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AIMS: The pharmacokinetics (PK) of a triple-secured fibrinogen concentrate (FC) was assessed in patients ≥40 kg by noncompartmental analysis over a period of 14 days with multiple blood samples. Limited PK time point assessments in children lead to consideration of using Bayesian estimation for paediatric data. The objectives were (i) to define the population PK of FC in patients with afibrinogenaemia; (ii) to detect age- and body weight-related differences and consequences for dose adjustment. METHODS: A population PK model was built using plasma fibrinogen activity data collected in 31 patients aged 1 to 48 years who had participated in a single-dose PK study with FC 0.06 g kg-1 . RESULTS: A 1-compartment model with allometric scaling accounting for body weight was found to best describe the kinetics of FC. Addition of age and sex as covariates did not improve the model. Incremental in vivo recovery assessed at the end of infusion with the predicted maximal concentrations was lower, weight-adjusted clearance was higher, and fibrinogen elimination half-life was shorter in patients <40 kg than patients ≥40 kg. Interpatient variability was similar in both groups. CONCLUSION: Dosing in patients ≥40 kg based on the previous empirical finding using noncompartmental analysis where FC 1 g kg-1 raises the plasma fibrinogen activity by 23 g L-1 was confirmed. In patients <40 kg, (covering the age range from birth up to about 12 years old) FC 1 g kg-1 raises the plasma fibrinogen by 19 g L-1 . Dosing should be adapted accordingly unless therapy is individualized.
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Afibrinogenemia , Afibrinogenemia/tratamiento farmacológico , Factores de Edad , Teorema de Bayes , Peso Corporal , Niño , Fibrinógeno , HumanosRESUMEN
PURPOSE: This paper describes the pharmacokinetic/pharmacodynamic modelling of clazosentan in patients with aneurysmal subarachnoid haemorrhage (aSAH), and the impact of collecting data in an intensive care unit (ICU) setting. Factors influencing data quality, analysis, and interpretation are provided with recommendations for future clinical studies in ICU settings. METHODS: CONSCIOUS-2 was a phase III study involving 1,157 patients with aSAH. Secured by surgical clipping, patients were infused with clazosentan or placebo for up to 14 days post-aSAH. Clazosentan exposure relationships with vital signs, QT intervals, and AST/ALT values as well as efficacy and safety endpoints were characterised using population PK/PD and logistic regression models. RESULTS: Clazosentan clearance was influenced by age, sex, Asian origin, and disease status at baseline, and increased with time. Volume of distribution showed a sex difference. Exposure had no relationship with any efficacy endpoint or ALT/AST values, but was related to the increasing probability of lung complications. Blood pressure decreased proportionally to clazosentan concentrations, and the presence of clazosentan was associated with QT interval increases. Implausible values in the concentration data reflect the specific ICU challenges, possibly arising from PK sampling from the infusion arm or haemodilution. CONCLUSIONS: Population PK/PD modelling of CONCIOUS-2 data provided clinically relevant knowledge about various effects of clazosentan in the aSAH patient population in a real clinical setting. The quality of data and analyses could be improved by the collection of additional data and stricter training of study personnel. Differences in clinical practice between sites and geographical regions are more challenging to overcome.
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Dioxanos/farmacología , Dioxanos/farmacocinética , Piridinas/farmacología , Piridinas/farmacocinética , Pirimidinas/farmacología , Pirimidinas/farmacocinética , Hemorragia Subaracnoidea/tratamiento farmacológico , Sulfonamidas/farmacología , Sulfonamidas/farmacocinética , Tetrazoles/farmacología , Tetrazoles/farmacocinética , Adolescente , Cuidados Críticos , Método Doble Ciego , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Eslicarbazepine acetate (Zebenix®) is a voltage-gated sodium channel blocker approved in 2009 by the European Medicines Agency as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization. OBJECTIVES: The objectives of the current population pharmacokinetic (PK) and PK/pharmacodynamic analyses were to characterize the population PK of eslicarbazepine (the main active metabolite of eslicarbazepine acetate), to evaluate the influence of patient factors and concomitant antiepileptic drugs (AEDs) on the PK variability of eslicarbazepine, to assess the effect of eslicarbazepine acetate on the PK of concomitant AEDs and to investigate the relationship between eslicarbazepine systemic exposure and eslicarbazepine acetate antiepileptic activity in patients with partial-onset seizures uncontrolled with one to three AEDs. METHODS: Sparse plasma