RESUMO
BACKGROUND: Catheter ablation in patients with atrial fibrillation is associated with a transient increase in thromboembolic risk and adequate anticoagulation is highly important. When patients are anticoagulated with apixaban, monitoring of plasma concentrations of the drug is not routinely performed. This study aimed to assess the influence of clinical patient characteristics, concomitant drug treatment and self-reported adherence on apixaban concentrations, and to describe the intra- and inter-individual variability in apixaban concentrations in this group of patients. Method Apixaban concentrations from 141 patients were measured in plasma one week before ablation and two, six and ten weeks after ablation, employing ultra-high performance liquid chromatography coupled with tandem mass spectrometry. In samples not obtained at trough, apixaban concentrations were adjusted to trough levels. Self-reported adherence was registered by means of the 8-item Morisky Medication Adherence Scale before and after ablation. RESULTS: There were statistically significant, positive correlations between apixaban concentrations and increased age, female sex, lower glomerular filtration rate, higher CHA2DS2-VASc score, use of cytochrome P450 3A4 and/or p-glycoprotein inhibitors, and use of amiodarone. Self-reported adherence was generally high. The mean intra-individual and inter-individual coefficients of variation were 29% and 49%, respectively. CONCLUSION: In patients undergoing catheter ablation for atrial fibrillation, age, sex, renal function, interacting drugs and cerebrovascular risk profile were all associated with altered plasma apixaban concentration. In this group of patients with a generally high self-reported adherence, intra-individual variability was modest, but the inter-individual variability was substantial, and similar to those previously reported in other patient apixaban-treated populations. If a therapeutic concentration range is established, there might be a need for a more flexible approach to apixaban dosing, guided by therapeutic drug monitoring.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Pirazóis , Piridonas , Humanos , Piridonas/sangue , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/cirurgia , Fibrilação Atrial/sangue , Pirazóis/sangue , Pirazóis/uso terapêutico , Pirazóis/farmacocinética , Pirazóis/administração & dosagem , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/uso terapêutico , Adesão à MedicaçãoRESUMO
OBJECTIVE: This study was the first to evaluate the effect of CYP3A4 gene polymorphisms on the plasma concentration and effectiveness of perampanel (PER) in Chinese pediatric patients with epilepsy. METHODS: We enrolled 102 patients for this investigation. The steady-state concentration was determined after patients maintained a consistent PER dosing regimen for at least 21 days. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final check-up. RESULTS: The CYP3A4×10 GC phenotype exhibited the highest average plasma concentration of PER at 491.1⯱â¯328.1â¯ng/mL, in contrast to the CC phenotype at 334.0⯱â¯161.1â¯ng/mL. The incidence of adverse events was most prominent in the CYP3A4×1â¯G TT and CYP3A4×10 GC groups, with rates of 77.8â¯% (7 of 9 patients) and 50.0â¯% (46 of 92 patients), respectively. Moreover, the percentage of patients for whom PER was deemed ineffective was least in the CYP3A4×1â¯G TT and CYP3A4×10 CC groups, recorded at 11.1â¯% (1 of 9 patients) and 10.0â¯% (1 of 10 patients), respectively. There was a significant correlation between PER plasma concentration and either exposure or toxicity (both with pâ¯<â¯0.05). We suggest a plasma concentration range of 625-900â¯ng/mL as a suitable reference for PER in Chinese patients with epilepsy. CONCLUSION: The CYP3A4×10 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A4 genetic phenotype should be factored in when prescribing PER to patients with epilepsy.
Assuntos
Anticonvulsivantes , Citocromo P-450 CYP3A , Epilepsia , Nitrilas , Piridonas , Humanos , Citocromo P-450 CYP3A/genética , Criança , Feminino , Masculino , Piridonas/farmacocinética , Piridonas/uso terapêutico , Piridonas/sangue , Epilepsia/tratamento farmacológico , Epilepsia/genética , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Nitrilas/farmacocinética , Pré-Escolar , Adolescente , Polimorfismo Genético/genética , China , Povo Asiático/genética , Genótipo , Resultado do Tratamento , População do Leste AsiáticoRESUMO
PURPOSE: Routine therapeutic drug monitoring of apixaban is currently not recommended but may however be warranted in some situations and for some patient groups to provide better and safer treatment. Due to limited data on apixaban concentrations in different subpopulations, it is still unclear which group of patients could possibly gain from monitoring. The purpose of this study was to examine apixaban exposure in patients with obesity compared with normal-weight patients. METHODS: Forty patients with obesity (mean BMI 39.4 kg/m2) and 40 controls with normal weight (mean BMI 23.4 kg/m2), treated with apixaban 5 mg twice daily were included. The patients were matched for age, sex, and renal function. Trough and peak apixaban concentrations were measured with LCâMS/MS methodology. RESULTS: The median trough concentrations in patients with obesity (58.7, range 10.7-200.7 ng/ml) were slightly higher than those in patients with normal weight (52.0, range 31.0-150.9 ng/ml) (p < 0.05). Notably, the variability in trough concentration was considerably higher in patients with obesity. Peak concentrations were similar in both groups, with a median of 124.5 ng/ml (range 82.0-277.5) and 113.5 ng/ml (range 75.5-334.6) in patients with obesity and normal weight, respectively. CONCLUSION: Apixaban exposure did not vary substantially between obese and normal weight matched controls, implying that general dose adjustments are not required. However, vast interindividual variability was observed in patients with obesity, suggesting that measuring the concentrations could be valuable for specific patients. Further research is needed to identify which specific patients may benefit from this approach.
