RESUMO
OBJECTIVE: This study was undertaken to describe patterns of benzodiazepine use as first-line treatment of status epilepticus (SE) and test the association of benzodiazepine doses with response to second-line agents in patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT). METHODS: Patients refractory to an adequate dose of benzodiazepines for the treatment of SE were enrolled in ESETT. Choice of benzodiazepine, doses given prior to administration of second-line agent, route of administration, setting, and patient weight were characterized. These were compared with guideline-recommended dosing. Logistic regression was used to determine the association of the first dose of benzodiazepine and the cumulative benzodiazepine dose with the response to second-line agent. RESULTS: Four hundred sixty patients were administered 1170 doses of benzodiazepines (669 lorazepam, 398 midazolam, 103 diazepam). Lorazepam was most frequently administered intravenously in the emergency department, midazolam intramuscularly or intravenously by the emergency medical services personnel, and diazepam rectally prior to ambulance arrival. The first dose of the first benzodiazepine (N = 460) was lower than guideline recommendations in 76% of midazolam administrations and 81% of lorazepam administrations. Among all administrations, >85% of midazolam and >76% of lorazepam administrations were lower than recommended. Higher first or cumulative benzodiazepine doses were not associated with better outcomes or clinical seizure cessation in response to second-line medications in these benzodiazepine-refractory seizures. SIGNIFICANCE: Benzodiazepines as first-line treatment of SE, particularly midazolam and lorazepam, are frequently underdosed throughout the United States. This broad and generalizable cohort confirms prior single site reports that underdosing is both pervasive and difficult to remediate. (ESETT ClinicalTrials.gov identifier: NCT01960075.).
Assuntos
Benzodiazepinas/administração & dosagem , Estado Epiléptico/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Benzodiazepinas/uso terapêutico , Criança , Diazepam/administração & dosagem , Diazepam/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Lorazepam/administração & dosagem , Lorazepam/uso terapêutico , Midazolam/administração & dosagem , Midazolam/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.
Assuntos
Anticonvulsivantes/administração & dosagem , Peso Corporal/efeitos dos fármacos , Levetiracetam/administração & dosagem , Fenitoína/análogos & derivados , Estado Epiléptico/tratamento farmacológico , Ácido Valproico/administração & dosagem , Adolescente , Adulto , Peso Corporal/fisiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Fenitoína/administração & dosagem , Método Simples-Cego , Estado Epiléptico/fisiopatologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an antibody with affinity for Trop-2 coupled to SN-38 via hydrolyzable linker. SG is approved for patients with metastatic triple-negative breast cancer (mTNBC) who have received two or more prior chemotherapies (at least one in a metastatic setting) and for patients with pretreated hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. METHODS: In these analyses, the pharmacokinetics of SG, free SN-38, and total antibody (tAB) were characterized using data from 529 patients with mTNBC or other solid tumors across two large clinical trials (NCT01631552; ASCENT, NCT02574455). Three population pharmacokinetic models were constructed using non-linear mixed-effects modeling; clinically relevant covariates were evaluated to assess their impact on exposure. Models for SG and tAB were developed independently whereas free SN-38 was sequentially generated via a first-order release process from SG. RESULTS: Pharmacokinetics of the three analytes were each described by a two-compartment model with estimated body weight-based scaling exponents for clearance and volume. Typical parameter estimates for clearance and steady-state volume of distribution were 0.133 L/h and 3.68 L for SG and 0.0164 L/h and 4.26 L for tAB, respectively. Mild-to-moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, tumor type, UGT1A1 genotype, or Trop-2 expression did not have a clinically relevant impact on exposure for any of the three analytes. CONCLUSIONS: These analyses support the approved SG dosing regimen of 10 mg/kg as intravenous infusion on days 1 and 8 of 21-day cycles and did not identify a need for dose adjustment based on evaluated covariates or disease characteristics.
