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2.
Expert Rev Clin Pharmacol ; 17(3): 225-234, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38345044

ABSTRACT

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have revolutionized survival rates of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and replaced hematopoietic stem cell transplantation (hSCT) as the key treatment option for these patients. More recently, the so-called Philadelphia chromosome-like (Ph-like) ALL has similarly benefitted from TKIs. However, many patients shift from the first generation TKI, imatinib, due to treatment-related toxicities or lack of treatment efficacy. A more personalized approach to TKI treatment could counteract these challenges and potentially be more cost-effective. Therapeutic drug monitoring (TDM) has led to higher response rates and less treatment-related toxicity in adult CML but is rarely used in ALL or in childhood CML. AREAS COVERED: This review summarizes different antileukemic treatment indications for TKIs with focus on imatinib and its pharmacokinetic/-dynamic properties as well as opportunities and pitfalls of TDM for imatinib treatment in relation to pharmacogenetics and co-medication for pediatric and adult Ph+/Ph-like leukemias. EXPERT OPINION: TDM of imatinib adds value to standard monitoring of ABL-class leukemia by uncovering non-adherence and potentially mitigating adverse effects. Clinically implementable pharmacokinetic/-dynamic models adjusted for relevant pharmacogenetics could improve individual dosing. Prospective trials of TDM-based treatments, including both children and adults, are needed.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Philadelphia Chromosome , Adult , Humans , Child , Imatinib Mesylate/adverse effects , Drug Monitoring , Prospective Studies , Protein Kinase Inhibitors/adverse effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Drug Resistance, Neoplasm/genetics
3.
J Antimicrob Chemother ; 78(11): 2630-2636, 2023 11 06.
Article in English | MEDLINE | ID: mdl-37796931

ABSTRACT

Voriconazole is a triazole antifungal indicated for invasive fungal infections that exhibits a high degree of inter-individual and intra-individual pharmacokinetic variability. Voriconazole pharmacokinetics is non-linear, making dosage adjustments more difficult. Therapeutic drug monitoring is recommended by measurement of minimum plasma concentrations. Several factors are responsible for the high pharmacokinetic variability of voriconazole: age, feeding (which decreases absorption), liver function, genetic polymorphism of the CYP2C19 gene, drug interactions and inflammation. Invasive fungal infections are indeed very frequently associated with inflammation, which engenders a risk of voriconazole overexposure. Many studies have reviewed this topic in both the adult and paediatric populations, but few studies have focused on the specific point of the prediction, to evaluate the influence of inflammation on voriconazole pharmacokinetics. Predicting the impact of inflammation on voriconazole pharmacokinetics could help optimize antifungal therapy and improve patient management. This review summarizes the existing data on the influence of inflammation on voriconazole pharmacokinetics in adult populations. We also evaluate the role of C-reactive protein, the impact of inflammation on patient metabolic phenotypes, and the tools that can be used to predict the effect of inflammation on voriconazole pharmacokinetics.


Subject(s)
Invasive Fungal Infections , Voriconazole , Adult , Child , Humans , Antifungal Agents/pharmacokinetics , Inflammation , Invasive Fungal Infections/drug therapy , Voriconazole/pharmacokinetics
4.
Eur J Clin Pharmacol ; 79(11): 1549-1556, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37725122

ABSTRACT

PURPOSE: Therapeutic drug monitoring of tacrolimus using trough concentration (Cmin) is mandatory to ensure drug efficacy and safety in solid organ transplantation. However, Cmin is just a proxy for the area under the curve of drug concentrations (AUC) which is the best pharmacokinetic parameter for exposure evaluation. Some studies suggest that patients may present discrepancies between these two parameters. AUC is now easily available through mini-invasive microsampling approach. The aim of this study is to evaluate the relationship between AUC and Cmin in patients benefiting from a complete pharmacokinetic profile using a microsampling approach. METHODS: Fifty-one transplant recipients benefited from a complete pharmacokinetic profile using a microsampling approach, and their 24-h AUC were calculated using the trapezoidal method. The correlation with Cmin was then explored. In parallel, we estimated AUC using the sole Cmin and regression equations according to the post-transplantation days and the galenic form. RESULTS: Weak correlations were found between 24-h AUC observed and the corresponding Cmin (R2 = 0.60) and between AUC observed and expected using the sole Cmin (R2 = 0.62). Therapeutic drug monitoring of tacrolimus using Cmin leads to over- or under-estimate drug exposure in 40.3% of patients. CONCLUSION: Tacrolimus Cmin appears to be an imperfect reflection of drug exposure. Evaluating AUC using a microsampling approach offers a mini-invasive strategy to monitor tacrolimus treatment in transplant recipients.


