following subcutaneous injection.
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- 2020
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10. Effects of a dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240, on endocrine and renal functions in healthy volunteers
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Philippe Rousso, Thierry Buclin, Jürg Nussberger, Laurent A. Décosterd, Salome D. La Roche, Françoise Brunner-Ferber, Hans R. Brunner, and Jérôme Biollaz
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Adult ,Male ,medicine.medical_specialty ,Physiology ,Pyridines ,Posture ,Angiotensin-Converting Enzyme Inhibitors ,Blood Pressure ,Endocrine System ,Peptidyl-Dipeptidase A ,Kidney ,Plasma renin activity ,Excretion ,Atrial natriuretic peptide ,Reference Values ,Internal medicine ,Renin–angiotensin system ,Internal Medicine ,Medicine ,Humans ,Infusions, Intravenous ,Cyclic GMP ,Cross-Over Studies ,Renal sodium reabsorption ,biology ,business.industry ,Angiotensin II ,Angiotensin-converting enzyme ,Stereoisomerism ,Effective renal plasma flow ,Benzazepines ,Diet, Sodium-Restricted ,Renal Plasma Flow, Effective ,Endocrinology ,biology.protein ,Neprilysin ,Safety ,Cardiology and Cardiovascular Medicine ,business ,Atrial Natriuretic Factor ,Follow-Up Studies - Abstract
OBJECTIVE To investigate the endocrine and renal effects of the dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240. DESIGN A randomized, placebo-controlled, crossover study was performed in 12 healthy volunteers. METHODS MDL 100,240 was administered intravenously over 20 min at single doses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n = 6) or 80 (n = 6) mmol/day. Measurements were taken of supine and standing blood pressure, plasma angiotensin converting enzyme activity, angiotensin II, atrial natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP excretion, effective renal plasma flow and the glomerular filtration rate as p-aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance. RESULTS Supine systolic blood pressure was consistently decreased by MDL 100,240, particularly after the high dose and during the low-salt intake. Diastolic blood pressure and heart rate did not change. Plasma angiotensin converting enzyme activity decreased rapidly and dose-dependently. In both the high- and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic peptide levels remained unchanged. In contrast, urinary atrial natriuretic peptide excretion increased dose-dependently under both diets, as did urinary cyclic GMP excretion. Effective renal plasma flow and the glomerular filtration rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100,240 (P < 0.001) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P = 0.07). Potassium excretion remained stable. Proximal and distal fractional sodium reabsorption were not significantly altered by the treatment. Uric acid excretion was increased. The safety and clinical tolerance of MDL 100,240 were good. CONCLUSIONS The increased fall in blood pressure in normal volunteers together with the preservation of renal hemodynamics and the increased urinary volume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100,240 as a double-enzyme inhibitor from inhibitors of the angiotensin converting enzyme alone. The differences appear to be due, at least in part, to increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade.
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- 1999
11. Population pharmacokinetics and pharmacodynamics of the artesunate–mefloquine fixed dose combination for the treatment of uncomplicated falciparum malaria in African children
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Monia Guidi, Thomas Mercier, Manel Aouri, Laurent A. Decosterd, Chantal Csajka, Bernhards Ogutu, Gwénaëlle Carn, and Jean-René Kiechel
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Population pharmacokinetics ,Mefloquine ,Artesunate ,Dihydroartemisinin ,Arctic medicine. Tropical medicine ,RC955-962 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background The World Health Organization (WHO) recommends combinations of an artemisinin derivative plus an anti-malarial drug of longer half-life as treatment options for uncomplicated Plasmodium falciparum infections. In Africa, artesunate–mefloquine (ASMQ) is an infrequently used artemisinin-based combination therapy (ACT) because of perceived poor tolerance to mefloquine. However, the WHO has recommended reconsideration of the use of ASMQ in Africa. In this large clinical study, the pharmacokinetics (PK) of a fixed dose combination of ASMQ was investigated in an African paediatric population to support dosing recommendations used in Southeast Asia and South America. Methods Among the 472 paediatric patients aged 6–59 months from six African centres included in the large clinical trial, a subset of 50 Kenyan children underwent intensive sampling to develop AS, its metabolite dihydroartemisinin (DHA) and MQ PK models. The final MQ PK model was validated using sparse data collected in the remaining participants (NONMEM®). The doses were one or two tablets containing 25/55 mg AS/MQ administered once a day for 3 days according to patients’ age. A sensitive LC–MS/MS method was used to quantify AS, DHA and MQ concentrations in plasma. An attempt was made to investigate the relationship between the absence/presence of malaria recrudescence and MQ area under the curve (AUC) using logistic regression. Results AS/DHA concentration–time profiles were best described using a one-compartment model for both compounds with irreversible AS conversion into DHA. AS/DHA PK were characterized by a significant degree of variability. Body weight affected DHA PK parameters. MQ PK was characterized by a two-compartment model and a large degree of variability. Allometric scaling of MQ clearances and volumes of distribution was used to depict the relationship between MQ PK and body weight. No association was found between the model predicted AUC and appearance of recrudescence. Conclusions The population pharmacokinetic models developed for both AS/DHA and MQ showed a large variability in drug exposure in the investigated African paediatric population. The largest contributor to this variability was body weight, which is accommodated for by the ASMQ fixed dose combination (FDC) dosing recommendation. Besides body weight considerations, there is no indication that the dosage should be modified in children with malaria compared to adults. Trial registration Pan African Clinical Trials Registry PACTR201202000278282 registration date 2011/02/16
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- 2019
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12. The Steps to Therapeutic Drug Monitoring: A Structured Approach Illustrated With Imatinib
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Thierry Buclin, Yann Thoma, Nicolas Widmer, Pascal André, Monia Guidi, Chantal Csajka, and Laurent A. Decosterd
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drug monitoring ,molecular targeted therapies ,pharmacokinetic-pharmacodynamic models ,pharmacometrics ,precision medicine ,dosage individualization ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Pharmacometric methods have hugely benefited from progress in analytical and computer sciences during the past decades, and play nowadays a central role in the clinical development of new medicinal drugs. It is time that these methods translate into patient care through therapeutic drug monitoring (TDM), due to become a mainstay of precision medicine no less than genomic approaches to control variability in drug response and improve the efficacy and safety of treatments. In this review, we make the case for structuring TDM development along five generic questions: 1) Is the concerned drug a candidate to TDM? 2) What is the normal range for the drug's concentration? 3) What is the therapeutic target for the drug's concentration? 4) How to adjust the dosage of the drug to drive concentrations close to target? 5) Does evidence support the usefulness of TDM for this drug? We exemplify this approach through an overview of our development of the TDM of imatinib, the very first targeted anticancer agent. We express our position that a similar story shall apply to other drugs in this class, as well as to a wide range of treatments critical for the control of various life-threatening conditions. Despite hurdles that still jeopardize progress in TDM, there is no doubt that upcoming technological advances will shape and foster many innovative therapeutic monitoring methods.
