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2.
J Antimicrob Chemother ; 78(11): 2630-2636, 2023 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-37796931

RESUMO

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.


Assuntos
Infecções Fúngicas Invasivas , Voriconazol , Adulto , Criança , Humanos , Antifúngicos/farmacocinética , Inflamação , Infecções Fúngicas Invasivas/tratamento farmacológico , Voriconazol/farmacocinética
3.
Br J Dermatol ; 188(4): 482-490, 2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-36760148

RESUMO

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.


Assuntos
Melanoma , Inibidores da Bomba de Prótons , Humanos , Inibidores da Bomba de Prótons/efeitos adversos , Proteínas Proto-Oncogênicas B-raf , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/patologia , Inibidores de Proteínas Quinases/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno
4.
Br J Clin Pharmacol ; 89(2): 762-772, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36104927

RESUMO

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.


Assuntos
Deficiência da Di-Hidropirimidina Desidrogenase , Humanos , Deficiência da Di-Hidropirimidina Desidrogenase/diagnóstico , Di-Hidrouracila Desidrogenase (NADP)/genética , Uracila , Fenótipo , Plasma , Fluoruracila
5.
Ther Drug Monit ; 45(2): 229-235, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36006706

RESUMO

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.


Assuntos
Inibidores de Calcineurina , Transplante de Coração , Humanos , Inibidores de Calcineurina/uso terapêutico , Ciclosporina/uso terapêutico , Leucócitos Mononucleares , Imunossupressores/efeitos adversos , Rejeição de Enxerto/prevenção & controle
6.
Eur J Clin Pharmacol ; 79(11): 1549-1556, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37725122

RESUMO

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.


Assuntos
Transplante de Órgãos , Tacrolimo , Humanos , Tacrolimo/uso terapêutico , Tacrolimo/farmacocinética , Imunossupressores/farmacocinética , Medicina de Precisão , Transplantados , Monitoramento de Medicamentos/métodos , Área Sob a Curva
7.
Mycoses ; 66(5): 396-404, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36698317

RESUMO

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.


Assuntos
Monitoramento de Medicamentos , Infecções Fúngicas Invasivas , Humanos , Voriconazol , Monitoramento de Medicamentos/métodos , Cromatografia Líquida , Espectrometria de Massas em Tandem , Antifúngicos , Infecções Fúngicas Invasivas/tratamento farmacológico , Óxidos
8.
BMC Infect Dis ; 21(1): 1143, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749667

RESUMO

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.


Assuntos
Infecções por Citomegalovirus , Ganciclovir , Antivirais/uso terapêutico , Pré-Escolar , Infecções por Citomegalovirus/tratamento farmacológico , Monitoramento de Medicamentos , Ganciclovir/uso terapêutico , Humanos , Masculino , Carga Viral
9.
Biomed Chromatogr ; 35(12): e5208, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34212399

RESUMO

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.


Assuntos
Amoxicilina , Fibrose Cística/tratamento farmacológico , Escarro/química , Combinação Trimetoprima e Sulfametoxazol , Amoxicilina/análise , Amoxicilina/química , Amoxicilina/uso terapêutico , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Combinação Trimetoprima e Sulfametoxazol/análise , Combinação Trimetoprima e Sulfametoxazol/química , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
10.
Ther Drug Monit ; 42(2): 163-164, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32195986
11.
Ther Drug Monit ; 42(5): 671-678, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32941395

RESUMO

BACKGROUND: Currently, the recommended tacrolimus (TAC) trough level (Cmin) after liver transplantation (LT) is 6-10 ng/mL (when associated in triple immunosuppressive therapy). However, few studies have achieved the lower limit of this range, especially below 7 ng/mL. This study evaluated the efficacy of a target TAC Cmin of 4-7 ng/mL after LT. METHODS: Of 1677 LTs performed between 2002 and 2017, 904 LT cases were analyzed. The cases were categorized into the following 3 groups and compared: low- (n = 247, 27.3%), intermediate- (n = 344, 37.9%), and high-exposure groups (n = 313, 34.5%) with TAC Cmin of 4-7 ng/mL, 7-10 ng/mL, and >10 ng/mL, respectively. In addition, propensity score matching was performed to reduce heterogeneity and population bias. RESULTS: At months 1 and 3, when compared with the 2 other groups, the low-exposure group had similar grafts (P = 0.75) and patient (P = 0.77) survival, but lower alanine aminotransferase (P < 0.001), bilirubin (P < 0.001), international normalized ratio (P = 0.046), and creatinine (P < 0.001) levels. After propensity score matching, the bilirubin (P < 0.001) and creatinine (P = 0.001) levels in the low-exposure group still improved at months 3, but the graft (P = 0.86) and patient (P = 0.99) survival were still similar. CONCLUSIONS: A TAC Cmin of 4-7 ng/mL seems safe and capable of improving graft and kidney function. This finding should be confirmed in a prospective randomized trial.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Tacrolimo/efeitos adversos , Tacrolimo/uso terapêutico , Adolescente , Adulto , Idoso , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Transplante de Rim/métodos , Transplante de Fígado/métodos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Ther Drug Monit ; 42(5): 665-670, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32520841