Subject(s)
Organ Transplantation , Tacrolimus , Humans , Tacrolimus/therapeutic use , Tacrolimus/pharmacokinetics , Immunosuppressive Agents/pharmacokinetics , Precision Medicine , Transplant Recipients , Drug Monitoring/methods , Area Under Curve
5.
Clin Biochem ; 118: 110601, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37353137

ABSTRACT

BACKGROUND: The use of the selective Janus Kinase 1/2 inhibitor baricitinib has shown a survival benefit in mechanically ventilated COVID-19 patients but this is not without adverse drug reactions. Although critically ill patients are at risk of altered drug exposure, data on baricitinib pharmacokinetics (PK) are scarce. This study describes real-life baricitinib plasma exposure in critically ill COVID-19 patients. METHODS: This retrospective observational study was conducted in critically ill patients with COVID-19 treated with baricitinib 4 mg/day. Plasma concentrations were measured at predose (C0), 1 h (C1) and 3 h (C3) after the drug intake. PK and area under the curve (AUC) were estimated using non-compartmental pharmacokinetic analysis. RESULTS: Seven patients contributed to 22 baricitinib plasma concentration measurements after a median [range] of 3 days [2-3] of treatment. Median baricitinib plasma concentrations were 2.2 ng/mL [1.4-8.0], 24.0 ng/mL [4.9-37.3] and 14.1 ng/mL [8.3-15.1] for trough (C0), C1 and C3 concentrations respectively. The median AUC 0-24 h was 188.8 ng.h/mL [141.3-236.3]. No difference was observed in C0 and C1 when comparing patients according to body mass index < or > 30. The patient with the lowest glomerular filtration rate (74 mL/min) had the highest baricitinib trough concentration. Overall, 2 patients had liver function test perturbation and both of them had atypical PK with delayed time to reach maximum concentration. CONCLUSION: High inter-patient variability and relatively low baricitinib trough concentrations and AUC were observed in critically ill COVID-19 patients receiving the usual dosage of 4 mg/day. This preliminary study encourages further exploration of the concentration-effect relationship of baricitinib in this clinical context.


Subject(s)
Azetidines , COVID-19 , Humans , Critical Illness , COVID-19 Drug Treatment , Azetidines/therapeutic use
7.
Antibiotics (Basel) ; 12(4)2023 Mar 30.
Article in English | MEDLINE | ID: mdl-37107042

ABSTRACT

BACKGROUND: Amoxicillin (AMX)-induced neurotoxicity is well described and may be associated with AMX overexposure. No neurotoxic concentration threshold has been determined thus far. A better knowledge of maximum tolerable AMX concentrations is of importance to improve the safety of high doses of AMX. METHODS: We conducted a retrospective study using the local hospital data warehouse EhOP® to generate a specific query related to AMX neurotoxicity symptomatology. All patient medical reports containing a mention of neurotoxicity clinical symptoms coupled with AMX plasma concentration measurements were explored. Patients were classified into two groups according to the imputability of AMX in the onset of their neurotoxicity, on the basis of chronological and semiological criteria. A receiver-operating characteristic curve was performed to identify an AMX neurotoxic steady-state concentration (Css) threshold. RESULTS: The query identified 101 patients among 2054 patients benefiting from AMX TDM. Patients received a median daily dose of 9 g AMX, with a median creatinine clearance of 51 mL/min. A total of 17 of the 101 patients exhibited neurotoxicity attributed to AMX. The mean Css was higher for patients with neurotoxicity attributed to AMX (118 ± 62 mg/L) than those without 74 ± 48 mg/L (p = 0.002). A threshold AMX concentration of 109.7 mg/L predicted the occurrence of neurotoxicity. CONCLUSIONS: This study identified, for the first time, an AMX Css threshold of 109.7 mg/L associated with an excess risk of neurotoxicity. This approach needs to be confirmed by a prospective study with systematic neurological evaluation and TDM.

