RESUMEN
Transdermal drug delivery is suitable for low-molecular-weight drugs with specific lipophilicity, like fentanyl, which is widely used for cancer-induced pain management. However, fentanyl's transdermal therapy displays high intra-individual variability. Factors like skin characteristics at application sites and ambient temperature contribute to this variation. In this study, we developed a physics-based digital twin of the human body to cope with this variability and propose better adapted setups. This twin includes an in-silico skin model for drug penetration, a pharmacokinetic model, and a pharmacodynamic model. Based on the results of our simulations, applying the patch on the flank (side abdominal area) showed a 15.3 % higher maximum fentanyl concentration in the plasma than on the chest. Additionally, the time to reach this maximum concentration when delivered through the flank was 19.8 h, which was 10.3 h earlier than via the upper arm. Finally, this variation led to an 18 % lower minimum pain intensity for delivery via the flank than the chest. Moreover, the impact of seasonal changes on ambient temperature and skin temperature by considering the activity level was investigated. Based on our result, the fentanyl uptake flux by capillaries increased by up to 11.8 % from an inactive state in winter to an active state in summer. We also evaluated the effect of controlling fentanyl delivery by adjusting the temperature of the patch to alleviate the pain to reach a mild pain intensity (rated three on the VAS scale). By implementing this strategy, the average pain intensity decreased by 1.1 points, and the standard deviation for fentanyl concentration in plasma and average pain intensity reduced by 37.5 % and 33.3 %, respectively. Therefore, our digital twin demonstrated the efficacy of controlled drug release through temperature regulation, ensuring the therapy toward the intended target outcome and reducing therapy outcome variability. This holds promise as a potentially useful tool for physicians.
Asunto(s)
Administración Cutánea , Analgésicos Opioides , Sistemas de Liberación de Medicamentos , Fentanilo , Absorción Cutánea , Fentanilo/administración & dosificación , Fentanilo/farmacocinética , Fentanilo/sangre , Humanos , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/sangre , Sistemas de Liberación de Medicamentos/métodos , Piel/metabolismo , Temperatura , Temperatura Cutánea/efectos de los fármacos , Parche Transdérmico , Modelos Biológicos , Simulación por ComputadorRESUMEN
Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.
Asunto(s)
Analgésicos , Hipnóticos y Sedantes , Unidades de Cuidados Intensivos , Midazolam , Humanos , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/sangre , Analgésicos/administración & dosificación , Analgésicos/farmacocinética , Analgésicos/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Adulto , Midazolam/administración & dosificación , Midazolam/farmacocinética , Midazolam/sangre , Cuidados Críticos/métodos , Dexmedetomidina/administración & dosificación , Dexmedetomidina/farmacocinética , Dexmedetomidina/sangre , Fentanilo/administración & dosificación , Fentanilo/sangre , Fentanilo/farmacocinética , Enfermedad Crítica , Propofol/administración & dosificación , Propofol/farmacocinética , Propofol/sangre , Clonidina/administración & dosificación , Clonidina/farmacocinética , Clonidina/sangre , Ketamina/administración & dosificación , Ketamina/sangre , Ketamina/farmacocinética , Morfina/administración & dosificación , Morfina/sangre , Morfina/farmacocinética , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Tiopental/administración & dosificación , Tiopental/farmacocinética , Acetaminofén/administración & dosificación , Acetaminofén/sangre , Acetaminofén/farmacocinéticaRESUMEN
Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. Since both perinatal asphyxia (PA) and TH influence physiology, altered pharmacokinetics (PK) and pharmacodynamics (PD) are expected. Given that TH is the standard of care for PA with moderate to severe hypoxic-ischemic encephalopathy, disentangling the effect of PA versus TH on PK/PD is not possible in clinical settings. However, animal models can provide insights into this matter. The (neonatal) Göttingen Minipig, the recommended strain for nonclinical drug development, was selected as translational model. Four drugs-midazolam (MDZ), fentanyl (FNT), phenobarbital (PHB), and topiramate (TPM)-were intravenously administered under four conditions: control (C), therapeutic hypothermia (TH), hypoxia (H), and hypoxia plus TH (H+TH). Each group included six healthy male neonatal Göttingen Minipigs anesthetized for 24 hours. Blood samples were drawn at 0 (predose) and 0.5, 2, 2.5, 3, 4, 4.5, 6, 8, 12, and 24 hours post drug administration. Drug plasma concentrations were determined using validated bioanalytical assays. The PK parameters were estimated through compartmental and noncompartmental PK analysis. The study showed a statistically significant decrease in FNT clearance (CL; 66% decrease), with an approximately threefold longer half-life (t1/2) in the TH group. The H+TH group showed a 17% reduction in FNT CL, with a 62% longer t1/2 compared with the C group; however, it was not statistically significant. Although not statistically significant, trends toward lower CL and longer t1/2 were observed in the TH and H+TH groups for MDZ and PHB. Additionally, TPM demonstrated a 28% decrease in CL in the H group compared with controls. SIGNIFICANCE STATEMENT: The overarching goal of this study using the neonatal Göttingen Minipig model was to disentangle the effects of systemic hypoxia and TH on PK using four model drugs. Such insights can subsequently be used to inform and develop a physiologically based pharmacokinetic model, which is useful for drug exposure prediction in human neonates.