Assuntos
Monitoramento de Medicamentos , Inibidores do Fator Xa , Obesidade , Pirazóis , Piridonas , Humanos , Piridonas/sangue , Piridonas/farmacocinética , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Pirazóis/sangue , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Feminino , Obesidade/sangue , Masculino , Pessoa de Meia-Idade , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Adulto , Idoso , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem , Estudos de Casos e ControlesRESUMO
Although antiretroviral therapy (ART) is highly effective for the treatment of HIV-1 infection to suppress virus in the blood, HIV persists in tissues. HIV persistence in the tissues is due to numerous factors, and one of those factors are antiretroviral (ARV) concentrations. ARV concentrations in tissues must be adequate to suppress HIV at the sites of action. While therapeutic drug monitoring in the plasma is well-known, drug monitoring in the tissues provides local assessments of adequate ARV exposure to prevent localized HIV resistance formation. Towards these efforts, we validated an ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method in human tissues (cervical, rectal, and vaginal tissues) for the simultaneous quantification of five ARVs: bictegravir, cabotegravir, dolutegravir, doravirine, and raltegravir. For this assay, protein precipitation with acetonitrile with stable, isotopically-labeled internal standards followed by supernatant pre-concentration was performed. Analyte separation was accomplished using a multistep UPLC gradient mixture of 0.1 % formic acid in water (A) and acetonitrile (B) with a Waters Cortecs T3 (2.1x100 mm) column. The assay was extensively validated as per the United States Food and Drug Administration Bioanalytical Method Validation Guidance over a clinically observed range (0.05-50 ng/mL) with superb linearity (R2 > 0.99 across all ARVs). The assay run time was 8.5 min. This analytical method achieves appropriate performance of trueness (85.5-107.4 %), repeatability, and precision (CV < 15 %). Our method will be employed for the therapeutic monitoring of guideline-recommended ARVs in human tissues for monitoring therapeutic efficacy in HIV treatment and prevention research efforts.
Assuntos
Monitoramento de Medicamentos , Compostos Heterocíclicos com 3 Anéis , Piperazinas , Piridonas , Espectrometria de Massas em Tandem , Humanos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Compostos Heterocíclicos com 3 Anéis/análise , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/sangue , Reprodutibilidade dos Testes , Piridonas/análise , Piridonas/sangue , Piperazinas/análise , Piperazinas/sangue , Limite de Detecção , Modelos Lineares , Feminino , Oxazinas/química , Raltegravir Potássico/análise , Raltegravir Potássico/uso terapêutico , Triazóis/análise , Triazóis/sangue , Compostos Heterocíclicos de 4 ou mais Anéis/análise , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/sangue , Piridazinas/análise , Piridazinas/farmacocinética , Antirretrovirais/análise , Antirretrovirais/farmacocinética , Antirretrovirais/sangue , Antirretrovirais/uso terapêutico , Piridinas/análise , Piridinas/sangue , Piridinas/farmacocinética , Piridinas/uso terapêutico , Colo do Útero/química , Infecções por HIV/tratamento farmacológico , Amidas , DicetopiperazinasRESUMO
Perampanel belongs to a novel class of antiseizure medications (ASMs). Studies examining the effect of hemodialysis on perampanel serum levels in clinical settings are lacking. We aimed to evaluate the changes in serum perampanel levels during hemodialysis. We studied patients with seizures who received oral perampanel between April 2020 and March 2023 and whose serum concentration of perampanel was measured before and after hemodialysis. We analyzed the serum concentrations of levetiracetam and lacosamide for comparison. Fourteen patients, with a mean age of 76.1 ± 7.88 years, were included. The dose of perampanel was 2.14 ± 1.27 mg. The hemodialysis clearance rate of perampanel, levetiracetam, and lacosamide was 0 ± 13%, 69 ± 11%, and 59.6 ± 8.2%, respectively. The post-dialysis CD ratio decreased significantly with levetiracetam but not with perampanel. Adverse but acceptable effects of perampanel were observed in two patients. The serum concentrations of several ASMs have been shown to be reduced during hemodialysis. Our study revealed that the serum perampanel concentration does not decrease during hemodialysis. Owing to the low rate of adverse effects and the stability of perampanel serum concentration during hemodialysis, perampanel could be a favorable choice as an ASM for patients with seizures undergoing hemodialysis. PLAIN LANGUAGE SUMMARY: Our study looked at how hemodialysis affects the serum levels of perampanel, a new type of medication for seizures. In 14 patients who started treatment between April 2020 and March 2023, perampanel serum levels did not decrease during hemodialysis, unlike other seizure medications. This shows that perampanel can be a good option for patients with seizures who need hemodialysis, with fewer side effects compared to other medications.
