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Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we perform first-in-human dynamic 18F-pretomanid positron emission tomography (PET) in eight human subjects to visualize 18F-pretomanid biodistribution as concentration-time exposures in multiple compartments (NCT05609552), demonstrating preferential brain versus lung tissue partitioning. Preferential, antibiotic-specific partitioning into brain or lung tissues of several antibiotics, active against multidrug resistant (MDR) Mycobacterium tuberculosis strains, are confirmed in experimentally-infected mice and rabbits, using dynamic PET with chemically identical antibiotic radioanalogs, and postmortem mass spectrometry measurements. PET-facilitated pharmacokinetic modeling predicts human dosing necessary to attain therapeutic brain exposures. These data are used to design optimized, pretomanid-based regimens which are evaluated at human equipotent dosing in a mouse model of TB meningitis, demonstrating excellent bactericidal activity without an increase in intracerebral inflammation or brain injury. Importantly, several antibiotic regimens demonstrate discordant activities in brain and lung tissues in the same animal, correlating with tissue antibiotic exposures. These data provide a mechanistic basis for the compartmentalized activities of antibiotic regimens, with important implications for developing treatments for meningitis and other infections in compartments with unique antibiotic penetration.
Assuntos
Antituberculosos , Encéfalo , Pulmão , Mycobacterium tuberculosis , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Coelhos , Antituberculosos/farmacocinética , Antituberculosos/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Tomografia por Emissão de Pósitrons/métodos , Distribuição Tecidual , Tuberculose Meníngea/diagnóstico por imagem , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico por imagem , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoAssuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Rim Policístico Autossômico Dominante , Tolvaptan , Humanos , Tolvaptan/uso terapêutico , Rim Policístico Autossômico Dominante/tratamento farmacológico , Concentração Osmolar , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Masculino , Feminino , Adulto , Resultado do Tratamento , Biomarcadores/sangue , Pessoa de Meia-IdadeRESUMO
Regulatory T cells (Tregs) are essential for maintaining immune homeostasis by serving as negative regulators of adaptive immune system effector cell responses. Reduced production or function of Tregs has been implicated in several human autoimmune diseases. The cytokine interleukin 2 plays a central role in promoting Treg differentiation, survival, and function in vivo and may therefore have therapeutic benefits for autoimmune diseases. mRNA-6231 is an investigational, lipid nanoparticle-encapsulated, mRNA-based therapy that encodes a modified human interleukin 2 mutein fused to human serum albumin (HSA-IL2m). Herein, we report the development of a semi-mechanistic kinetic-pharmacodynamic model to quantify the relationship between subcutaneous dose(s) of mRNA-6231, HSA-IL2m protein expression, and Treg expansion in nonhuman primates. The nonclinical kinetic-pharmacodynamic model was extrapolated to humans using allometric scaling principles and the physiological basis of pharmacological mechanisms to predict the clinical response to therapy a priori. Model-based simulations were used to inform the dose selection and design of the first-in-human clinical study (NCT04916431). The modeling approach used to predict human responses was validated when data became available from the phase I clinical study. This validation indicates that the approach is valuable in informing clinical decision-making.
Assuntos
Interleucina-2 , RNA Mensageiro , Humanos , Interleucina-2/farmacocinética , Interleucina-2/genética , Interleucina-2/farmacologia , Interleucina-2/administração & dosagem , Animais , RNA Mensageiro/genética , Linfócitos T Reguladores/efeitos dos fármacos , Nanopartículas , Modelos Biológicos , Masculino , LipossomosRESUMO
Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we performed first-in-human dynamic 18F-pretomanid positron emission tomography (PET) studies in eight human subjects for three-dimensional, multi-compartmental in situ visualization of antibiotic concentration-time exposures (area under the curve - AUC), demonstrating preferential brain (AUCtissue/plasma 2.25) versus lung (AUCtissue/plasma 0.97) tissue partitioning. Preferential, antibiotic-specific partitioning into brain or lung tissues of antibiotics active against MDR strains were confirmed in experimentally-infected mice and rabbits, using dynamic PET with chemically identical antibiotic radioanalogs, and postmortem mass spectrometry measurements. PET-facilitated pharmacokinetic modeling predicted human dosing necessary to attain therapeutic brain exposures in human subjects. These data were used to design optimized, pretomanid-based regimens which were evaluated at human equipotent dosing in a mouse model of TB meningitis, demonstrating excellent bactericidal activity without an increase in intracerebral inflammation or brain injury. Importantly, several antibiotic regimens demonstrated discordant activities in brain and lung tissues in the same animal, correlating with the compartmentalized tissue exposures of the component antibiotics. These data provide a mechanistic basis for the compartmentalized activities of antibiotic regimens, with important implications for the development of antimicrobial regimens for meningitis and other infections in compartments with unique antibiotic penetration.