Asunto(s)
Animales Recién Nacidos , Asfixia Neonatal , Hipotermia Inducida , Midazolam , Porcinos Enanos , Animales , Porcinos , Hipotermia Inducida/métodos , Asfixia Neonatal/terapia , Asfixia Neonatal/tratamiento farmacológico , Masculino , Midazolam/farmacocinética , Fenobarbital/farmacocinética , Fentanilo/farmacocinética , Modelos Animales de Enfermedad , Recién Nacido , Hipoxia-Isquemia Encefálica/terapia , Hipoxia-Isquemia Encefálica/metabolismo , HumanosRESUMEN
The rapid growth in the use of pediatric physiologically based pharmacokinetic (PBPK) models, particularly for regulatory applications, has focused emphasis on model verification and ensuring system parameters are robust, including how these change with age. Uncertainty remains regarding the ontogeny of some enzymes and transporters, in this study 2 published ontogeny profiles for hepatic CYP3A4 were compared. Clinical pharmacokinetic data on 4 intravenously administered CYP3A4 substrates (alfentanil, fentanyl, midazolam, and sildenafil) used across the pediatric age range was collected from the literature. The PBPK models were verified in the adult population and then used to compare the Salem and a modified Upreti ontogeny profiles for CYP3A4 in terms of parent drug clearance and area under the curve from birth onward. Overall, the modified Upreti ontogeny profile resulted in 15 out of 17 age-related predictions within 2-fold and 12 out of 17 predictions within 1.5-fold ranges of observed values, for the Salem ontogeny these values were 12 out of 17 and 8 out of 17, respectively. The Upreti ontogeny profile performed better than Salem, average fold error and absolute average fold error were 1.14 and 1.35 compared to 1.56 and 1.90, respectively. Identifying the optimal CYP3A4 ontogeny is important for regulatory use of PBPK especially given the number of drugs cleared by this enzyme. This study broadens the evidence from previous studies that Upreti is more favorable than Salem, but further work is needed especially in the neonatal and early infant age range.
Asunto(s)
Citocromo P-450 CYP3A , Hígado , Midazolam , Modelos Biológicos , Humanos , Citocromo P-450 CYP3A/metabolismo , Niño , Lactante , Hígado/metabolismo , Preescolar , Midazolam/farmacocinética , Recién Nacido , Citrato de Sildenafil/farmacocinética , Alfentanilo/farmacocinética , Alfentanilo/administración & dosificación , Fentanilo/farmacocinética , Fentanilo/administración & dosificación , Adulto , Adolescente , Masculino , Femenino , Factores de EdadRESUMEN
The New Zealand white rabbit (Oryctolagus cuniculus) is a frequently used surgical model. Pain management after surgery is a critical aspect of animal welfare. Recently, a long-acting buprenorphine formulation (Ethiqa XR; EXR) was approved for use in rats and mice but has not yet been investigated in rabbits. The current study aimed to determine whether a single subcutaneous dose of 0.15mg/kg of EXR could achieve and maintain therapeutic buprenorphine plasma concentrations (0.1ng/mL) for 72h in male and female rabbits. We also evaluated the safety profiles of EXR and the fentanyl patch (FP) by assessing fecal output after surgery, because opioids are known to decrease intestinal motility. Behavior and pain scores were compared for rabbits that received either EXR or the FP after undergoing an annulus puncture procedure to induce osteoarthritis. EXR at 0.15mg/kg SC provided a shorter time to onset and sustained analgesia for 72h in male and female rabbits, whereas the FP provided suboptimal analgesia after 48h. Both EXR and FP reduced fecal output after surgery. Output returned to baseline levels within 72h for the EXR group and remained slightly below baseline at 96h after surgery for the fentanyl group. Grimace pain scores revealed no significant difference between treatment groups. These results suggest that EXR is a safe and effective option for postoperative pain management in rabbits.