concentrations of eslicarbazepine and concomitant AEDs, along with efficacy data, were obtained from 641 patients enrolled in eslicarbazepine acetate phase III studies. Data were analysed using nonlinear mixed-effect modelling methods. Most analyses used a model using log-transformed data from trough concentration (minimum steady-state plasma concentration during a dosage interval [C(min,ss)]). The model estimated the apparent total body clearance from plasma (CL/F), which is sufficient to predict average plasma concentrations at steady state (C(av,ss)). After the final model was validated, individual concentrations at steady state were predicted, and exposure parameters (area under the plasma concentration-time curve over 24 hours, C(min,ss) and C(av,ss)) for a one-compartmental model with first-order elimination were calculated. RESULTS: Eslicarbazepine CL/F was affected by bodyweight, dose of carbamazepine (D(CAR)) and co-administration of barbiturates or phenytoin (AED(PB)), as predicted by the equation CL/F = (2.36 + 0.00149 ⢠D(CAR) + 1.41 ⢠AED(PB)) ⢠(weight/70)0.75, which means that CL/F is 2.36 L/h for a subject with a bodyweight of 70 kg and without concomitant carbamazepine and barbiturates/phenytoin. Concomitant use of lamotrigine, valproic acid, topiramate, gabapentin, clobazam and levetiracetam showed no effect on the exposure to eslicarbazepine. Inter-individual variability of eslicarbazepine CL/F was 44% and the residual error (intra-subject variability) was proportional to the log of concentrations, with a coefficient of variation of 6%. Age, ethnicity, sex and creatinine clearance did not affect eslicarbazepine CL/F. Eslicarbazepine acetate did not affect the CL/F of clobazam, gabapentin, phenytoin, phenobarbital, levetiracetam and valproic acid. Eslicarbazepine acetate slightly increased the CL/F of carbamazepine (up to 14%), lamotrigine (up to 12%) and topiramate (up to 16%). The antiepileptic effect of eslicarbazepine acetate, as assessed by a decrease in seizure frequency, increased with the increase of eslicarbazepine acetate dose and eslicarbazepine concentrations. The concomitant administration of other AEDs did not affect the eslicarbazepine acetate exposure-response relationship. CONCLUSIONS: The magnitude of the effect of eslicarbazepine acetate on the CL/F of the concomitant AEDs assessed appears to be not clinically relevant and does not justify the need for dose adjustment in most patients. A continuous dose-response relationship was observed between eslicarbazepine concentrations and seizure frequency reduction, which was not affected by concomitant AEDs.
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Dibenzazepinas/farmacocinética , Dibenzazepinas/uso terapéutico , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Adulto , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Ensayos Clínicos Fase III como Asunto/métodos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/fisiología , HumanosRESUMEN
BACKGROUND AND OBJECTIVES: Oral risperidone is licensed globally for the treatment of several psychiatric disorders in children, adolescents and adults. The pharmacokinetic profile of risperidone is well documented in adults. In this study, the pharmacokinetics of oral risperidone in children and adolescents were investigated along with population pharmacokinetics in paediatric and adult subjects. METHODS: The pharmacokinetics of oral risperidone in children and adolescents were investigated through non-compartmental analysis (paediatric phase I study; n = 24) and population pharmacokinetic analysis using nonlinear mixed-effects modelling software (NONMEM) on a pooled database including both paediatric (n = 304) and adult (n = 476) data. Monte Carlo simulations were performed to evaluate the relevance of the effects of covariates on the plasma exposure of the active antipsychotic fraction. RESULTS: Non-compartmental pharmacokinetic analysis showed that, after correcting doses for bodyweight, plasma exposure was comparable between children and adolescents and in line with historical adult data. Pooled population pharmacokinetic analysis, using a priori allometric scaling of the clearance and volume of distribution, showed that apparent renal clearance of the active antipsychotic fraction was 0.96 L/h and apparent metabolic clearance was 4.26 L/h for a typical patient weighing 62 kg, aged 18.1 years, with a median creatinine clearance of 117.6 mL/min. For a typical child (11 years, 39 kg), adolescent (15 years, 60 kg) and adult (33 years, 70 kg), the apparent total oral clearance values were 4.35, 5.30 and 5.04 L/h, respectively. None of the tested demographic or biochemical characteristics were found to have a relevant effect on any of the pharmacokinetic parameters of risperidone and the active antipsychotic fraction. CONCLUSION: Population pharmacokinetics and Monte Carlo simulations demonstrated similar pharmacokinetics of risperidone in children, adolescents and adults.