Assuntos
Anticonvulsivantes , Nitrilas , Piridonas , Diálise Renal , Convulsões , Humanos , Masculino , Piridonas/sangue , Piridonas/uso terapêutico , Piridonas/farmacocinética , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Feminino , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Nitrilas/uso terapêutico , Idoso , Convulsões/tratamento farmacológico , Idoso de 80 Anos ou mais , Lacosamida/uso terapêutico , Levetiracetam/uso terapêutico , Levetiracetam/sangue , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations. METHODS: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia. RESULTS: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses. CONCLUSIONS: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV.
Assuntos
Carbamazepina , Darunavir , Interações Medicamentosas , Infecções por HIV , Humanos , Darunavir/uso terapêutico , Darunavir/farmacocinética , Masculino , Pessoa de Meia-Idade , Carbamazepina/uso terapêutico , Carbamazepina/farmacocinética , Infecções por HIV/tratamento farmacológico , Neuralgia do Trigêmeo/tratamento farmacológico , Ritonavir/uso terapêutico , Ritonavir/administração & dosagem , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/administração & dosagem , Piridonas/farmacocinética , Piridonas/uso terapêutico , Piridonas/sangue , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Piperazinas/uso terapêutico , Piperazinas/farmacocinética , Oxazinas/uso terapêutico , Oxazinas/farmacocinética , Relação Dose-Resposta a Droga , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Monitoramento de Medicamentos/métodosRESUMO
The present study aimed to assess the bioequivalence of a new apixaban generic with reference formulation. Twenty-six healthy volunteers were recruited for an open-label, balanced, randomized, 2-treatment, 2-sequence, 2-period, single oral dose study. Following overnight fasting, each volunteer received 5 mg of apixaban test and reference formulations as single doses, separated by a 1-week washout period. Twenty blood samples were collected at predose and multiple time points between 0.5 and 72 hours after dosing. A validated ultra-performance liquid chromatography-tandem mass spectrometry detection method following a protein precipitation step was implemented to determine apixaban concentrations. Noncompartmental analysis was used to derive the pharmacokinetic parameters, which were then compared between the test and reference products using a multivariate analysis of variance. The pharmacokinetic parameters of the test product were not statistically different from the reference product, and the 90% confidence intervals of apixaban natural log-transformed area under the concentration-time curve from time 0 to infinity, area under the concentration-time curve from time 0 to the last measurable concentration, and maximum concentration were within 80%-125% based on the bioequivalence acceptance range criteria. The test and reference formulations of apixaban are bioequivalent in healthy subjects under fasting conditions.
Assuntos
Estudos Cross-Over , Jejum , Voluntários Saudáveis , Pirazóis , Piridonas , Comprimidos , Equivalência Terapêutica , Humanos , Piridonas/farmacocinética , Piridonas/administração & dosagem , Piridonas/sangue , Pirazóis/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/sangue , Adulto , Masculino , Adulto Jovem , Indonésia , Feminino , Área Sob a Curva , Administração Oral , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/administração & dosagem , Espectrometria de Massas em Tandem/métodos , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/administração & dosagemRESUMO
OBJECTIVE: The purposes of this study were to explore the pharmacokinetics of perampanel (PER) in children with epilepsy, identify factors that contribute to pharmacokinetic variations among subjects, evaluate the connection between PER exposure and clinical outcome, and establish an evidence-based approach for tailoring individualized antiepileptic treatment in this specific population. METHODS: In this prospective study, PER plasma concentrations and genetic information on metabolic enzymes were obtained from 194 patients younger than 18 years. The disposition kinetics of PER in pediatric patients following oral dosing were characterized using nonlinear mixed effect models. The effective range for the plasma concentration of PER was determined by assessing the efficacy and safety of PER treatment and analyzing the relationship between drug exposure and clinical response. Monte Carlo simulations were then performed to evaluate and optimize the current dosing regimens. RESULTS: The pharmacokinetic profile of PER was adequately described by a one-compartment model with first-order absorption and elimination. Body weight, total bilirubin level, and concomitant oxcarbazepine were found to have significant influences on PER pharmacokinetics. Model estimates of apparent clearance and volume of distribution were .016 ± .009 L/h/kg and 1.47 ± .78 L/kg, respectively. The effective range predicted from plasma concentration data in responders was 215-862 µg/L. Dosing scenarios stratified according to essential covariates were proposed through simulation analysis. SIGNIFICANCE: In this study, we captured the pharmacokinetic/pharmacodynamic characteristics of PER in pediatric epilepsy patients through analysis of real-world data and adopted a pharmacometric approach to support an individualized dosing strategy for PER in this specific population.