Asunto(s)
Analgésicos Opioides , Buprenorfina , Fentanilo , Dolor Postoperatorio , Animales , Conejos , Buprenorfina/administración & dosificación , Buprenorfina/uso terapéutico , Buprenorfina/farmacocinética , Fentanilo/administración & dosificación , Fentanilo/farmacocinética , Femenino , Masculino , Dolor Postoperatorio/veterinaria , Dolor Postoperatorio/tratamiento farmacológico , Analgésicos Opioides/administración & dosificación , Defecación/efectos de los fármacos , Preparaciones de Acción RetardadaRESUMEN
RATIONALE: Understanding mechanisms of drug use decisions will inform the development of treatments for opioid use disorder (OUD). Decision-making experiments using neurobehavioral approaches require many trials or events of interest for statistical analysis, but the pharmacokinetics of most opioids limit dosing in humans. OBJECTIVES: This experiment characterized the effects of repeated infusions of the ultra-short acting opioid remifentanil in people with OUD and physical opioid dependence. METHODS: An inpatient study using a within-subjects, single-blind, escalating, within-session, pre-post design was conducted. Seven (3 female) subjects were maintained on oral oxycodone (40-60 mg, 4x/day = 160-240 total mg/day) for seven days prior to the dose-ranging session. Subjects received infusions of three ascending remifentanil doses (0.03, 0.1, 0.3 mcg/kg/infusion in 2 subjects; 0.1, 0.3, 1.0 mcg/kg/infusion in 5 subjects) every minute for 40 min per dose, with infusions administered over 5 s to model naturalistic delivery rates. End tidal carbon dioxide, respiration rate, oxygen saturation (SpO2) and heart rate were measured continuously. Blood pressure (BP), pupil diameter and self-reported drug effects were measured every 5 min. RESULTS: Pupil diameter, SpO2 and systolic BP decreased, and ratings on prototypic subjective effects questionnaire items increased, as a function of remifentanil dose. The number of infusions held because of sedation or physiological parameters exceeding predetermined cutoffs also increased with dose. CONCLUSIONS: This experiment established doses and procedures for the safe delivery of rapid, repeated remifentanil infusions to individuals with OUD and physical fentanyl dependence, which can be applied to the mechanistic study of opioid use decisions.
Asunto(s)
Analgésicos Opioides , Presión Sanguínea , Relación Dosis-Respuesta a Droga , Fentanilo , Frecuencia Cardíaca , Trastornos Relacionados con Opioides , Piperidinas , Remifentanilo , Humanos , Remifentanilo/administración & dosificación , Remifentanilo/farmacología , Femenino , Masculino , Adulto , Trastornos Relacionados con Opioides/tratamiento farmacológico , Fentanilo/administración & dosificación , Fentanilo/farmacocinética , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacocinética , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Piperidinas/farmacología , Método Simple Ciego , Frecuencia Cardíaca/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Infusiones Intravenosas , Persona de Mediana Edad , Autoinforme , Adulto Joven , Oxicodona/administración & dosificación , Oxicodona/farmacocinéticaRESUMEN
BACKGROUND: Fentanyl is widely used for analgesia and sedation in neonates, but pharmacokinetic (PK) analysis in this population has been limited by the relatively large sample volumes required for plasma-based assays. METHODS: In this multicenter observational study of fentanyl kinetics in neonates up to 42 weeks of postmenstrual age (PMA) who received fentanyl boluses and continuous infusions, dried blood spots were used for small-volume sampling. A population PK analysis was used to describe fentanyl disposition in term and preterm neonates. Covariates for the model parameters, including body weight, PMA, birth status (preterm or term), and presence of congenital cardiac disease, were assessed in a stepwise manner. RESULTS: Clearance was estimated to be greater than adult clearance of fentanyl and varied with weight. Covariate selection did not yield a significant relationship for age as a continuous or dichotomous variable (term or preterm, the latter defined as birth with PMA of <37 weeks) and clearance. CONCLUSIONS: A supra-allometric effect on clearance was determined during covariate analyses (exponential scaling factor for body weight >0.75), as has been described in population PK models that account for maturation of intrinsic clearance (here, predominantly hepatic microsomal activity) in addition to scaling for weight, both of which impact clearance in this age group.