8.
Br J Dermatol ; 188(4): 482-490, 2023 03 30.
Article in English | MEDLINE | ID: mdl-36760148

ABSTRACT

BACKGROUND: Proton-pump inhibitors (PPIs) are commonly used by patients with cancer, although they could reduce the absorption of oral anticancer targeted therapies. The US Food and Drug Administration states that the effect of PPIs on the efficacy of dabrafenib use by patients with metastatic melanoma is unknown. As a precautionary measure, the European Society for Medical Oncology recommends avoiding PPIs for patients receiving dabrafenib. OBJECTIVES: To determine the effect of the concomitant use of PPIs and BRAF/MEK inhibitors in patients with metastatic melanoma. METHODS: Patients with advanced melanoma receiving BRAF/MEK inhibitors as first-line treatments between 2015 and 2017 in France were selected using the French National Health Insurance database. We compared time-to-treatment discontinuation (TTD) and overall survival (OS) according to concomitant PPI exposure. We balanced the baseline characteristics of patients exposed and nonexposed to PPIs using an overlap weighting method based on a propensity score. RESULTS: The metastatic melanoma cohort comprised 1028 patients receiving BRAF/MEK inhibitors, including 361 (35.1%) patients using PPIs. PPI users had more comorbidities and a more severe metastatic disease. After having equally distributed metastatic sites and comorbidities across patients exposed and nonexposed to PPIs, concomitant PPI use was not associated with shorter TTD [weighted hazard ratio (wHR) 1.03, 95% confidence interval (CI) 0.86-1.24] or OS (wHR 1.11, 95% CI 0.88-1.39). Consistent results were observed when restricting the population to patients receiving dabrafenib, or when narrowing exposure to PPIs with stronger inhibition of cytochromes. CONCLUSIONS: In a population-based cohort of patients with advanced melanoma, the concomitant use of PPIs and BRAF/MEK inhibitors was not associated with worse outcome.


Subject(s)
Melanoma , Proton Pump Inhibitors , Humans , Proton Pump Inhibitors/adverse effects , Proto-Oncogene Proteins B-raf , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/pathology , Protein Kinase Inhibitors/pharmacology , Mitogen-Activated Protein Kinase Kinases
9.
Mycoses ; 66(5): 396-404, 2023 May.
Article in English | MEDLINE | ID: mdl-36698317

ABSTRACT

BACKGROUND: Voriconazole (VRC), a widely used triazole antifungal, exhibits significant inter- and intra-individual pharmacokinetic variability. The main metabolite voriconazole N-oxide (NOX) can provide information on the patient's drug metabolism capacity. OBJECTIVES: Our objectives were to implement routine measurement of NOX concentrations and to describe the metabolic ratio (MR), and the contribution of the MR to VRC therapeutic drug monitoring (TDM) by proposing a suggested dosage-adjustment algorithm. PATIENTS AND METHODS: Sixty-one patients treated with VRC were prospectively included in the study, and VRC and NOX levels were assayed by LC-MS/MS. A mixed logistic model on repeated measures was implemented to analyse risk factors for the patient's concentration to be outside the therapeutic range. RESULTS: Based on 225 measurements, the median and interquartile range were 2.4 µg/ml (1.2; 4.2), 2.1 µg/ml (1.5; 3.0) and 1.0 (0.6; 1.9) for VRC, NOX and the MR, respectively. VRC Cmin <2 µg/ml were associated with a higher MR during the previous visit. MR values >1.15 and <0.48 were determined to be the best predictors for having a VRC Cmin lower than 2 µg/ml and above 5.5 µg/ml, respectively, at the next visit. CONCLUSIONS: Measurement of NOX resulted useful for TDM of patients treated with VRC. The MR using NOX informed interpretation and clinical decision-making and is very interesting for complex patients. VRC phenotyping based on the MR is now performed routinely in our institution. A dosing algorithm has been suggested from these results.