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BACKGROUND: 6-Mercaptopurine (6MP) is the mainstay chemotherapy for acute lymphoblastic leukemia (ALL) and is conventionally available as 50 mg tablets. A new 6MP powder for oral suspension (PFOS 10 mg/mL) was developed recently by IDRS Labs, India, intended for pediatric use. A comparative pharmacokinetics of PFOS with T. mercaptopurine was conducted to determine the dose equivalence. METHODS: An open-label, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study was conducted on 51 healthy adult subjects. Post hoc, a population pharmacokinetic (PopPK) model was developed using the healthy volunteer data to perform simulations with various PFOS doses and select a bioequivalent dose. Further, to confirm the safety of PFOS in pediatrics, a simulation of 6MP and 6-thioguanine exposures was performed by incorporating the formulation-specific parameters derived from the healthy volunteer study into the PopPK model in childhood ALL available in literature. RESULTS: The 6MP PFOS had 47% higher oral bioavailability compared to the reference product. Simulations using a two-compartmental PopPK model with dissolution and transit compartments showed that 40 mg of PFOS was found to be equivalent to 50 mg tablets. The simulated 6-thioguanine nucleotide concentrations in children using the dose adjusted for PFOS were between 114 and 703.6 pmol/8 × 108 RBC, which was within the range reported in pediatric ALL studies. CONCLUSION: 6MP PFOS 10 mg/mL should be administered at a 20% lower dose than the tablet to achieve comparable exposure. 6MP PFOS addresses an unmet medical need for a liquid formulation of 6MP in the Indian subcontinent.
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Mercaptopurina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Criança , Humanos , Administração Oral , Estudos Cross-Over , Mercaptopurina/administração & dosagem , Pós , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Comprimidos , Equivalência Terapêutica , TioguaninaRESUMO
Propionic acidemia (PA) is an ultrarare disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), composed of PCCA and PCCB subunits. An enzyme replacement therapy is being developed using dual messenger RNA (mRNA) therapy composed of lipid nanoparticles (LNPs) encapsulating mRNAs encoding PCCA and PCCB subunits of the PCC enzyme. We herein report on development of a translational semimechanistic pharmacokinetic (PK) and PK/pharmacodynamic (PD) model to quantify the relationship between the mRNA components of mRNA-3927 (an LNP encapsulating PCCA and PCCB mRNAs) and dose levels; PCCA/B mRNA PK and PD responses were assessed as circulating levels of primary disease markers 2-methyl citrate, 3-hydroxypropionate, and propionyl carnitine normalized to acetyl carnitine (C3/C2 ratio) to inform the first-in-human dose range and regimen selection. The translational PK/PD model was developed using preclinical data available in mice with PA, Sprague Dawley rats, and cynomolgus monkeys at dose levels ranging from 0.2 to 9 mg/kg. PCCA/B mRNA PK in mice, rats, and monkeys was adequately described using allometric scaling of volume and clearance parameters. The interspecies preclinical model was scaled allometrically to humans to predict the dose-response relationship in adult and pediatric patients with PA to guide selection of dose range and regimen for the Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT04159103).
Assuntos
Acidemia Propiônica , Adulto , Humanos , Criança , Camundongos , Ratos , Animais , Acidemia Propiônica/tratamento farmacológico , Acidemia Propiônica/genética , Mutação , RNA Mensageiro/genética , Ratos Sprague-Dawley , Metilmalonil-CoA Descarboxilase/genéticaRESUMO
The severity of the ongoing opioid crisis, recently exacerbated by the COVID-19 pandemic, emphasizes the importance for individuals suffering from opioid use disorder (OUD) to have access to and receive efficacious, evidence-based treatments. Optimal treatment of OUD should aim at blocking the effects of illicit opioids while controlling opioid craving and withdrawal to facilitate abstinence from opioid use and promote recovery. The present work analyses the relationship between buprenorphine plasma exposure and clinical efficacy in participants with moderate to severe OUD using data from two clinical studies (39 and 504 participants). Leveraging data from placebo-controlled measures assessing opioid blockade, craving, withdrawal and abstinence, we found that buprenorphine plasma concentrations sustained at 2-3 ng/ml (corresponding to ≥70% brain mu-opioid receptor occupancy) optimized treatment outcomes in the majority of participants, while some individuals (e.g., injecting opioid users) needed higher concentrations. Our work also included non-linear mixed effects modeling and survival analysis, which identified a number of demographic, genetic and social factors modulating treatment response and retention. Altogether, these findings provide key information on buprenorphine plasma levels that optimize clinical outcomes and increase the likelihood of individual treatment success. NLM identifiers: NCT02044094, NCT02357901.