Asunto(s)
Fentanilo , Cardiopatías Congénitas , Recién Nacido , Adulto , Humanos , Lactante , Fentanilo/farmacocinética , Dolor , Peso Corporal , Tasa de Depuración MetabólicaRESUMEN
Fentanyl is an anesthetic/analgesic commonly used in surgical and recovery settings. CYP3A4 and CYP3A5 encode enzymes, which metabolize fentanyl; genetic variants in these genes impact fentanyl pharmacokinetics in adults. Pharmacokinetic (PK) studies are difficult to replicate in children due to the burden of additional blood taken solely for research purposes. The aim of this study is to test the effect of CYP3A5 and CYP3A4 genetic variants on fentanyl PKs in children using opportunistically collected samples. Fentanyl concentrations were measured from remnant blood specimens and dosing data were extracted from electronic health records. Variant data defining CYP3A4*1G and CYP3A5*3 and *6 alleles were available from prior genotyping; alleles with no variant were defined as *1. The study cohort included 434 individuals (median age 9 months, 52% male subjects) and 1,937 fentanyl concentrations were available. A two-compartment model was selected as the base model, and the final covariate model included age, weight, and surgical severity score. Clearance was significantly associated with either CYP3A5*3 or CYP3A5*6 alleles, but not the CYP3A4*1G allele. A genotype of CYP3A5*1/*3 or CYP3A5*1/*6 (i.e., intermediate metabolizer status) was associated with a 0.84-fold (95% confidence interval (CI): 0.71-1.00) reduction in clearance vs. CYP3A5*1/*1 (i.e., normal metabolizer status). CYP3A5*3/*3, CYP3A5*3/*6, or CYP3A5*6/*6 (i.e., poor metabolizer status) was associated with a 0.76-fold (95% CI: 0.58-0.99) reduction in clearance. In the final model, expected clearance was 8.9 and 6.8 L/hour for a normal and poor metabolizer, respectively, with median population covariates (9 months old, 7.7 kg, low surgical severity).
Asunto(s)
Citocromo P-450 CYP3A , Fentanilo , Alelos , Estudios de Cohortes , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Femenino , Fentanilo/farmacocinética , Genotipo , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Matrix fentanyl patches have not been investigated in horses and may represent an effective means of providing analgesia over an extended time period without venous catheterisation. OBJECTIVES: To describe the pharmacokinetics of a matrix transdermal fentanyl patch in horses. STUDY DESIGN: Randomised experiment, Latin-square design. METHODS: Six adult horses were given each of three treatments with a 96-hour washout. For each treatment, two 100 µg/h matrix fentanyl patches were applied to the inguinal region (TXA), metacarpus (TXM) or ventral tail base (TXT) for 72 hours. Blood samples for fentanyl analysis were obtained and heart rate (HR), respiratory rate (RR) and rectal temperature (RT) were measured at various time points for 96 hours. Fentanyl plasma concentrations were measured with LC-MS/MS for pharmacokinetic analysis. A mixed-effects model was used to analyse pharmacodynamic variables. RESULTS: The time to maximum plasma concentration, maximum plasma concentration and area under the curve extrapolated to infinity were 10 ± 3.79, 14.3 ± 5.13 and 10.3 ± 4.8 hours; 2.07 ± 0.74, 1.55 ± 0.53 and 2.07 ± 0.72 ng/mL; and 46.6 ± 9.3, 44.6 ± 6.0 and 46.2 ± 7.68 ng hours/mL for TXA, TXM and TXT respectively. There was no significant difference among groups. There was no significant change from baseline or among treatment groups with regard to HR, RR or RT (P > .1 for all). MAIN LIMITATIONS: There was no intravenous treatment group for determination of bioavailability. CONCLUSIONS: Fentanyl was rapidly absorbed and persisted in the plasma for up to 96 hours. No adverse effects of treatment on HR, RR or RT were observed. Further controlled prospective studies are needed to determine what plasma concentration, if any, of fentanyl achieves an analgesic effect in horses when administered via a transdermal patch system.