Subject(s)
Drug Monitoring , Invasive Fungal Infections , Humans , Voriconazole , Drug Monitoring/methods , Chromatography, Liquid , Tandem Mass Spectrometry , Antifungal Agents , Invasive Fungal Infections/drug therapy , Oxides
11.
Br J Clin Pharmacol ; 89(2): 762-772, 2023 02.
Article in English | MEDLINE | ID: mdl-36104927

ABSTRACT

AIMS: Determining dihydropyrimidine dehydrogenase (DPD) activity by measuring patient's uracil (U) plasma concentration is mandatory before fluoropyrimidine (FP) administration in France. In this study, we aimed to refine the pre-analytical recommendations for determining U and dihydrouracil (UH2 ) concentrations, as they are essential in reliable DPD-deficiency testing. METHODS: U and UH2 concentrations were collected from 14 hospital laboratories. Stability in whole blood and plasma after centrifugation, the type of anticoagulant and long-term plasma storage were evaluated. The variation induced by time and temperature was calculated and compared to an acceptability range of ±20%. Inter-occasion variability (IOV) of U and UH2 was assessed in 573 patients double sampled for DPD-deficiency testing. RESULTS: Storage of blood samples before centrifugation at room temperature (RT) should not exceed 1 h, whereas cold (+4°C) storage maintains the stability of uracil after 5 hours. For patients correctly double sampled, IOV of U reached 22.4% for U (SD = 17.9%, range = 0-99%). Notably, 17% of them were assigned with a different phenotype (normal or DPD-deficient) based on the analysis of their two samples. For those having at least one non-compliant sample, this percentage increased up to 33.8%. The moment of blood collection did not affect the DPD phenotyping result. CONCLUSION: Caution should be taken when interpreting U concentrations if the time before centrifugation exceeds 1 hour at RT, since it rises significantly afterwards. Not respecting the pre-analytical conditions for DPD phenotyping increases the risk of DPD status misclassification.


Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency , Humans , Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , Dihydrouracil Dehydrogenase (NADP)/genetics , Uracil , Phenotype , Plasma , Fluorouracil
12.
Ther Drug Monit ; 45(2): 229-235, 2023 04 01.
Article in English | MEDLINE | ID: mdl-36006706

ABSTRACT

BACKGROUND: After heart transplantation, calcineurin inhibitors (CNI) (cyclosporin A and tacrolimus) are key immunosuppressive drugs to prevent graft rejection. Whole-blood concentration (C blood )-guided therapeutic drug monitoring (TDM) is systematically performed to improve graft outcomes. However, some patients will still experience graft rejection and/or adverse events despite CNI C blood within the therapeutic range. Other pharmacokinetic parameters, such as the intragraft, or intracellular concentration at the CNI site of action could refine their TDM. Nonetheless, these remain to be explored. The objective of the INTRACAR study was to describe the relationship between whole blood, intragraft, and intracellular CNI concentrations as well as their efficacy in heart transplant recipients (HTR). METHODS: In a cohort of HTR, protocol endomyocardial biopsies (EMB) were collected to assess rejection by anatomopathological analysis. Part of the EMB was used to measure the intragraft concentrations of CNI (C EMB ). C blood and the concentration inside peripheral blood mononuclear cells, (C PBMC ), a cellular fraction enriched with lymphocytes, were also monitored. Concentrations in the 3 matrices were compared between patients with and without biopsy-proven acute rejection (BPAR). RESULTS: Thirty-four HTR were included, representing nearly 100 pharmacokinetic (PK) samples for each CNI. C blood , C EMB , and C PBMC correlated for both CNI. BPAR was observed in 74 biopsies (39.6%) from 26 patients (76.5%), all except one was of low grade. None of the PK parameters (C blood , C EMB , C PBMC , C EMB/blood , and C PBMC/blood ) was associated with BPAR. CONCLUSIONS: In this cohort of well-immunosuppressed patients, no association was observed for any of the PK parameters, including C blood , with the occurrence of BPAR. However, a trend was noticed for the C EMB and C EMB/blood of cyclosporin A. Further studies in higher-risk patients may help optimize the use of C EMB and C PBMC for CNI TDM in HTR.