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Migalastat is approved for the treatment of Fabry disease (FD) with amenable variants. Objectives were to characterize effects of estimated glomerular filtration rate (eGFR) on oral clearance (CL), predict doses in mild to moderate renal impairment and in pediatric patients with FD, and to improve designs of FD studies. A 2-compartment model was fit to data from 260 subjects with/without FD and iteratively refined with evolving data. FD, eGFR, and weight affected CL, while weight and FD affected volume. Optimal sampling theory was used to choose pharmacokinetic sampling times for pediatric studies. Doses in patients with renal impairment and in pediatrics were determined by targeting exposure in adults receiving migalastat 123 mg every other day. A clinical study was conducted in 20 adolescent patients with FD ≥45 kg. eGFR had the largest effect on CL. Simulations showed that exposures in moderate renal impairment were within phase 2-3 exposures; patients aged 2-17 years require weight-based dosing; and predicted exposures in adolescent patients ≥45 kg receiving migalastat 123 mg every other day were similar to adults (data confirmed in a clinical study). Model-informed drug development optimized dosing and design of clinical studies and supported that no dose adjustments were needed in patients with mild to moderate renal impairment or in adolescent patients ≥45 kg.
Assuntos
Doença de Fabry , Insuficiência Renal , Adulto , Humanos , Adolescente , Criança , 1-Desoxinojirimicina/efeitos adversos , Doença de Fabry/tratamento farmacológico , Taxa de Filtração Glomerular , Insuficiência Renal/tratamento farmacológicoRESUMO
We determined optimal vancomycin starting dose regimens in infants ≤180 days of age to achieve the highest probability of target attainment with an area under the concentration-time curve for 24 h (AUC24) of ≥400 using population pharmacokinetic (PK) modeling. Secondarily, determination of the relationship between serum creatinine (SCR) and vancomycin clearance in neonates was done. A retrospective population PK study was designed and included pediatric patients ≤180 days old who had received vancomycin and had a serum vancomycin concentration sampled. A population PK model was developed using Pumas (v1.0.5). Simulation was performed with various dosing regimens to evaluate the probability of AUC24 target attainment and probability of trough of ≤20 mg/liter, and comparison to published models was performed. Individual clearance estimates, obtained from the final model, were plotted against SCR and faceted by age quartiles to assess the relationship between SCR and vancomycin clearance. A total of 934 patients were included in the study (58.6% male; median age, 43.6 days [range of 0 to 184]; median number of concentration samples, 1 [range of 1 to 29]). A one-compartment model was developed with body weight (WT), SCR, and postmenstrual age (PMA) identified as significant covariates on clearance. Plotting vancomycin clearance versus SCR demonstrated no clear relationship between the two at <10 days postnatal age (PNA). Dosing regimens to attain AUC24 and trough targets were stratified according to SCR for ≥10 days PNA and PMA for <10 days PNA. A vancomycin population PK model was developed for pediatric patients <180 days of age incorporating WT, SCR, and PMA. The relationship between vancomycin clearance and serum creatinine is not clear at <10 days PNA.