Assuntos
Anticonvulsivantes , Epilepsia , Nitrilas , Piridonas , Humanos , Piridonas/farmacocinética , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Piridonas/sangue , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Criança , Nitrilas/farmacocinética , Feminino , Masculino , Epilepsia/tratamento farmacológico , Pré-Escolar , Adolescente , Estudos Prospectivos , Relação Dose-Resposta a Droga , Lactente , Método de Monte Carlo , Resultado do TratamentoRESUMO
ABSTRACT: This study evaluated perampanel pharmacokinetics and cytochrome P450 3A4 (CYP3A4) activity, assessed using the level of 4ß-hydroxycholesterol (4ß-OHC) as an endogenous biomarker of CYP3A4, before, during, and after pregnancy in a woman with epilepsy and compared these measurements with those from a control group of nonpregnant women with epilepsy. A 21-year-old pregnant woman was being treated with perampanel (serum concentration: 1120 ng/mL), lacosamide, and lamotrigine. After the first trimester, the lamotrigine concentration decreased markedly; however, the perampanel concentration remained almost unchanged (range, 1130-1320 ng/mL). Similarly, serum 4ß-OHC levels did not change during pregnancy (before pregnancy, 78.2 ng/mL; during pregnancy, 62.2-83.2 ng/mL). To compare these measurements with those in nonpregnant women, we enrolled 27 nonpregnant women with epilepsy (age range, 16-40 years). In the control patients, we found a strong negative correlation between the concentration-to-dose ratio of perampanel and the 4ß-OHC level ( r = -0.78, P < 0.001). As there was no significant change in CYP3A4 activity, we concluded that the serum perampanel concentration did not change significantly before, during, or after pregnancy. More patients need to be studied to confirm these early results.
Assuntos
Anticonvulsivantes , Citocromo P-450 CYP3A , Epilepsia , Nitrilas , Piridonas , Humanos , Feminino , Piridonas/farmacocinética , Piridonas/sangue , Piridonas/uso terapêutico , Gravidez , Citocromo P-450 CYP3A/metabolismo , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/sangue , Nitrilas/farmacocinética , Adulto , Adulto Jovem , Epilepsia/tratamento farmacológico , Adolescente , Lamotrigina/farmacocinética , Lamotrigina/uso terapêutico , Lamotrigina/sangue , Complicações na Gravidez/tratamento farmacológico , Lacosamida/farmacocinética , Lacosamida/uso terapêutico , HidroxicolesteróisRESUMO
Perampanel (PER) is a new type of antiseizure medication used for partial or generalized seizures. However, the plasma concentration shows obvious individual variability in children. The present study aims to ascertain the effect of age, comedications, and cytochrome P450 (CYP) 3A4/5 polymorphisms on PER exposure in Chinese pediatric patients with epilepsy. Clinical data were retrospectively collected in a tertiary children's hospital medical records system from January 2021 to December 2022. The influence factors on the daily dose, plasma concentration, and concentration-to-dose ratio (CDR) of PER were investigated. A total of 135 pediatric patients with 178 blood samples were involved. With a median daily dose of 4.0 mg (interquartile range, 3.0-5.0 mg), the median plasma concentration was 409.4 ng/mL (interquartile range, 251.7-639.4 ng/mL). The CDR in patients aged less than 4 years was significantly decreased by 48.0% and 39.1% compared with those aged 4-11 years and 12 years or older, respectively. Enzyme inducers significantly decreased the CDR of PER by 34.5%, while valproic acid showed an increase of 71.7%. In addition, genotype CYP3A5*3/*3 carriers presented a significant increase of 21.5% compared to the CYP3A5*1/*3 expresser. No correlations were observed between the CDR and CYP3A4∗1G polymorphism. PER showed high variations in individual plasma concentrations. Age younger than 4 years, comedication with enzyme inducers or valproic acid, and possession of the CYP3A5*3 genotype potentially predicted PER exposure in pediatric patients with epilepsy.