Subject(s)
Calcineurin Inhibitors , Heart Transplantation , Humans , Calcineurin Inhibitors/therapeutic use , Cyclosporine/therapeutic use , Leukocytes, Mononuclear , Immunosuppressive Agents/adverse effects , Graft Rejection/prevention & control
13.
Clin Biochem ; 109-110: 86-89, 2022.
Article in English | MEDLINE | ID: mdl-36108718

ABSTRACT

The most appropriate renal function estimation equation to predict drug clearance is a matter of debate. In this study, we compare the Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) and the Cockroft-Gault (CG) equations to predict amoxicillin and cloxacillin clearance among hospitalized patients receiving high doses of these antibiotic treatments. This study aimed to compare different equations used to predict amoxicillin and cloxacillin clearance among hospitalized patients receiving amoxicillin or cloxacillin treatments outside the intensive care unit. Data from 128 patients contributing 268 plasma samples was analyzed, and correlations between the equations and the amoxicillin and cloxacillin antibiotic clearance rates were calculated. We found a correlation between antibiotic clearance and all the renal function estimation equations, CG being the best, with a R2 of 0.35 for amoxicillin and 0.29 for cloxacillin (compared to 0.26 and 0.21 for MDRD and 0.12 and 0.24 for CKD-EPI). CG should be preferentially used as a proxy for amoxicillin and cloxacillin drug clearance, but the use of completely different tools such as therapeutic drug monitoring could help individualize antibiotic dosage.


Subject(s)
Amoxicillin , Renal Insufficiency, Chronic , Humans , Glomerular Filtration Rate , Cloxacillin , Anti-Bacterial Agents , Renal Insufficiency, Chronic/epidemiology , Drug Elimination Routes , Kidney/physiology , Creatinine
14.
Drug Metab Pharmacokinet ; 47: 100473, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36166890

ABSTRACT

Because of a narrow therapeutic index and a wide inter- and intra-patient variability, therapeutic drug monitoring of the immunosuppressant drug tacrolimus (TAC) based on whole-blood concentrations (Cblood) is mandatory in solid organ transplant recipients. Using peripheral blood mononuclear cells concentrations (CPBMC) could improve patient outcomes. The poor correlation between Cblood and CPBMC makes hypothesize that drug transporters are implicated in the intracellular accumulation of TAC. The aim of this work was therefore to clinically study: i) the role of genetic variants and ii) the effect of mRNA and protein expression of 4 drug transporters on the TAC CPBMC/blood ratio. In addition, functional in vitro experiments were performed to mechanistically validate the clinical observations. Genetic variants of ABCB1/P-gp and SLC28A3/CNT3 did not influence TAC CPBMC in liver transplant recipients (LTR). ABCC2/MRP2 at the mRNA level; ABCB1/P-gp, SLC28A3/CNT3 and SLC29A1/ENT1 at the protein level; correlated with the CPBMC/blood in kidney and LTR. In vitro results suing transporter-expressing cells confirmed that TAC is substrate of P-gp but not MRP2, whereas experiments remained inconclusive for CNT3 and ENT1. In conclusion, the genetic-transcription-protein-functional approach presented in this work provides new insights in the understanding of TAC transport at the T lymphocyte plasma membrane.