Assuntos
Antibacterianos , Vancomicina , Adulto , Antibacterianos/uso terapêutico , Peso Corporal , Criança , Simulação por Computador , Creatinina , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Vancomicina/farmacocinéticaRESUMO
Optimal pediatric dosing of unfractionated heparin (UFH) is challenging because of the paucity of clinical outcome and pharmacokinetic-pharmacodynamic (PK/PD) studies in pediatrics. This study aimed to: (i) develop a PK/PD model for UFH, quantified by anti-factor Xa assay, and the UFH effect, measured by activated partial thromboplastin time (aPTT); and (ii) use simulations to evaluate pediatric UFH infusions for achieving the anti-factor Xa (0.3-0.7 IU/mL) therapeutic target. Electronic health record data were retrospectively collected from 633 patients aged <19 years admitted to Texas Children's Hospital. The PK/PD model was developed using a 70% (training)/30% (testing) split-sample approach. A 1-compartment PK model with linear elimination adequately described the UFH PK. An allometrically scaled body weight on clearance (CL) and volume of distribution (Vd) with an age-dependent maturation function of extracellular water on Vd were the covariates identified. Comparable with literature, the typical values for CL and Vd were 3.28 L/(h·50 kg) and 8.83 L/50 kg, respectively. A linear model adequately described the UFH-aPTT relationship with an estimated slope of 150 seconds/(IU/mL). Simulations of the currently recommended starting infusions (28 IU/h/kg for pediatrics <1 year old or 20 IU/h/kg for pediatrics >1 year old) showed that the anti-factor Xa therapeutic target was achieved only in 15.3%, 14.6%, 36.9%, and 45.11% of subjects in the age groups of <1 year, 1-6 years, 6-12 years, and 12-19 years, respectively. In conclusion, the UFH anti-factor Xa target is not achieved initially, especially in young pediatrics, suggesting the need to optimize UFH dosing to achieve higher therapeutic success.
Assuntos
Heparina , Pediatria , Anticoagulantes/uso terapêutico , Criança , Inibidores do Fator Xa , Heparina/uso terapêutico , Humanos , Lactente , Tempo de Tromboplastina Parcial , Estudos RetrospectivosRESUMO
AIM: The study objective was to develop a population pharmacokinetic model for busulfan to comprehensively examine drug-drug interactions in paediatric patients undergoing haematopoietic stem cell transplantation. Currently, there is limited evidence to substantiate potential drug-drug interactions with busulfan. METHODS: This retrospective study population was comprised of 250 patients receiving, on average, 0.8 mg/kg intravenous busulfan as pretreatment. All model analyses were conducted using nonlinear mixed effects modelling in Pumas v2.0. The metabolic pathways of primary interest were glutathione conjugation and cytochrome P450 (CYP) activity. Concomitant medications were categorized as CYP inhibitors, inducers or glutathione S-transferase depleters, and included in the model as conditional covariates. A bootstrap simulation and visual predictive check were conducted to qualify the final model. RESULTS: The final 1-compartment model incorporates covariates of weight and age in relation to their effects on both total body clearance and volume of distribution. The estimated typical values of clearance and volume were 1.138 L/h (CI: 1.095-1.179 L/h) and 3.527 L (CI: 3.418-3.621 L), respectively. No significant changes in clearance were observed when medications that alter proposed hepatic and metabolic pathways of busulfan were coadministered. CONCLUSION: To the best of our knowledge, this is the largest single centre study of busulfan in children and the first to quantify the maturation effect of both clearance and volume. This study could not demonstrate a difference in busulfan clearance when comparing patients who received medications that alter the glutathione S-transferase, CYP3A4 or CYP2C9 pathway to those who did not.
Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Bussulfano/farmacocinética , Criança , Interações Medicamentosas , Glutationa Transferase/metabolismo , Humanos , Estudos RetrospectivosRESUMO
OBJECTIVE: To determine a safe dose of clonidine (CLON) to be used in infants with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). STUDY DESIGN: A pilot prospective study was performed to determine the effect of CLON on autonomic parameters, the pharmacokinetics (PK) of CLON, and the amount of morphine (MOR) given "as needed" for shivering and agitation in a cohort of infants (n = 12) with HIE undergoing TH compared to a historical control group (n = 28). RESULTS: The CLON group received less "as needed" MOR than the MOR-only group for agitation/shivering (p < 0.001), and the CLON vs. MOR-only group spent 92% vs. 79% of cooling time at the target core body temperature (CBT; p = 0.03, CLON vs. MOR). CONCLUSIONS: Intravenous CLON (1 mcg/kg Q8h) is well tolerated in infants treated with TH for HIE. CLON stabilizes CBT in the ideal range during cooling, which may be optimal for neuroprotection.