Assuntos
Anticonvulsivantes , Citocromo P-450 CYP3A , Epilepsia , Nitrilas , Piridonas , Humanos , Citocromo P-450 CYP3A/genética , Criança , Pré-Escolar , Feminino , Masculino , Epilepsia/tratamento farmacológico , Epilepsia/genética , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/sangue , Anticonvulsivantes/administração & dosagem , Piridonas/farmacocinética , Piridonas/sangue , Piridonas/uso terapêutico , Nitrilas/uso terapêutico , Estudos Retrospectivos , Fatores Etários , Adolescente , Povo Asiático/genética , Interações Medicamentosas , China , Polimorfismo Genético , Ácido Valproico/uso terapêutico , Ácido Valproico/farmacocinética , Ácido Valproico/sangue , Quimioterapia Combinada , Polimorfismo de Nucleotídeo Único , Lactente , População do Leste AsiáticoRESUMO
BACKGROUND: Routine monitoring of direct oral anticoagulant (DOAC) levels is not recommended but may be useful in certain clinical situations. There is a knowledge gap regarding the clinical use of DOAC levels in Australian hospitals. AIMS: To evaluate the clinical settings, indications and changes to anticoagulant management associated with DOAC levels in a tertiary hospital in Northern Tasmania, Australia. METHODS: Patients with one or more DOAC levels (dabigatran, rivaroxaban or apixaban) requested between January 2017 and December 2022 were identified. Retrospective chart review was performed to evaluate the clinical settings, indications, adequacy of request information and changes to clinical management associated with the measurement of DOAC levels. RESULTS: One hundred and twenty-nine DOAC measurements (54 rivaroxaban, 66 apixaban and nine dabigatran) were performed in 98 patients between January 2017 and December 2022. Annual requests for DOAC levels increased significantly between 2017 and 2019 and remained stable between 2020 and 2021 but declined in 2022. Overall, the most common indication for a DOAC level was renal impairment, followed by bleeding and recurrent thrombosis. Approximately 25% of requests were for acute bleeding with a reversal/haemostatic agent given in 45% of patients, while 10% were prior to urgent surgery. Measurement of DOAC levels was associated with a change in management in 50% of cases. 10% of requests did not specify anticoagulant history. CONCLUSION: Trends in requests for DOAC levels have changed over time. Clinician education regarding the importance of providing specific anticoagulant history is essential. Future prospective studies investigating the clinical utility of DOAC levels in different clinical settings are needed.
Assuntos
Dabigatrana , Pirazóis , Piridonas , Rivaroxabana , Humanos , Estudos Retrospectivos , Tasmânia , Feminino , Masculino , Idoso , Pirazóis/sangue , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Rivaroxabana/sangue , Rivaroxabana/uso terapêutico , Rivaroxabana/administração & dosagem , Piridonas/sangue , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Dabigatrana/sangue , Dabigatrana/uso terapêutico , Dabigatrana/administração & dosagem , Hemorragia/sangue , Monitoramento de Medicamentos/métodos , Administração Oral , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Trombose/sangue , Trombose/prevenção & controleRESUMO
Contezolid is a novel oxazolidinone antibiotic with good antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus. For the purpose to further characterize the pharmacokinetics of contezolid and its major metabolite M2, accurate and rapid ultra-performance liquid chromatography-tandem mass spectrometric assays (UPLC-MS/MS) were developed and validated for simultaneous quantification of contezolid and M2 in human plasma and urine. The plasma samples were pretreated by liquid-liquid extraction. The automated solid phase extraction method was used to preprocess urine samples. ACQUITY UPLC® BEH C8 (2.1 mm × 100 mm, 1.7 µm) column was used to separate the analytes with a gradient mobile phase of acetonitrile and water at a flow rate of 0.4 mL/min. The calibration curves showed good linearity over the concentration ranges of 0.0100-5.00 µg/mL for contezolid in plasma and urine, 0.00200-1.00 µg/mL in plasma and 0.0200-10.0 µg/mL in urine for M2, respectively. For both plasma and urine assays, the intra- and inter-batch accuracy and precision were within 15% for all quality control levels, including the lower limit of quantitation. The methods were fully validated and successfully applied to a pharmacokinetic study of contezolid tablets in subjects with moderate hepatic impairment.
Assuntos
Antibacterianos/sangue , Antibacterianos/urina , Cromatografia Líquida de Alta Pressão/métodos , Hepatopatias/tratamento farmacológico , Oxazolidinonas/sangue , Oxazolidinonas/urina , Piridonas/sangue , Piridonas/urina , Espectrometria de Massas em Tandem/métodos , Administração Oral , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Humanos , Limite de Detecção , Extração Líquido-Líquido , Hepatopatias/sangue , Hepatopatias/urina , Oxazolidinonas/administração & dosagem , Oxazolidinonas/farmacocinética , Plasma/química , Piridonas/administração & dosagem , Piridonas/farmacocinética , Urina/químicaRESUMO
ABSTRACT: Direct-acting oral anticoagulants (DOACs) vary in bioavailability and sites of absorption in the gastrointestinal tract (GIT). Data on DOAC use after major GIT surgery are limited. The aim of this case series was to report the impact of surgical resection or bypass of the GIT on rivaroxaban and apixaban peak plasma concentrations. This was a case series of patients who received rivaroxaban or apixaban after GIT surgery, during the period of July 1, 2019, to December 31, 2020. Peak plasma concentrations of rivaroxaban and apixaban were assessed for the expected concentrations. Of the 27 assessed patients, 18 (66.7%) received rivaroxaban, and 9 (33.3%) received apixaban. After rivaroxaban therapy, 4 of 5 patients (80%) who underwent gastrectomy, and 3 of 3 patients (100%) who underwent duodenum and proximal jejunum exclusion had peak plasma concentrations of rivaroxaban lower than the effective range, whereas 11 of 11 patients (100%) who underwent distal bowel or ileostomy had peak rivaroxaban plasma within the effective range. After apixaban therapy, 5 of 6 patients (83.3%) who underwent total or partial gastrectomy achieved effective peak concentrations. All the patients who underwent proximal and distal bowel resection or bypass had peak concentrations of apixaban within the effective range. In conclusion, surgical resection or bypass of the upper GIT could affect DOAC absorption and subsequently peak plasma concentrations. This effect was more observed among rivaroxaban recipients. An injectable anticoagulant or vitamin K antagonist may be preferred if DOAC concentrations cannot be measured after GIT surgery.