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- 2020
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13. Sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses: A pilot study in healthy volunteers
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Kim Dao, Paul Thoueille, Laurent A. Decosterd, Thomas Mercier, Monia Guidi, Carine Bardinet, Sébastien Lebon, Eva Choong, Arnaud Castang, Catherine Guittet, Luc‐André Granier, and Thierry Buclin
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clearance ,healthy volunteers ,pharmacokinetic ,sultiame ,volume of distribution ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract A pilot study was conducted aiming at specifying sultiame's pharmacokinetic profile, completed by in vitro assays evaluating the intraerythrocytic transfer of sultiame and by a pharmacokinetic model assessing its distribution. Single oral doses of sultiame (Ospolot® 50, 100, and 200 mg) were administered in open‐label to four healthy volunteers. Serial plasma, whole blood, and urine samples were collected. A spiking experiment was also performed to characterize sultiame's exchanges between plasma and erythrocytes in vitro. Pharmacokinetic parameters were evaluated using standard noncompartmental calculations and nonlinear mixed‐effect modeling. The plasma maximal concentrations (Cmax) showed striking nonlinear disposition of sultiame, with a 10‐fold increase while doses were doubled. Conversely, whole blood Cmax increased less than dose proportionally while staying much higher than in plasma. Quick uptake of sultiame into erythrocytes observed in vivo was confirmed in vitro, with minimal efflux. A two‐compartment model with first‐order absorption, incorporating a saturable ligand to receptor binding, described the data remarkably well, indicating apparent plasma clearance of 10.0 L/h (BSV: 29%) and distribution volume of 64.8 L; saturable uptake into an intracellular compartment of 3.3 L with a maximum binding capacity of 111 mg accounted for nonlinearities observed in plasma and whole blood concentrations. Pharmacokinetic characteristics of sultiame are reported, including estimates of clearance and volume of distribution that were so far unpublished. The noticeable nonlinearity in sultiame disposition should be taken into account for the design of future studies and the interpretation of therapeutic drug monitoring results.
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- 2020
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14. Dosage Optimization of Treatments Using Population Pharmacokinetic Modeling and Simulation
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M. Guidi, Mona Arab-Alameddine, Margalida Rotger, Manel Aouri, Amalio Telenti, Laurent A. Decosterd, Thierry Buclin, and Chantal Csajka
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Hiv ,Nevirapine ,Nonmem ,Pharmacokinetics ,Population ,Chemistry ,QD1-999 - Abstract
Pharmacokinetic variability in drug levels represent for some drugs a major determinant of treatment success, since sub-therapeutic concentrations might lead to toxic reactions, treatment discontinuation or inefficacy. This is true for most antiretroviral drugs, which exhibit high inter-patient variability in their pharmacokinetics that has been partially explained by some genetic and non-genetic factors. The population pharmacokinetic approach represents a very useful tool for the description of the dose-concentration relationship, the quantification of variability in the target population of patients and the identification of influencing factors. It can thus be used to make predictions and dosage adjustment optimization based on Bayesian therapeutic drug monitoring (TDM). This approach has been used to characterize the pharmacokinetics of nevirapine (NVP) in 137 HIV-positive patients followed within the frame of a TDM program. Among tested covariates, body weight, co-administration of a cytochrome (CYP) 3A4 inducer or boosted atazanavir as well as elevated aspartate transaminases showed an effect on NVP elimination. In addition, genetic polymorphism in the CYP2B6 was associated with reduced NVP clearance. Altogether, these factors could explain 26% in NVP variability. Model-based simulations were used to compare the adequacy of different dosage regimens in relation to the therapeutic target associated with treatment efficacy. In conclusion, the population approach is very useful to characterize the pharmacokinetic profile of drugs in a population of interest. The quantification and the identification of the sources of variability is a rational approach to making optimal dosage decision for certain drugs administered chronically.
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- 2012
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