Asunto(s)
Analgésicos Opioides/farmacocinética , Fentanilo , Caballos/sangre , Espectrometría de Masas en Tándem , Administración Cutánea , Animales , Cromatografía Liquida/veterinaria , Fentanilo/farmacocinética , Espectrometría de Masas en Tándem/veterinariaRESUMEN
BACKGROUND: Transdermal fentanyl is not yet approved for pediatric and adolescent use in Japan. OBJECTIVE: Serum fentanyl concentration and the safety and efficacy of once-a-day fentanyl citrate patch were investigated in pediatric and adolescent patients with cancer pain. METHODS: In this open-label, uncontrolled study, cancer patients aged 2-19 years being treated with strong opioid analgesics were switched to fentanyl citrate patch for 2 weeks. Serum fentanyl concentration was measured at steady state, and severity of pain was evaluated. RESULTS: Eleven patients (four patients aged 2-5 years and seven patients aged 6-19 years) were enrolled. No patient received a dose exceeding 2 mg. Mean serum fentanyl concentrations after administration of 0.5 mg, 1 mg, and 2 mg were 144 pg/mL (n = 4), 277 pg/mL (n = 3), and 2070 pg/mL (n = 4), respectively. All patients were included in the efficacy and safety analysis, but one patient was excluded from the pharmacokinetic analysis because blood was sampled on the day after blood transfusion. A subgroup analysis showed that the mean serum fentanyl concentration tended to be higher in pre-school patients (aged 2-5 years) than in school-aged and adolescent patients (aged 6-19 years) and than in reports of adult patients (aged 20 years and above) who received the same dose. No respiratory adverse events were observed, and pain was well controlled. CONCLUSION: Fentanyl citrate patch tended to result in a higher serum fentanyl concentration in pre-school patients than in school-aged, adolescent, and adult patients who received the same dose. The patch provided adequate pain control, was well tolerated, and did not cause respiratory adverse events. TRIAL REGISTRATION NUMBER: JPRN-JapicCTI-183909.
Asunto(s)
Dolor en Cáncer , Fentanilo , Neoplasias , Administración Cutánea , Adolescente , Analgésicos Opioides , Dolor en Cáncer/tratamiento farmacológico , Dolor en Cáncer/etiología , Niño , Preescolar , Fentanilo/farmacocinética , Humanos , Japón , Neoplasias/complicaciones , Adulto JovenRESUMEN
Fentanyl is an opioid analgesic used to treat obstetrical pain in parturient women through epidural or intravenous route, and unfortunately can also be abused by pregnant women. Fentanyl is known to cross the placental barrier, but how the route of administration and time after dosing affects maternal-fetal disposition kinetics at different stages of pregnancy is not well characterized. To address this knowledge gap, we developed a maternal-fetal physiologically based pharmacokinetic (mf-PBPK) model for fentanyl to evaluate the feasibility to predict the maternal and fetal plasma concentration-time profiles of fentanyl after various dosing regimens. As fentanyl is typically given via the epidural route to control labor pain, an epidural dosing site was developed using alfentanil as a reference drug and extrapolated to fentanyl. Fetal hepatic clearance of fentanyl was predicted from CYP3A7-mediated norfentanyl formation in fetal liver microsomes (intrinsic clearance = 0.20 ± 0.05 µl/min/mg protein). The developed mf-PBPK model successfully captured fentanyl maternal and umbilical cord concentrations after epidural dosing and was used to simulate the concentrations after intravenous dosing (in a drug abuse situation). The distribution kinetics of fentanyl were found to have a considerable impact on the time course of maternal:umbilical cord concentration ratio and on interpretation of observed data. The data show that mf-PBPK modeling can be used successfully to predict maternal disposition, transplacental distribution, and fetal exposure to fentanyl. SIGNIFICANCE STATEMENT: This study establishes the modeling framework for predicting the time course of maternal and fetal exposures of fentanyl opioids from mf-PBPK modeling. The model was validated based on fentanyl exposure data collected during labor and delivery after intravenous or epidural dosing. The results show that mf-PBPK modeling is a useful predictive tool for assessing fetal exposures to fentanyl opioid therapeutic regimens and potentially can be extended to other drugs of abuse.