Assuntos
Procedimentos Cirúrgicos do Sistema Digestório , Inibidores do Fator Xa/administração & dosagem , Trato Gastrointestinal/cirurgia , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Rivaroxabana/administração & dosagem , Administração Oral , Adulto , Idoso , Disponibilidade Biológica , Monitoramento de Medicamentos , Inibidores do Fator Xa/sangue , Inibidores do Fator Xa/farmacocinética , Feminino , Absorção Gástrica , Trato Gastrointestinal/metabolismo , Humanos , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Pirazóis/sangue , Pirazóis/farmacocinética , Piridonas/sangue , Piridonas/farmacocinética , Estudos Retrospectivos , Rivaroxabana/sangue , Rivaroxabana/farmacocinéticaRESUMO
It is unclear whether elderly patients established on direct oral anticoagulants (DOACs) have greater exposure to these drugs, which could subsequently increase their risk of bleeding. We assessed DOAC exposure and factors affecting it in a real-world elderly cohort of patients. For this, 151 medically stable hospital inpatients (76 established on apixaban, 61 on rivaroxaban, 14 on dabigatran) with a median [interquartile range (IQR)] age of 84 (78-89) years were recruited. Patients provided blood samples for measurement of peak and trough plasma DOAC concentrations. There was up to 48-fold and 13-fold variation in trough and peak plasma drug concentrations respectively. A significantly greater proportion of patients on apixaban had peak plasma drug concentrations within the reported ranges compared to those on either rivaroxaban or dabigatran (82·9% vs. 44·3% vs. 64·3% respectively; P < 0·001). A third of the variability in DOAC plasma concentrations was attributed to the influences of DOAC dosage, renal function and gender. To what extent the observed increases in DOAC exposure in the older patients is the cause of their increased risk of bleeding, which could potentially be ameliorated by dosing titration, requires further investigation.
Assuntos
Inibidores do Fator Xa/uso terapêutico , Trombose/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Dabigatrana/sangue , Dabigatrana/uso terapêutico , Monitoramento de Medicamentos , Inibidores do Fator Xa/sangue , Feminino , Hospitalização , Humanos , Masculino , Pirazóis/sangue , Pirazóis/uso terapêutico , Piridonas/sangue , Piridonas/uso terapêutico , Rivaroxabana/sangue , Rivaroxabana/uso terapêutico , Trombose/prevenção & controleRESUMO
BACKGROUND: Bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination (BIC/FTC/TAF 50/200/25 mg) is recommended as an initial regimen in patients who are antiretroviral (ARV)-naïve or virologically suppressed on a stable ARV regimen. However, no real-world pharmacokinetic (PK) data are available in treatment-experienced patients with antiretroviral resistance receiving BIC/FTC/TAF plus a boosted protease inhibitor. SETTING/METHODS: This prospective, single-center, nonrandomized pharmacokinetic study enrolled adult treatment-experienced persons with HIV and creatinine clearance >30 mL/min receiving BIC/FTC/TAF + DRV/c as part of routine clinical care. Steady-state PK profiles of BIC, TAF, tenofovir (TFV), and DRV after daily dosing of BIC/FTC/TAF + darunavir/cobicistat (DRV/c) were obtained with samples at predose and 0.5, 1, 2, and 4 hours postdose. The AUC0-24 at steady state was extrapolated by imputing C0 for C24 for each participant (AUC0-tau,exp). RESULTS: Nine participants were enrolled with a median age of 59 years (range 54-67) and median number of years on ART of 19 (range 5.8-30). The median (interquartile range [IQR]) BIC AUC0-tau,exp and Cmax values were 128.9 µg*h/mL (78.1-159.5) and 6.9 µg/mL (5.1-9.8), respectively. The median (IQR) TAF AUC0-tau,exp and Cmax values were 0.376 µg*h/mL (0.199-0.430) and 0.276 µg/mL (0.149-0.543), respectively. Predose concentrations of TFV and DRV were comparable with historical data. CONCLUSION: Treatment-experienced persons with HIV receiving BIC/FTC/TAF + darunavir/cobicistat (DRV/c) had BIC exposures (AUC0-tau) that were increased by approximately 26% compared with historical PK data. Although TAF exposures were substantially increased, plasma TFV was only modestly higher. These results suggest that BIC/TAF/FTC + DRV/c is a viable antiviral regimen option for treatment-experienced persons.