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Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Doenças do Recém-Nascido , Clonidina/uso terapêutico , Humanos , Hipóxia-Isquemia Encefálica/terapia , Lactente , Recém-Nascido , Doenças do Recém-Nascido/terapia , Morfina , Projetos Piloto , Estudos ProspectivosRESUMO
Pharmacometrics could play a key role in shifting pediatric pharmacotherapy from dosing for an average patient to individualizing dosing. Clinicians can have these quantitative tools at their disposal without requiring significant training through the development of clinical decision support systems with easy-to-use interfaces that have a back-end analysis engine or pharmacometric model that uses extensive electronic health record data to predict an individualized dose for each patient. There has been increased development of these clinical decision support systems recently, and for these tools to make the proper breakthrough into clinical practice, it is of utmost importance to perform rigorous testing to ensure adequate predictive performance. In this article, we walk through the components of a decision support tool and the testing required to determine its robustness using an example of a decision support tool we developed for vancomycin dosing in pediatrics.
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Técnicas de Apoio para a Decisão , Atenção à Saúde/métodos , Pediatria/métodos , Adolescente , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antibacterianos/farmacocinética , Criança , Pré-Escolar , Registros Eletrônicos de Saúde , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Modelos Biológicos , Farmacocinética , Software , Vancomicina/administração & dosagem , Vancomicina/sangue , Vancomicina/farmacocinéticaRESUMO
Nivolumab monotherapy is approved as adjuvant treatment for melanoma based on results from the pivotal CheckMate 238 trial. We present a model-based, benefit-risk assessment of nivolumab in adjuvant melanoma supporting a posology change from a weight-based to a less frequent, flat-dosing regimen. The exposure-response (E-R) relationship for efficacy was evaluated using recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) end points from the CheckMate 238 trial. The E-R for safety was evaluated using data from 14 studies across a broad range of doses in several tumor types using grade 3+ adverse event (AE) and grade 2+ immune-mediated AE (IMAE) end points. Nivolumab trough exposures were not significant predictors of RFS or DMFS. Covariates significantly associated with increased risk of disease recurrence or death were programmed death ligand 1 (PD-L1; less than 5% cutoff), lower baseline lactate dehydrogenase, and higher age. Covariates associated with increased risk of distant metastasis or death were PD-L1 (less than 5% cutoff) and higher age. Higher nivolumab maximum concentration after first dose (Cmax1) was significantly associated with grade 2+ IMAEs, but not grade 3+ AEs. The risk of grade 3+ AEs was significantly lower in adjuvant versus advanced melanoma. Eastern Cooperative Oncology Group Performance Status higher than zero was associated with higher incidences of grade 2+ IMAEs and grade 3+ AEs. Female patients had significantly higher incidences of grade 2+ IMAEs than male patients. Nivolumab monotherapy in adjuvant melanoma demonstrated a relatively flat E-R relationship over the range of exposures produced by 3 mg/kg every 2 weeks and predicted a comparable benefit-risk profile to flat-dosing regimens.
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Melanoma/tratamento farmacológico , Modelos Biológicos , Nivolumabe/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Quimioterapia Adjuvante , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Fatores Sexuais , 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.
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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
Polyarticular juvenile idiopathic arthritis (pJIA) is a pediatric chronic inflammatory arthritis, much like rheumatoid arthritis (RA) in adults. Drug development for pJIA can potentially be expedited by using extrapolation of efficacy from adult RA; however, the lack of understanding of the response and exposure relationship between pJIA and RA to therapeutic interventions has been a major roadblock. To address this, the objective of our analysis was to conduct a systematic response and exposure comparison between pJIA and RA trials for biologic products. Data from registration RA and pJIA clinical trials (parallel or withdrawal design) for infliximab, tocilizumab, golimumab, and adalimumab were utilized. First, exposure was compared between the pJIA trials and RA pivotal trials. Subsequently, the pJIA vs. RA response similarity was assessed by comparing similar individual subcomponents of the American College of Rheumatology (ACR) scores between the two populations. The exposure comparison demonstrated that at the pJIA trial dose, exposure in pediatric patients was similar to or higher than adults for all biologics evaluated except infliximab, where lower exposure was observed in pJIA patients ≤ 35 kg. Response comparison for individual subcomponents indicated that in a majority of the cases, pJIA response was similar or higher as compared with response from RA trials. Overall, this analysis suggests response similarity between pJIA and RA across the biologic products when exposures are matched between the two populations. These analyses provide support for the use of pharmacokinetic exposure-matching for extrapolation of efficacy from adult RA to pediatric pJIA for the products with established mechanism(s) of action.
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Antirreumáticos/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/administração & dosagem , Adulto , Fatores Etários , Antirreumáticos/farmacocinética , Produtos Biológicos/farmacocinética , Criança , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Humanos , Resultado do TratamentoRESUMO
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.