Assuntos
Anticorpos Monoclonais Humanizados , Camptotecina , Imunoconjugados , Neoplasias de Mama Triplo Negativas , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Camptotecina/administração & dosagem , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Imunoconjugados/administração & dosagem , Irinotecano/farmacocinética , Irinotecano/administração & dosagem , Irinotecano/uso terapêutico , Modelos Biológicos , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Elevated cytokine levels in inflammatory diseases are associated with downregulation of certain cytochrome P450 (CYP) enzymes. Upon treatment with some cytokine-targeting therapeutic proteins, the CYP enzymes levels may be restored resulting in therapeutic protein-mediated drug interactions (TP-DI). These analyses characterized the worst-case scenario for CYP1A2, 2C9, and 3A-based TP-DI potential in patients with psoriasis by comparing the pharmacokinetics of probe substrates between healthy volunteers and subjects with moderate to severe psoriasis. Data for the CYP probe substrates midazolam (CYP3A), caffeine (CYP1A2), and S-warfarin (CYP2C9) from 7 drug interaction studies (1 in patients with psoriasis and 6 in healthy subjects) were pooled to develop a population pharmacokinetics model for each substrate. A 2-compartment model with absorption lag time for midazolam, a 1-compartment model with 5 transit absorption compartments for caffeine, and a 3-compartment model with absorption lag time for S-warfarin best described the observed data. Apparent oral clearance and relative bioavailability for caffeine and S-warfarin were not significantly different between the subject populations. Psoriasis patients were estimated to have 17% lower midazolam oral bioavailability than healthy volunteers. Compounded with other covariate effects, the ratio of median post hoc area under the plasma concentration-time estimates in subjects with psoriasis relative to healthy subjects was 0.96, 1.13, and 0.65 for midazolam, caffeine, and S-warfarin, respectively. Therefore, inflammation in psoriasis had no relevant effect on reducing CYP1A2, 2C9, and 3A activities in vivo and no significant TP-DIs mediated through these enzymes are expected in patients with psoriasis. This approach can potentially be used in lieu of dedicated TP-DI studies to identify TP-DI risks within a disease area.
Assuntos
Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Modelos Biológicos , Psoríase/fisiopatologia , Adulto , Disponibilidade Biológica , Cafeína/farmacocinética , Estudos de Casos e Controles , Citocinas/metabolismo , Interações Medicamentosas , Feminino , Humanos , Masculino , Midazolam/farmacocinética , Pessoa de Meia-Idade , Gravidade do Paciente , Varfarina/farmacocinética , Adulto JovemRESUMO
Estimating early exposure of drugs used for the treatment of emergent conditions is challenging because blood sampling to measure concentrations is difficult. The objective of this work was to evaluate predictive performance of two early concentrations and prior pharmacokinetic (PK) information for estimating early exposure. The performance of a modeling approach was compared with a noncompartmental analysis (NCA). A simulation study was performed using literature-based models for phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA). These models were used to simulate rich concentration-time profiles from 0 to 2 h. Profiles without residual unexplained variability (RUV) were used to obtain the true partial area under the curve (pAUC) until 2 h after the start of drug infusion. From the profiles with the RUV, two concentrations per patient were randomly selected. These concentrations were analyzed under a population model to obtain individual population PK (PopPK) pAUCs. The NCA pAUCs were calculated using a linear trapezoidal rule. Percent prediction errors (PPEs) for the PopPK pAUCs and NCA pAUCs were calculated. A PPE within ±20% of the true value was considered a success and the number of successes was obtained for 100 simulated datasets. For PHT, LEV, and VPA, respectively, the median value of the success statistics obtained using the PopPK approach of 81%, 92%, and 88% were significantly higher than the 72%, 80%, and 67% using the NCA approach (p < 0.05; Mann-Whitney U test). This study provides a means by which early exposure can be estimated with good precision from two concentrations and a PopPK approach. It can be applied to other settings in which early exposures are of interest.
Assuntos
Coleta de Amostras Sanguíneas/métodos , Monitoramento de Medicamentos/métodos , Modelos Biológicos , Adolescente , Adulto , Área Sob a Curva , Variação Biológica da População , Criança , Pré-Escolar , Simulação por Computador , Tratamento de Emergência , Feminino , Voluntários Saudáveis , Humanos , Levetiracetam/administração & dosagem , Levetiracetam/sangue , Levetiracetam/farmacocinética , Masculino , Pessoa de Meia-Idade , Fenitoína/administração & dosagem , Fenitoína/sangue , Fenitoína/farmacocinética , Ácido Valproico/administração & dosagem , Ácido Valproico/sangue , Ácido Valproico/farmacocinética , Adulto JovemRESUMO
Abnormal energy metabolism associated with mitochondrial dysfunction is thought to be a major contributor to the progression of neurodegenerative diseases such as Parkinson's disease (PD). Recent advancements in the field of magnetic resonance (MR) based metabolic imaging provide state-of-the-art technologies for non-invasively probing cerebral energy metabolism under various brain conditions. In this proof-of-principle clinical study, we employed quantitative 31P MR spectroscopy (MRS) imaging techniques to determine a constellation of metabolic and bioenergetic parameters, including cerebral adenosine triphosphate (ATP) and other phosphorous metabolite concentrations, intracellular pH and nicotinamide adenine dinucleotide (NAD) redox ratio, and ATP production rates in the occipital lobe of cognitive-normal PD patients, and then we compared them with age-sex matched healthy controls. Small but statistically significant differences in intracellular pH, NAD and ATP contents and ATPase enzyme activity between the two groups were detected, suggesting that subtle defects in energy metabolism and mitochondrial function are quantifiable before regional neurological deficits or pathogenesis begin to occur in these patients. Pilot data aiming to evaluate the bioenergetic effect of mitochondrial-protective bile acid, ursodeoxycholic acid (UDCA) were also obtained. These results collectively demonstrated that in vivo 31P MRS-based neuroimaging can non-invasively and quantitatively assess key metabolic-energetic metrics in the human brain. This provides an exciting opportunity to better understand neurodegenerative diseases, their progression and response to treatment.