Assuntos
Amidas/farmacocinética , Fármacos Anti-HIV/farmacocinética , Cobicistat/farmacocinética , Darunavir/farmacocinética , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Piperazinas/farmacocinética , Piridonas/farmacocinética , Tenofovir/farmacocinética , Idoso , Amidas/sangue , Fármacos Anti-HIV/sangue , Terapia Antirretroviral de Alta Atividade/métodos , Cromatografia Líquida , Cobicistat/sangue , Darunavir/sangue , Feminino , Compostos Heterocíclicos com 3 Anéis/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/sangue , Estudos Prospectivos , Piridonas/sangue , Espectrometria de Massas em Tandem , Tenofovir/sangueRESUMO
In this study, we evaluated the in vitro stability of direct oral anticoagulants (DOACs) in blood samples of 57 patients under different storage conditions using functional coagulation assays. We determined the analyte concentrations (1) immediately after blood collection (baseline); (2) after storage of citrated whole blood (agitated) at room temperature and citrated plasma at room temperature and at 4 °C for 4, 8, and 24 h, respectively; and (3) after storage of citrated plasma at -20 °C for 30, 60, and 90 days. According to the concept of acceptable change limits (ACL), analytes were considered stable if the mean relative analyte recovery at a given time was >78%. The mean baseline values (range) of dabigatran, rivaroxaban, apixaban, and edoxaban were 115 ng/mL (62-217), 129 ng/mL (31-215), 156 ng/mL (49-362), and 101 ng/mL (33-283), respectively. After applying the analyte stability limit, all four DOACs were stable for 24 h at room temperature and at 4 °C. The mean recovery after 24 h was 102-111% for dabigatran, 88-97% for rivaroxaban, 95-98% for apixaban, and 90-96% for edoxaban. When plasma samples were stored at -20 °C, the mean percentage deviation after 90 days for all four DOACs was ≤10%, even after three freeze-thaw cycles. Thus, for the correct determination of DOAC plasma concentrations, blood samples do not have to be analyzed immediately and can be stored at room temperature for up to 24 h before analysis. In clinical practice, blood sample transport and storage for DOAC measurements appear to be unproblematic.
Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/sangue , Coleta de Amostras Sanguíneas , Preservação Biológica , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Dabigatrana/sangue , Humanos , Pessoa de Meia-Idade , Pirazóis/sangue , Piridinas/sangue , Piridonas/sangue , Rivaroxabana/sangue , Tiazóis/sangueRESUMO
In some clinical situations, measurements of anticoagulant effect of apixaban may be needed. We investigated the inter- and intra-individual apixaban variability in patients with atrial fibrillation and correlated these results with clinical outcome. We included 62 patients receiving either 5 mg (A5, n = 32) or 2.5 mg (A2.5, n = 30) apixaban twice-daily. We collected three trough and three peak blood samples 6-8 weeks apart. Apixaban concentration was measured by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) and by anti-Xa. Patients on A2.5 were older, had lower creatinine clearance, higher CHA2DS2VASc (4.7 ± 1.0 vs. 3.4 ± 1.7) and lower trough (85 ± 39 vs. 117 ± 53 ng/mL) and peak (170 ± 56 vs. 256 ± 91 ng/mL) apixaban concentrations than patients on A5 (all p < 0.01). In patients on A5, LC-MS/MS showed a significant difference between through levels and between peak levels (p < 0.01). During apixaban treatment, 21 patients suffered bleeding (2 major). There was no association between bleeding and apixaban concentrations or variability. Four patients who suffered thromboembolic event had lower peak apixaban concentrations than patients without it (159 ± 13 vs. 238 ± 88 ng/mL, p = 0.05). We concluded, that there was a significant intra- and inter-individual variability in apixaban trough and peak concentrations. Neither variability nor apixaban concentrations were associated with clinical outcomes.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/sangue , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pirazóis/efeitos adversos , Pirazóis/sangue , Pirazóis/farmacologia , Piridonas/efeitos adversos , Piridonas/sangue , Piridonas/farmacologia , Tromboembolia/induzido quimicamente , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: Islatravir (MK-8591) is a novel nucleoside analogue in development for the treatment and prevention of HIV-1 infection. Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. This study evaluated the pharmacokinetics, safety, and tolerability of islatravir and doravirine coadministration in a double-blind, placebo-controlled, randomized, fixed-sequence study. METHODS: Adult participants without HIV infection were administered oral doravirine 100 mg (n = 10) or placebo (n = 4) once daily (QD) for 5 days, immediately followed by oral islatravir 2.25 mg (n = 10) or placebo QD (n = 4) for 14 days; islatravir 2.25 mg and doravirine 100 mg QD, or placebo QD, were then coadministered for 5 days. Pharmacokinetic and safety data were collected. RESULTS: Doravirine geometric least-squares mean ratios (90% confidence intervals (CIs)) of (doravirine + islatravir)/doravirine for the area under the plasma drug concentration-time curve over 24 h (AUC0-24h), maximum plasma concentration (Cmax), and plasma concentration at 24 h post-dose (C24h) were not meaningfully impacted. Islatravir geometric least-squares mean ratios (90% CI) of (islatravir + doravirine)/islatravir for AUC0-24h and Cmax were both close to unity, 1.06 (1.01, 1.12) and 1.08 (0.91, 1.27), respectively. All study regimens were generally well tolerated. CONCLUSION: These results indicate that coadministration of islatravir and doravirine had no clinically meaningful effect on the pharmacokinetics of either drug, and support further clinical investigation of islatravir in combination with doravirine for the treatment of HIV-1 infection.