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Trastornos Mentales/tratamiento farmacológico , Grupos de Población , Risperidona/administración & dosificación , Risperidona/farmacocinética , Administración Oral , Adolescente , Adulto , Factores de Edad , Anciano , Antipsicóticos/farmacocinética , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Método de Montecarlo , Farmacocinética , Adulto JovenRESUMEN
Rufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose-proportional plasma concentrations up to 1,600 mg/day, but less than dose-proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half-life of 6-10 h. The apparent volume of distribution (V(d)/F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age-related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme-inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were <20%). These changes in the pharmacokinetics of associated AEDs are unlikely to make it necessary to change the dosages of these AEDs given concomitantly with rufinamide, with the exception that consideration should be given to reducing the dose of phenytoin. Based on population pharmacokinetic modeling, lamotrigine, topiramate, or benzodiazepines do not affect the pharmacokinetics of rufinamide, but valproic acid may increase plasma rufinamide concentrations, especially in children in whom plasma rufinamide concentrations could be increased substantially. Conversely, comedication with carbamazepine, vigabatrin, phenytoin, phenobarbital, and primidone was associated with a slight-to-moderate decrease in plasma rufinamide concentrations, ranging from a minimum of -13.7% in female children comedicated with vigabatrin to a maximum of -46.3% in female adults comedicated with phenytoin, phenobarbital, or primidone. In population modeling using data from placebo-controlled trials, a positive correlation has been identified between reduction in seizure frequency and steady-state plasma rufinamide concentrations. The probability of adverse effects also appears to be concentration-related.
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Anticonvulsivantes/farmacocinética , Epilepsia/tratamiento farmacológico , Triazoles/farmacocinética , Administración Oral , Adolescente , Factores de Edad , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Índice de Masa Corporal , Niño , Preescolar , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Alimentos , Semivida , Humanos , Factor Intrinseco/metabolismo , Enfermedades Renales/metabolismo , Enfermedades Renales/terapia , Hepatopatías/metabolismo , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Diálisis Renal , Factores Sexuales , Síndrome , Triazoles/sangre , Triazoles/uso terapéuticoRESUMEN
WST11, a novel generation of photo sensitizers to be used for vascular-targeted phototherapy (VTP), is effective at short interval between injection and illumination and it is expected to enable selective destruction of neovasculature with minimal side effects or skin photo toxicity. This study was conducted to evaluate the clinical and laboratory safety, tolerability and pharmacokinetic profile of WST11 given as a single intravenous administration (1.25, 2.5, 5, 7.5, 10, or 15 mg/kg) during an escalating dose study in healthy male subjects. This article describes WST11 population pharmacokinetic modeling and simulations performed to optimize the IV infusion-dosing regimen in combination with illumination, the target PK profile being plateau concentrations during approximately 30 min. The study included 42 healthy male subjects, administered 1.25, 2.5, 5, 7.5, 10, or 15 mg/kg as a 10-min IV infusion. A population pharmacokinetic model was developed using nonlinear mixed effects modeling (NONMEM). Monte Carlo simulations of the population PK dataset (NONMEM) were performed to select series of dosing regimen which would result in a plateau of concentration lasting at least 30 min and allow laser illumination. A two-compartment model with nonlinear elimination best described the data. No demographic factor was shown to affect the WST11 pharmacokinetics. The clearance was shown to decreases with the dose administered, ranging from 6 L/h (dose of 79 mg) to 2 L/h (dose of 1110 mg). The duration of the infusion was estimated at 12 min. The volume of distribution of the central compartment was 3 L and the volume of the peripheral compartment was 1.15 L. The apparent inter-compartmental clearance was 0.137 L/h. The between subjects variability on clearance and on volume was low. Residual variability was moderate with a CV of 21%. Due to the dose effect on clearance and the rapid elimination, simulations showed that different dosing inputs are necessary: for 5 and 10 mg/kg BW, a sufficiently good dosing scenario is to administer 80% of the dose over 5 min, 15% over 10 min and the remaining 5% over 10 min. For lower doses, the sequence 70% in 5 min/20% in 10 min/10% in 10 min is preferable. The pharmacokinetic profile of WST11 by IV administration would allow a treatment by laser illumination in good clinical conditions using controlled infusions. The study results do not indicate that the dose should be adjusted for body size. The only factor that determines the drug input profile is the dose level, since the elimination half-life decreases when the dose administered increases. The use of the population PK model for simulations has shown that, at dose level of 5 mg/kg or more, a loading dose of 80% dose given over 5 min followed by 15% of dose during 10 min and remained dose to give over 10 min would result in a favorable PK profile.