RESUMO
Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 µg/mL for LEV, 11.3 to 26.7 µg/mL for PHT and 126 to 223 µg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.
Assuntos
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Anticonvulsivantes/administração & dosagem , Benzodiazepinas/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Levetiracetam/administração & dosagem , Levetiracetam/farmacocinética , Masculino , Fenitoína/administração & dosagem , Fenitoína/análogos & derivados , Fenitoína/farmacocinética , Ligação Proteica , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacocinéticaRESUMO
Mitochondrial dysfunction is implicated in the pathogenesis of Parkinson's disease. Preliminary data have shown lower brain adenosine triphosphate (ATP) levels in Parkinson's disease versus age-matched healthy controls. Ursodeoxycholic acid (UDCA) may improve impaired mitochondrial function. Our objective was to evaluate UDCA tolerability, pharmacokinetics, and its effect on brain bioenergetics in individuals with Parkinson's disease. An open-label, prospective, multiple-ascending-dose study of oral UDCA in 5 individuals with Parkinson's disease was completed. A blood safety panel, plasma concentrations of UDCA and UDCA conjugates, and brain ATP levels were measured before and after therapy (week 1: 15 mg/kg/day; week 2: 30 mg/kg/day; and weeks 3-6: 50 mg/kg/day). UDCA and conjugates were measured using liquid chromatography-mass spectrometry. ATP levels and ATPase activity were measured using 7-Tesla 31 P magnetic resonance spectroscopy. Secondary measures included the Unified Parkinson's Disease Rating Scale and Montreal Cognitive Assessment. UDCA was generally well tolerated. The most frequent adverse event was gastrointestinal discomfort, rated by subjects as mild to moderate. Noncompartmental pharmacokinetic analysis resulted in (mean ± standard deviation) a maximum concentration of 8749 ± 2840 ng/mL and half-life of 2.1 ± 0.71 hr. Magnetic resonance spectroscopy data were obtained in 3 individuals with Parkinson's disease and showed modest increases in ATP and decreases in ATPase activity. Changes in Unified Parkinson's Disease Rating Scale (parts I-IV) and Montreal Cognitive Assessment scores (mean ± standard deviation) were -4.6 ± 6.4 and 2 ± 1.7, respectively. This is the first report of UDCA use in individuals with Parkinson's disease. Its pharmacokinetics are variable, and at high doses it appears reasonably well tolerated. Our findings warrant additional studies of its effect on brain bioenergetics.
Assuntos
Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacocinética , Doença de Parkinson/tratamento farmacológico , Ácido Ursodesoxicólico/efeitos adversos , Ácido Ursodesoxicólico/farmacocinética , Trifosfato de Adenosina/metabolismo , Administração Oral , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Esquema de Medicação , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/sangue , Projetos Piloto , Estudos Prospectivos , Resultado do Tratamento , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/sangueRESUMO
Despite six decades of clinical experience with the polymyxin class of antibiotics, their dose-limiting nephrotoxicity remains difficult to predict due to a paucity of sensitive biomarkers. Here, we evaluate the performance of standard of care and next-generation biomarkers of renal injury in the detection and monitoring of polymyxin-induced acute kidney injury in male Han Wistar rats using colistin (polymyxin E) and a polymyxin B (PMB) derivative with reduced nephrotoxicity, PMB nonapeptide (PMBN). This study provides the first histopathological and biomarker analysis of PMBN, an important test of the hypothesis that fatty acid modifications and charge reductions in polymyxins can reduce their nephrotoxicity. The results indicate that alterations in a panel of urinary kidney injury biomarkers can be used to monitor histopathological injury, with Kim-1 and α-GST emerging as the most sensitive biomarkers outperforming clinical standards of care, serum or plasma creatinine and blood urea nitrogen. To enable the prediction of polymyxin-induced nephrotoxicity, an in vitro cytotoxicity assay was employed using human proximal tubule epithelial cells (HK-2). Cytotoxicity data in these HK-2 cells correlated with the renal toxicity detected via safety biomarker data and histopathological evaluation, suggesting that in vitro and in vivo methods can be incorporated within a screening cascade to prioritize polymyxin class analogs with more favorable renal toxicity profiles.