RESUMO

BACKGROUND: Therapeutic drug monitoring (TDM) of the 2 calcineurin inhibitors (CNIs), tacrolimus (TAC) and cyclosporin A, has resulted in improvements in the management of patients who have undergone solid organ transplantation. As a result of TDM, acute rejection (AR) rates and treatment-related toxicities have been reduced. Irrespective, AR and toxicity still occur in patients who have undergone transplantation, showing blood CNI concentrations within the therapeutic range. Moreover, the AR rate is no longer decreasing. Hence, smarter TDM approaches are necessary. Because CNIs exert their action inside T lymphocytes, intracellular CNIs may be a promising candidate for improving therapeutic outcomes. The intracellular CNI concentration may be more directly related to the drug effect and has been favorably compared with the standard, whole-blood TDM for TAC in liver transplant recipients. However, measuring intracellular CNIs concentrations is not without pitfalls at both the preanalytical and analytical stages, and standardization seems essential in this area. To date, there are no guidelines for the TDM of intracellular CNI concentrations. METHODS: Under the auspices of the International Association of TDM and Clinical Toxicology and its Immunosuppressive Drug committees, a group of leading investigators in this field have shared experiences and have presented preanalytical and analytical recommendations for measuring intracellular CNI concentrations.


Assuntos
Inibidores de Calcineurina/metabolismo , Ciclosporina/metabolismo , Monitoramento de Medicamentos/métodos , Rejeição de Enxerto/metabolismo , Humanos , Imunossupressores/metabolismo , Transplante de Órgãos/métodos , Tacrolimo/metabolismo
13.
Int J Mol Sci ; 21(24)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348915

RESUMO

Regarding several cytotoxic agents, it was evidenced that genetic polymorphisms in genes encoding enzymes involved in their metabolism are associated with higher risk of toxicity. Genotyping these genes before treatment is a valuable strategy to prevent side effects and to predict individual response to drug therapy. This pharmacogenetic approach is recommended for chemotherapies such as thiopurines (azathioprine, 6-mercaptopurine, thioguanine), irinotecan, and fluoropyrimidines (capecitabine and 5-fluorouracil). In this study, we aimed at developing and validating a fast, cost-effective, and easily implementable multiplex genotyping method suitable for analyzing a panel of nine variants involved in the pharmacogenetics of widely prescribed anticancer drugs. We designed a multiplex-specific PCR assay where fragments were labeled by two different fluorescent dye markers (HEX/FAM) identifiable by fragment analysis. These two labels were used to discriminate bi-allelic variants, while the size of the fragment allowed the identification of a particular polymorphism location. Variants of interest were TPMT (rs1800462, rs1142345, rs1800460), NUDT15 (rs116855232), DPYD (rs55886062, rs3918290, rs67376798, rs75017182), and UGT1A1 (rs8175347). The assay was repeatable, and genotypes could be determined when DNA sample amounts ranged from 25 to 100 ng. Primers and dye remained stable in a ready-to-use mixture solution after five freeze-thaw cycles. Accuracy was evidenced by the consistency of 187 genotyping results obtained with our multiplex assay and a reference method. The developed method is fast and cost-effective in simultaneously identifying nine variants involved in the pharmacological response of anticancer drugs. This assay can be easily implemented in laboratories for widespread access to pharmacogenetics in clinical practice.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/patologia , Farmacogenética , Polimorfismo de Nucleotídeo Único , Testes Genéticos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética
15.
Ther Drug Monit ; 39(4): 305-307, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28700519

RESUMO

No drug-drug interaction study has been conducted to date for the combination of ombitasvir, paritaprevir/ritonavir, dasabuvir (3D), and mycophenolic acid (MPA). We here report the case of a hepatitis C virus-infected patient treated with 3D and MPA for vasculitis. In light of the threat of drug-drug interaction, the concentration of MPA was measured before, during, and 15 days after the end of the 3D treatment. Similar values were found at all 3 time points, thus indicating that there is probably no need to adapt MPA dosage to 3D.