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Bacterioclorofilas/administración & dosificación , Bacterioclorofilas/farmacocinética , Simulación por Computador , Modelos Biológicos , Método de Montecarlo , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacocinética , Fototerapia/métodos , Adulto , Bacterioclorofilas/efectos adversos , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Semivida , Humanos , Bombas de Infusión , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Fármacos Fotosensibilizantes/efectos adversos , Valores de ReferenciaRESUMEN
OBJECTIVE: To develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of onercept (recombinant human tumour necrosis factor [TNF] receptor-1) in healthy subjects. SUBJECTS AND METHODS: Onercept pharmacokinetics data were obtained from 48 healthy male and female subjects (four phase I studies). In study A, 12 subjects received increasing single intravenous doses of onercept either 5 and 50mg or 15 and 150mg. In study B, 12 subjects received single intravenous, subcutaneous and intramuscular doses of onercept 50mg. Study C investigated the pharmacokinetics of onercept following repeat subcutaneous administration of six doses of 50mg every 48 hours in 12 subjects. Study D investigated the pharmacokinetics of onercept following repeat subcutaneous administration of six doses of 100mg and 150mg over 2 weeks in 12 subjects. Nonlinear mixed-effects modelling software NONMEM was used to build a base model, while the final model was determined after selection of the covariates. RESULTS: The disposition of onercept was described using a two-compartment model with two absorption processes (a first-order followed by a zero-order) and included a constant baseline, accounting for the endogenous TNF receptor-1 levels. Slow absorption of onercept following subcutaneous and intramuscular administration was observed and suggested that absorption was the rate-limiting process. The population mean (coefficient of variation %) values for clearance, absorption rate constant, volume of distribution of the central compartment, bioavailability of onercept and baseline TNF receptor-1 levels were 4.03 L/h (13.3%), 0.04 h-1 (29.1%), 4.42L (6.2%), 0.90 (23.8%) and 1.68 microg/L (20.4%), respectively. The only significant covariates were found to be dose (which affected clearance), and day (which affected absorption rate constant); however, the effects were small (10-15%) and are unlikely to be of any clinical relevance. CONCLUSION: The proposed population pharmacokinetic model characterises well the overall pharmacokinetic profile of onercept after intramuscular, subcutaneous and intravenous administration in healthy subjects. The pharmacokinetics of onercept showed modest intersubject variability.
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Modelos Biológicos , Receptores del Factor de Necrosis Tumoral , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacocinética , Adolescente , Adulto , Femenino , Humanos , Inyecciones Intramusculares , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Receptores del Factor de Necrosis Tumoral/sangre , Receptores Tipo I de Factores de Necrosis Tumoral , Proteínas Recombinantes/sangre , Receptores Señuelo del Factor de Necrosis TumoralRESUMEN
The authors studied the pharmacokinetics of sumatriptan nasal spray after a single dose in children migraineurs outside of migraine attack. Seventeen subjects (9 females) ages 6 to 11 years were given one dose of sumatriptan nasal spray based on age and weight; children 6 to 8 years of age weighing = 25 kg received 5 mg (n = 3), children ages 6 to 8 years weighing > 25 kg and children ages 9 to 11 years of age weighing = 40 kg received 10 mg (n = 10), and children ages 9 to 11 years weighing > 40 kg received 20 mg (n = 4). Plasma sumatriptan concentrations were determined in serial blood samples obtained over 8 hours. Pharmacokinetic analysis included both noncompartmental and population modeling methods. The pharmacokinetic parameter estimates (geometric mean [95% confidence interval]) following 5, 10, and 20 mg sumatriptan were, respectively, as follows: maximum concentration = 8.1 ng/mL (3.6-18.4), 10.8 ng/mL (7.7-15.4), and 12.3 ng/mL (7.6-19.9); half-life = 1.4 hours (1.2-1.8), 1.7 hours (1.4-2.0), and 1.7 hours (1.3-2.3); and AUC = 27.8 ng*h/mL (9.7-79.8), 42.4 ng*h/mL (30.6-58.8), and 49.2 ng*h/mL (32.9-73.7). The median time to maximum concentration for all groups was 2 hours. Population pharmacokinetic modeling included pooled data from this study and from an adolescent study (n = 16). Clearance (CL/F) was 197 L/h for a 30-kg child with between-subject variability of 28%, and the volume of distribution was 751 L, normalized for an 11-year-old child with variability of 43%. The covariate analysis showed that volume increases with age and clearance increases with body size. The absorption was complex, often displaying double-peak plasma concentrations, with a rapid absorption phase and a delayed and rate-limited absorption phase. The dosing scheme based on age and weight resulted in maximal concentrations (C(max)) and systemic exposure (AUC) that were comparable to those observed in adolescents and adults treated with 20 mg. The age- and weight-adjusted dosing scheme appears to an appropriate initial dosing regimen for children with migraine headache. Appropriate safety and efficacy trials will need to be completed in children prior to recommending its use in children.