Subject(s)
Liver Transplantation , Tacrolimus , Humans , Leukocytes, Mononuclear/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Cytochrome P-450 CYP3A/metabolism , T-Lymphocytes , Immunosuppressive Agents , Kidney
15.
Bioanalysis ; 14(11): 831-844, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35735172

ABSTRACT

Background: This study compared the performance of plasma infliximab and adalimumab quantification using a commercially available kit (mAbXmise kit) and mass spectrometry readout to that of two ELISA methods in patients treated for inflammatory bowel disease. Methods & results: The mAbXmise method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) was linear from 2 to 100 µg/ml. It was validated according to international guidelines. Regarding cross-validation for infliximab (n = 70), the mean bias with LC-MS/MS assay was approximately threefold higher with the commercial ELISA assay compared with the in-house ELISA (-6.1 vs -1.8 µg/ml, respectively). The mean bias between the LC-MS/MS assay and in-house ELISA was -1.2 µg/ml for adalimumab (n = 35). Conclusion: The LC-MS/MS method is a powerful alternative to immunoassays to monitor concentrations of infliximab and adalimumab.


Subject(s)
Tandem Mass Spectrometry , Adalimumab , Chromatography, Liquid/methods , Enzyme-Linked Immunosorbent Assay/methods , Humans , Infliximab , Tandem Mass Spectrometry/methods
16.
Pharmaceuticals (Basel) ; 15(5)2022 May 22.
Article in English | MEDLINE | ID: mdl-35631462

ABSTRACT

In the field of pharmacogenetics, the trend is to analyze a panel of several actionable genetic polymorphisms. It may require the use of high-throughput sequencing which demands expensive reagents/instruments and specific skills to interpret results. As an alternative, the aim of this work was to validate an easy, fast, and inexpensive multiplex pharmacogenetics assay to simultaneously genotype a panel of 17 clinically actionable variants involved in drug pharmacokinetics/pharmacodynamics. We designed primers to perform a multiplex PCR assay using a single mix. Primers were labeled by two fluorescent dye markers to discriminate alleles, while the size of the PCR fragments analyzed by electrophoresis allowed identifying amplicon. Polymorphisms of interest were CYP3A4*22, CYP3A5*3, CYP1A2*1F, CYP2C9*2-*3, CYP2C19*2-*3-*17, VKORC1-1639G > A, ABCB1 rs1045642-rs1128503-rs2229109-rs2032582, and CYP2D6*3-*4-*6-*9. The assay was repeatable and a minimum quantity of 10 ng of DNA/ sample was needed to obtain accurate results. The method was applied to a validation cohort of 121 samples and genotyping results were consistent with those obtained with reference methods. The assay was fast and cost-effective with results being available within one working-day. This robust assay can easily be implemented in laboratories as an alternative to cumbersome simplex assays or expensive multiplex approaches. Together it should widespread access to pharmacogenetics in clinical routine practice.

17.
BMC Infect Dis ; 21(1): 1143, 2021 Nov 08.
Article in English | MEDLINE | ID: mdl-34749667

ABSTRACT

BACKGROUND: Ganciclovir pharmacokinetics is characterized by a high variability in drug exposure. Usually, monitoring of ganciclovir exposure is performed by measuring trough concentration. However, due to the specificity of pediatric pharmacokinetics, trough concentration measurements may not be a relevant surrogate of ganciclovir exposure. Area under the curve of concentration (AUC) may be a more appropriate biomarker. CASE PRESENTATION: We report the case of 3.6-year-old boy with Emberger syndrome with a cytomegalovirus reactivation occurring after allogenic hematopoietic stem cell transplantation. After a few days of treatment with intravenous ganciclovir, sub-therapeutic trough ganciclovir concentrations were measured (< 0.5 µg/mL) and viral load still increased. Ganciclovir dosage was increased by two-fold to deal with this treatment failure. Trough concentrations remained sub-therapeutic. The patient had hematologic disorder therefore it was decided to estimate ganciclovir AUC to assess more accurately drug exposure before any further dosage modification. AUC0-12 h was measured at 51 µg h/mL, which was within the therapeutic range (40-60 µg h/mL). Afterward, viral load decreased and became undetectable. CONCLUSIONS: This case report highlights that monitoring ganciclovir exposure based on AUC should be performed to tailor drug dosage in order to improve treatment efficacy and safety in pediatric patients.