Asunto(s)
Analgésicos Opioides/farmacocinética , Fentanilo/farmacocinética , Intercambio Materno-Fetal , Administración Intravenosa , Adulto , Analgesia Epidural , Analgésicos Opioides/administración & dosificación , Anestesia Epidural , Anestesia Obstétrica , Hidrocarburo de Aril Hidroxilasas/metabolismo , Familia 2 del Citocromo P450/metabolismo , Femenino , Fentanilo/administración & dosificación , Feto , Humanos , Recién Nacido , Inyecciones Epidurales , Hígado/metabolismo , Microsomas Hepáticos/metabolismo , Modelos Estadísticos , Valor Predictivo de las Pruebas , Embarazo , Distribución Tisular , Cordón Umbilical/química , Cordón Umbilical/metabolismoRESUMEN
PURPOSE: Subcutaneous fentanyl injection is commonly prescribed to manage acute pain in older patients; however, there is a gap in the literature describing the pharmacokinetic parameters for this route of administration in this population. The aim of this study was to develop and evaluate a population pharmacokinetic model for subcutaneous fentanyl injection in older patients. METHODS: Twenty-one patients who received subcutaneous fentanyl injections (50 to 75 µg) were recruited. Fentanyl concentrations were determined using a validated liquid chromatography/tandem mass spectrometry method. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. A base model was selected based on the Akaike information criterion. Age, sex, body weight, number of previous fentanyl doses, number of prescribed medications, creatinine clearance, Charlson Comorbidity Index, Identification of Seniors at Risk score and concurrent use of CYP3A4 inhibitors were covariates considered for inclusion. A p value of < 0.05 was considered statistically significant for inclusion of covariates in the final model by stepwise addition. The simulation performance of the model was assessed by visual predictive check. RESULTS: A one-compartment, first-order absorption with lag time and linear elimination model was the best to fit to the fentanyl concentration data. The absorption rate constant was 0.136 h-1 (between subject variability (BSV), 46%), lag time 0.66 h (BSV 51%), apparent volume of distribution 6.28 L (BSV 30%), and apparent clearance 16.3 L.h-1 (BSV 54%). The Charlson Comorbidity Index was the only covariate included in the final model, where a higher value of the index increased fentanyl exposure and Cmax. CONCLUSION: This is the first report of subcutaneous fentanyl population pharmacokinetic model to evaluate fentanyl pharmacokinetic in older patients. The between subject variability in clearance and subcutaneous absorption rate was relatively high, and some patients recorded high fentanyl concentrations in the context of their titration to effect.
Asunto(s)
Analgésicos Opioides/farmacocinética , Fentanilo/farmacocinética , Anciano , Anciano de 80 o más Años , Analgésicos Opioides/administración & dosificación , Comorbilidad , Femenino , Fentanilo/administración & dosificación , Humanos , Inyecciones Subcutáneas , Masculino , Tasa de Depuración Metabólica , Modelos Biológicos , Absorción Subcutánea , Factores de TiempoRESUMEN
The number of new psychoactive substances (NPS) on the illicit drug market increases fast, posing a need to urgently understand their toxicity and behavioural effects. However, with currently available rodent models, NPS assessment is limited to a few substances per year. Therefore, zebrafish (Danio rerio) embryos and larvae have been suggested as an alternative model that would require less time and resources to perform an initial assessment and could help to prioritize substances for subsequent evaluation in rodents. To validate this model, more information on the concordance of zebrafish larvae and mammalian responses to specific classes of NPS is needed. Here, we studied toxicity and behavioural effects of opioids in zebrafish early life stages. Synthetic opioids are a class of NPS that are often used in pain medication but also frequently abused, having caused multiple intoxications and fatalities recently. Our data shows that fentanyl derivatives were the most toxic among the tested opioids, with toxicity in the zebrafish embryo toxicity test decreasing in the following order: butyrfentanyl>3-methylfentanyl>fentanyl>tramadol> O-desmethyltramadol>morphine. Similar to rodents, tramadol as well as fentanyl and its derivatives led to hypoactive behaviour in zebrafish larvae, with 3-methylfentanyl being the most potent. Physico-chemical properties-based predictions of chemicals' uptake into zebrafish embryos and larvae correlated well with the effects observed. Further, the biotransformation pattern of butyrfentanyl in zebrafish larvae was reminiscent of that in humans. Comparison of toxicity and behavioural responses to opioids in zebrafish and rodents supports zebrafish as a suitable alternative model for rapidly testing synthetic opioids.