Assuntos
Anilidas/sangue , Carbamatos/sangue , Hepatite C/sangue , Compostos Macrocíclicos/sangue , Ácido Micofenólico/sangue , Ritonavir/sangue , Sulfonamidas/sangue , Uracila/análogos & derivados , 2-Naftilamina , Idoso , Anilidas/administração & dosagem , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/sangue , Antivirais/administração & dosagem , Antivirais/sangue , Carbamatos/administração & dosagem , Ciclopropanos , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/sangue , Gerenciamento Clínico , Interações Medicamentosas/fisiologia , Monitoramento de Medicamentos/métodos , Quimioterapia Combinada , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Humanos , Lactamas Macrocíclicas , Compostos Macrocíclicos/administração & dosagem , Masculino , Ácido Micofenólico/administração & dosagem , Prolina/análogos & derivados , Ritonavir/administração & dosagem , Sulfonamidas/administração & dosagem , Uracila/administração & dosagem , Uracila/sangue , Valina
16.
Ther Drug Monit ; 39(4): 429-440, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28700523

RESUMO

BACKGROUND: Risperidone, aripiprazole, and pipamperone are antipsychotic drugs frequently prescribed for the treatment of comorbid behavioral problems in children with autism spectrum disorders. Therapeutic drug monitoring (TDM) could be useful to decrease side effects and to improve patient outcome. Dried blood spot (DBS) sample collection seems to be an attractive technique to develop TDM of these drugs in a pediatric population. The aim of this work was to develop and validate a DBS assay suitable for TDM and home sampling. METHODS: Risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone were extracted from DBS and analyzed by ultra-high-performance liquid chromatography-tandem mass spectrometry using a C18 reversed-phase column with a mobile phase consisting of ammonium acetate/formic acid in water or methanol. The suitability of DBS for TDM was assessed by studying the influence of specific parameters: extraction solution, EDTA carryover, hematocrit, punching location, spot volume, and hemolysis. The assay was validated with respect to conventional guidelines for bioanalytical methods. RESULTS: The method was linear, specific without any critical matrix effect, and with a mean recovery around 90%. Accuracy and imprecision were within the acceptance criteria in samples with hematocrit values from 30% to 45%. EDTA or hemolysis did not skew the results, and no punching carryover was observed. No significant influence of the spot volume or the punch location was observed. The antipsychotics were all stable in DBS stored 10 days at room temperature and 1 month at 4 or -80°C. The method was successfully applied to quantify the 3 antipsychotics and their metabolites in patient samples. CONCLUSIONS: A UHPLC-MS/MS method has been successfully validated for the simultaneous quantification of risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone in DBS. The assay provided good analytical performances for TDM and clinical research applications.


Assuntos
Antipsicóticos/sangue , Aripiprazol/sangue , Butirofenonas/sangue , Teste em Amostras de Sangue Seco/métodos , Risperidona/sangue , Espectrometria de Massas em Tandem/métodos , Antipsicóticos/metabolismo , Aripiprazol/metabolismo , Butirofenonas/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Humanos , Masculino , Risperidona/metabolismo
19.
Expert Rev Clin Pharmacol ; 17(3): 225-234, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38345044

RESUMO

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.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Cromossomo Filadélfia , Adulto , Humanos , Criança , Mesilato de Imatinib/efeitos adversos , Monitoramento de Medicamentos , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética
20.
Therapie ; 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39174455

RESUMO

Nirmatrelvir/ritonavir is a protease inhibitor antiviral drug indicated in the treatment of severe acute respiratory syndrome coronavirus-2 infections in high-risk patients for a severe disease. Unfortunately, ritonavir, used to boost nirmatrelvir pharmacokinetics, can also inhibit or induce the metabolism of other co-administered drugs substrates. This may lead to a subsequent risk of adverse drug reaction and lack of efficacy. In this study, we aimed at describing the expert advices provided by the biological pharmacology network of the SFPT (i.e., the therapeutic drug monitoring specialists working in the laboratories of the pharmacology departments in France/Belgium). From February to August 2022, we collected all specialized advices provided by the biological pharmacology network of the SFPT. Seven pharmacology departments actively participated in the study (Brussels Saint-Luc Hospital in Belgium, Caen, Dijon, Nantes, Nancy, Rennes and Toulouse in France). We collected the following data: patient's age, date of nirmatrelvir/ritonavir initiation, clinical department requiring the expert advice, patient's treatments, and advice provided. One hundred and six expert advice on 753 drugs were provided during the seven months of data collection. Two centers provided 83% of all the expert advice (around 8/month). Patients originated form a transplantation department in 65% of the cases. The most common request were for cardiac drugs (28%), immunosuppressive drugs (24%) and endocrine drugs (18%). The advice were distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment, and treatment switch in 59%, 28%, 11%, and 1.6% of the cases, respectively. Only 2 pieces of advice (0.3%) constituted treatment contra-indications. Drug monitoring was proposed in 10% of prescription lines. Expert advice provided by the biological pharmacology network of the SFPT allows securing the combination of nirmatrelvir/ritonavir with other concomitant drugs. Most of eligible patients to the antiviral drug can benefit from it despite the risk of drug-drug interaction.

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