Subject(s)
Cytomegalovirus Infections , Ganciclovir , Antiviral Agents/therapeutic use , Child, Preschool , Cytomegalovirus Infections/drug therapy , Drug Monitoring , Ganciclovir/therapeutic use , Humans , Male , Viral Load
19.
Biomed Pharmacother ; 142: 112053, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34435591

ABSTRACT

Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue. We conducted a prospective, single-center study in 30 OAI patients hospitalized in the Rennes University Hospital to model ofloxacin pharmacokinetics and to define a limited sampling strategy (LSS) suitable for ofloxacin and levofloxacin treatments. Modeling was conducted with the Monolix software. The final model was externally validated using levofloxacin data. Monte-Carlo simulations were used to evaluate the probability of target attainment (PTA) of different dosing regimens. Two hundred and ninety-seven (297) ofloxacin concentrations were available for the pharmacokinetic modeling. Ofloxacin pharmacokinetics was best described using a bicompartmental model with a first order elimination, and a transit compartment model absorption. CKD-EPI and sex explained half of ofloxacin pharmacokinetic variability. For LSS, the 0, 1 h and 3 h sampling scheme resulted in the best approach both for BID and TID dosages (R2 adjusted = 91.1% and 95.0%, outliers = 4.8% and 5.0%, respectively). PTA allows choosing the best drug and dosage according to various hypotheses. A simple 3-sample protocol (pre-dose, 1 h after intake and 3 h after intake) to estimate ofloxacin and levofloxacin AUC allows optimal drug dosage for the treatment of osteoarticular infections.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Bone Diseases, Infectious/drug therapy , Fluoroquinolones/administration & dosage , Fluoroquinolones/pharmacokinetics , Joint Diseases/drug therapy , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/blood , Female , Fluoroquinolones/blood , Humans , Levofloxacin/administration & dosage , Levofloxacin/blood , Levofloxacin/pharmacokinetics , Male , Middle Aged , Models, Biological , Monte Carlo Method , Ofloxacin/administration & dosage , Ofloxacin/blood , Ofloxacin/pharmacokinetics , Prospective Studies , Staphylococcus/drug effects , Young Adult
20.
Biomed Chromatogr ; 35(12): e5208, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34212399

ABSTRACT

In the management of cystic fibrosis, treatments against Staphylococcus aureus and Haemophilus influenzae such as amoxicillin or cotrimoxazole have to be prescribed and the antibiotherapy's efficacy may be linked to the concentration that reaches the infected site. As cystic fibrosis patients present disturbed pharmacokinetics parameters, drug monitoring would be relevant to assess the lung distribution of antibiotics and to optimize dosing regimens. In this context, the aim of the study was to develop and validate HPLC-based methods for the determination of both antibiotics in bronchial sputum from cystic fibrosis patients, in order to assess the distribution of the drugs into the lungs. Plasma proteins were precipitated by acetonitrile and amoxicillin concentrations in sputum were determined by HPLC coupled with tandem-mass spectrometry. Following liquid extraction with ethyl acetate, cotrimoxazole was quantified by HPLC using ultraviolet detection. Both methods were rapid, specific, accurate and reproducible. The method was applied to patient samples. In three treated patients, concentrations of amoxicillin in sputum were similar and below the lower limit of quantification (0.1 µg/g) and in six patients, sputum concentrations up to 11.1 and 6.4 µg/g were measured for sulfamethoxazole and trimethoprim, respectively.


Subject(s)
Amoxicillin , Cystic Fibrosis/drug therapy , Sputum/chemistry , Trimethoprim, Sulfamethoxazole Drug Combination , Amoxicillin/analysis , Amoxicillin/chemistry , Amoxicillin/therapeutic use , Chromatography, High Pressure Liquid/methods , Drug Monitoring/methods , Humans , Limit of Detection , Linear Models , Reproducibility of Results , Trimethoprim, Sulfamethoxazole Drug Combination/analysis , Trimethoprim, Sulfamethoxazole Drug Combination/chemistry , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use
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