Assuntos
Desoxiadenosinas/administração & dosagem , Piridonas/administração & dosagem , Triazóis/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Desoxiadenosinas/efeitos adversos , Desoxiadenosinas/sangue , Desoxiadenosinas/farmacocinética , Método Duplo-Cego , Esquema de Medicação , Interações Medicamentosas , Feminino , Meia-Vida , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Piridonas/efeitos adversos , Piridonas/sangue , Piridonas/farmacocinética , Curva ROC , Sonolência , Triazóis/efeitos adversos , Triazóis/sangue , Triazóis/farmacocinética , Adulto JovemRESUMO
ABSTRACT: Patients with atrial fibrillation (AF) on long-term direct oral anticoagulants (DOACs) may be at higher risk of bleeding because of higher anti-Xa or anti-IIa levels. However, there is no postmarketing study investigating these DOAC plasma levels at the time of bleeding. The aim of this study was to evaluate DOAC levels at the time of a bleeding emergency. We analyzed 5440 patients examined at our Emergency Department in from April 1, 2019, to September 30, 2019. During this period, we prospective identified 105 consecutive patients with bleeding while on long-term antithrombotic therapy; 49 patients had AF on DOACs. We compared DOAC levels in patients who bled against a control sample of 55 patients who tolerated long-term high dose DOAC therapy without any emergency. Samples of these patients were tested with drug-specific anti-Xa chromogenic analysis (rivaroxaban and apixaban) and with Hemoclot Thrombin Inhibitor assay (dabigatran). Dabigatran-treated patients who bled had significantly higher anti-IIa levels when compared with trough (261.4 ± 163.7 vs. 85.4 ± 57.2 ng/mL, P < 0.001) and peak samples of controls (261.4 ± 163.7 vs. 138.8 ± 78.7 ng/mL, P < 0.05). Similarly, there were significantly higher anti-Xa levels in rivaroxaban-treated and apixaban-treated patients with bleeding compared with trough control samples (rivaroxaban: 245.9 ± 150.2 vs. 52.5 ± 36.4 ng/mL, P <0.001 and apixaban: 311.8 ± 142.5 vs. 119.9 ± 81.7 ng/mL, P < 0.001), as well as in apixaban-treated patients when compared with peak control samples (311.8 ± 142.5 vs. 210.9 ± 88.7 ng/mL, P < 0.05). Finally, rivaroxaban anti-Xa levels in patients who bled tended to be higher compared with peak control samples (245.9 ± 150.2 vs. 177.6 ± 38.6 ng/mL, P = 0.13). This observational study showed a significant difference in anti-IIa and anti-Xa plasma levels in patients with AF with bleeding complications compared with those who tolerated long-term high-dose DOAC therapy without bleeding complications.
Assuntos
Antitrombinas/efeitos adversos , Antitrombinas/sangue , Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/sangue , Hemorragia/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/administração & dosagem , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Estudos de Casos e Controles , Dabigatrana/efeitos adversos , Dabigatrana/sangue , Monitoramento de Medicamentos , Inibidores do Fator Xa/administração & dosagem , Feminino , Hemorragia/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Pirazóis/efeitos adversos , Pirazóis/sangue , Piridonas/efeitos adversos , Piridonas/sangue , Rivaroxabana/efeitos adversos , Rivaroxabana/sangue , Fatores de Tempo , Resultado do TratamentoRESUMO
A once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one (HIV-1) transmission. Extending CAB dosing to a yearly injectable advances efforts for the elimination of viral transmission. Here we report rigor, reproducibility and mechanistic insights for a year-long CAB injectable. Pharmacokinetic (PK) profiles of this nanoformulated CAB prodrug (NM2CAB) are affirmed at three independent research laboratories. PK profiles in mice and rats show plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for a year after a single dose. Sustained native and prodrug concentrations are at the muscle injection site and in lymphoid tissues. The results parallel NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals are stable in blood and tissue homogenates. The long apparent drug half-life follows pH-dependent prodrug hydrolysis upon slow prodrug nanocrystal dissolution and absorption. In contrast, solubilized prodrug is hydrolyzed in hours in plasma and tissues from multiple mammalian species. No toxicities are observed in animals. These results affirm the pharmacological properties and extended apparent half-life for a nanoformulated CAB prodrug. The report serves to support the mechanistic design for drug formulation safety, rigor and reproducibility.