Asunto(s)
Analgésicos Opioides/toxicidad , Fentanilo/toxicidad , Pez Cebra/embriología , Analgésicos Opioides/farmacocinética , Animales , Conducta Animal/efectos de los fármacos , Biotransformación , Carga Corporal (Radioterapia) , Relación Dosis-Respuesta a Droga , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Fentanilo/análogos & derivados , Fentanilo/farmacocinética , Larva/efectos de los fármacos , Larva/metabolismo , Locomoción/efectos de los fármacos , Modelos Animales , Reproducibilidad de los Resultados , Especificidad de la Especie , Toxicocinética , Pez Cebra/metabolismoRESUMEN
The clinical effects of remimazolam (an investigational, ultra-short acting benzodiazepine being studied in procedural sedation) were measured using the Modified Observer's Assessment of Awareness/Sedation Scale (MOAA/S). The objective of this analysis was to develop a population pharmacokinetic/pharmacodynamic model to describe remimazolam-induced sedation with fentanyl over time in procedural sedation. MOAA/S from 10 clinical phase I-III trials were pooled for analysis, where data were collected after administration of placebo or remimazolam with or without concomitant fentanyl. A Markov model described transition states for 35,356 MOAA/S-time observations from 1071 subjects. Effect-compartment models of remimazolam and fentanyl linked plasma concentrations to the Markov model, and drug effects were described using a synergistic maximum effect (Emax ) model. Simulations were performed to identify the optimal remimazolam-fentanyl combination doses in procedural sedation. Fentanyl showed synergistic effects with remimazolam in sedation. Increasing age was related to longer recovery from sedation. Patients with body mass index greater than 25 kg/m2 had ~30% higher rates of distribution from plasma to the effect site (keo), indicating a slightly faster onset of sedation. Simulations showed that remimazolam 5 mg was more appropriate than 4 or 6 mg when administered with fentanyl 50 µg. The model and simulations support that a combination of remimazolam 5 mg with fentanyl 50 µg is an appropriate dosing regimen and the dose of remimazolam does not need to be changed in elderly patients, but some elderly patients may have a longer duration of sedation.
Asunto(s)
Benzodiazepinas/farmacocinética , Sedación Profunda/métodos , Fentanilo/farmacocinética , Modelos Biológicos , Dolor Asociado a Procedimientos Médicos/prevención & control , Factores de Edad , Anciano , Benzodiazepinas/administración & dosificación , Variación Biológica Poblacional , Ensayos Clínicos como Asunto , Simulación por Computador , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Fentanilo/administración & dosificación , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Masculino , Cadenas de Markov , Persona de Mediana EdadRESUMEN
The opioid epidemic remains a dire public health crisis with millions of people currently suffering from opioid use disorder (OUD) and tens of thousands dying each year. Synthetic opioids are most responsible for the crisis because of their extreme potency and ease of manufacture. Carfentanil for example has an estimated potency 10,000 times greater than morphine and thus is highly dangerous for human use. Herein, we report two synthetic opioid vaccines that elicited high-affinity antibodies against carfentanil and fentanyl with cross-reactivity to other synthetic opioids in mice and offered protection against opioid-induced respiratory depression, the primary cause of overdose deaths. These vaccines also successfully diminished drug biodistribution to the brain and shielded against opioid analgesic effects. Collectively, these findings provide new insights into the development of immunotherapeutic strategies aimed at opioid abuse and overdose.
Asunto(s)
Fentanilo/análogos & derivados , Trastornos Relacionados con Opioides/terapia , Insuficiencia Respiratoria/terapia , Vacunas Sintéticas/uso terapéutico , Animales , Fentanilo/inmunología , Fentanilo/farmacocinética , Fentanilo/uso terapéutico , Inmunoconjugados/inmunología , Inmunoconjugados/farmacocinética , Inmunoconjugados/uso terapéutico , Ratones , Insuficiencia Respiratoria/inducido químicamente , Toxoide Tetánico/inmunología , Vacunas Sintéticas/inmunologíaRESUMEN
INTRODUCTION: Fentanyl pharmacokinetic and pharmacodynamic data are limited in mechanically ventilated children. This study aimed to assess the fentanyl pharmacokinetics (PK), the sedation outcome, and the development of tolerance in children receiving fentanyl continuous infusion. METHODS: This study included children admitted to the pediatric or cardiovascular intensive care unit between January 1 and October 31, 2016, who were >30 days to <18 years of age, receiving ventilatory support via endotracheal tube or tracheostomy, and receiving a fentanyl infusion. Population PK analysis was performed using a nonlinear mixed-effects model. The relationship between initial sedation outcome using State Behavioral Scale (SBS) and fentanyl exposure was assessed, and the observations consistent with tolerance were described. RESULTS: Seventeen children, with a median age of 0.83 years (range: 0.1-12) and weight of 8.7 kg (range: 3.4-52), were included. The fentanyl PK was adequately described by a weight-based allometry model with the power of 0.75 for clearance (CL=89.8 L/hr/70 kg) and distributional CL, and 1 for volumes of distribution. In infants <6.6 months, age was an additional factor for CL (31.4 L/h/70 kg) to account for age-related maturation. Seven of twelve nonparalyzed patients achieved goal sedation, defined as >80% of SBS scores ≤0 per 24 h, on the first day of fentanyl infusion with a median plasma concentration of 1.29 ng/ml (interquartile range: 0.78-2.05). Eight of the nine tolerant patients developed tolerance within a day of reaching goal sedation. CONCLUSION: Different weight-based fentanyl dosing rates may be required for infants and children of different ages to achieve similar plasma concentrations. Using SBS scores may guide the dosing titration of fentanyl that resulted in plasma concentrations within the therapeutic range of 1-3 ng/ml. For those who developed tolerance to fentanyl and/or a sedative, it was noted one day after goal sedation was achieved.
Asunto(s)
Fentanilo , Niño , Preescolar , Enfermedad Crítica , Tolerancia a Medicamentos , Fentanilo/farmacocinética , Fentanilo/farmacología , Humanos , Hipnóticos y Sedantes , Lactante , Unidades de Cuidados Intensivos , Respiración ArtificialRESUMEN
Chronic opioid consumption is associated with addiction, physical dependence, and tolerance. Tolerance results in dose escalation to maintain the desired opioid effect. Intake of high-dose or potent opioids may cause life-threatening respiratory depression, an effect that may be reduced by tolerance. We performed a pharmacokinetic-pharmacodynamic analysis of the respiratory effects of fentanyl in chronic opioid users and opioid-naïve subjects to quantify tolerance to respiratory depression. Fourteen opioid-naïve individuals and eight chronic opioid users received escalating doses of intravenous fentanyl (opioid-naïve subjects: 75-350 µg/70 kg; chronic users: 250-700 µg/70 kg). Isohypercapnic ventilation was measured and the fentanyl plasma concentration-ventilation data were analyzed using nonlinear mixed-effects modeling. Apneic events occurred in opioid-naïve subjects after a cumulative fentanyl dose (per 70 kg) of 225 (n = 3) and 475 µg (n = 6), and in 7 chronic opioid users after a cumulative dose of 600 (n = 2), 1,100 (n = 2), and 1,800 µg (n = 3). The time course of fentanyl's respiratory depressant effect was characterized using a biophase equilibration model in combination with an inhibitory maximum effect (Emax ) model. Differences in tolerance between populations were successfully modeled. The effect-site concentration causing 50% ventilatory depression, was 0.42 ± 0.07 ng/mL in opioid-naïve subjects and 1.82 ± 0.39 ng/mL in chronic opioid users, indicative of a 4.3-fold sensitivity difference. Despite higher tolerance to fentanyl-induced respiratory depression, apnea still occurred in the opioid-tolerant population indicative of the potential danger of high-dose opioids in causing life-threatening respiratory depression in all individuals, opioid-naïve and opioid-tolerant.
Asunto(s)
Analgésicos Opioides/efectos adversos , Apnea/etiología , Fentanilo/efectos adversos , Pulmón/efectos de los fármacos , Trastornos Relacionados con Opioides/complicaciones , Insuficiencia Respiratoria/etiología , Adulto , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacocinética , Apnea/fisiopatología , Simulación por Computador , Tolerancia a Medicamentos , Femenino , Fentanilo/administración & dosificación , Fentanilo/farmacocinética , Humanos , Infusiones Intravenosas , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Modelos Biológicos , Trastornos Relacionados con Opioides/fisiopatología , Insuficiencia Respiratoria/fisiopatología , Adulto JovenRESUMEN
Two open-label, single-dose, randomized crossover studies were conducted in healthy Japanesemen to (1) assess dose proportionality of 5 doses (1.38, 2.75, 5.5, 8.25, and 11.0 mg) of Lafenta, a novel matrix-type transdermal fentanyl patch with a rate-controlling membrane; and (2) compare patch bioequivalence (11.0 mg) with a commercially available reference patch (Durotep MT Patch [16.8 mg]). Pharmacokinetics, adhesion performance, residual fentanyl, and safety parameters were assessed. Increases in mean AUC0-t and Cmax after application of the test patch were dose proportional. The test patch (11.0 mg) was bioequivalent to the 16.8-mg reference patch in terms of mean AUC0-inf , AUC0-t , and Cmax . Residual fentanyl levels 72 hours postapplication were lower in the test than in the reference patch. Differences in adhesion performance between the test and the reference patch did not affect delivery efficacy and reliability of the novel matrix patch. Safety findings were in line with previous experiences with fentanyl. Both studies showed low variation in fentanyl exposure and delivery via the test patch. The test patch provided equivalent fentanyl exposure at a lower dose than the reference patch formulation with lower variability and the potential to lower medicinal waste.