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Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacocinética , Sumatriptán/administración & dosificación , Sumatriptán/farmacocinética , Administración Intranasal , Área Bajo la Curva , Niño , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Trastornos Migrañosos/tratamiento farmacológico , Agonistas de Receptores de Serotonina/sangre , Sumatriptán/sangreRESUMEN
OBJECTIVE: This paper describes a developed pharmacokinetic model for the estimation of valproic acid (VPA) clearance (CL) calculated from routine clinical data taken from Egyptian epileptic patients. METHODS: Retrospective clinical data from 81 adult and paediatric epileptic patients with one trough VPA serum concentration per patient were analysed using NONMEM to estimate drug CL and determine the influence of different covariates. A qualification group of 20 epileptic children (3-13 years old) was used to evaluate the final model. RESULTS: The population CL as estimated by base model (no covariates) was 0.581 l h(-1) with inter-individual variability (C.V. %) of 17.4% and SD of residual error was 6.82 mg l(-1). Univariate selection and backward deletion of different covariates led to the development of the final regression model of CL as follows: CL(Lh-1) = 0.101 + 0.151 * CBZ + 0.000248 * VPADD + 0.0968 * age/20 + 0.0803 * INDI, in which CBZ indicates co-administration of carbamazepine, VPADD the daily dose of VPA and INDI uncontrolled epilepsy. The between-subject variability in CL was 23.6% while the standard deviation of the residual error was 5.24 mg l(-1). The model predictions in the qualification group were found to have no bias and satisfactory precision. CONCLUSION: The population pharmacokinetic model for VPA could be used for a priori recommendation and dose optimisation of that drug in the Egyptian population of epileptic patients.
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Anticonvulsivantes/farmacocinética , Epilepsia/metabolismo , Modelos Biológicos , Ácido Valproico/farmacocinética , Adolescente , Adulto , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Carbamazepina/farmacología , Niño , Preescolar , Ensayos Clínicos como Asunto , Interacciones Farmacológicas , Egipto , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Estudios Retrospectivos , Ácido Valproico/sangre , Ácido Valproico/uso terapéuticoRESUMEN
Sumatriptan is a potent and selective vascular 5-HT1 receptor agonist effective for the treatment of migraine. In adults, intranasal sumatriptan is well absorbed and tolerated. The authors evaluated the pharmacokinetics and tolerability of a single dose of 20 mg intranasal sumatriptan in healthy adolescent migraineurs ages 12 to 17 years, administered outside of migraine attack. Serum sumatriptan levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection in serial samples collected over 8 hours. Physical exam, vital signs, clinical laboratory tests, and electrocardiogram measurements were monitored to assess safety and tolerability. A total of 16 subjects (10 males and 6 females) had pharmacokinetic data that could be analyzed, 2 withdrew from the study 30 and 60 minutes after dosing following the loss of venous access for blood sampling, and a bioanalysis failure resulted in loss of data from 3 subjects. Noncompartmental pharmacokinetic parameters (geometric mean and 95% confidence interval) for the remaining 16 subjects were as follows: Cmax was 13.9 (11.0, 17.6) ng/mL, AUC infinity was 57.3 (47.6, 69.0) ng/mL.h, and t1/2 was 2.0 (1.8, 2.3) hours. Population pharmacokinetic analysis for all subjects (n = 21) showed that clearance and volume of distribution increase slightly with age and body size, but the changes were minimal and would not warrant dose adjustment: CL/F was 316 L (coefficient of variance [CV] = 25%) and Vd/F was 1070 L (CV = 46%). Sumatriptan was well tolerated with only minor adverse events reported, which all resolved spontaneously. The pharmacokinetic parameters in these adolescent subjects were similar to those previously reported in adults, suggesting that adolescents should be dosed similar to adults.
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Agonistas de Receptores de Serotonina/farmacocinética , Sumatriptán/farmacocinética , Administración Intranasal , Adolescente , Factores de Edad , Área Bajo la Curva , Peso Corporal , Cromatografía Líquida de Alta Presión , Femenino , Semivida , Humanos , Masculino , Tasa de Depuración Metabólica , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Agonistas de Receptores de Serotonina/administración & dosificación , Sumatriptán/administración & dosificaciónRESUMEN
A substantial proportion of migraine patients have gastric stasis and suffer severe nausea and/or vomiting during their migraine attack. This may lead to erratic absorption from the gastrointestinal tract and make oral treatment unsatisfactory. For such patients, an intranasal formulation may be advantageous. Sumatriptan is a potent serotonin 5HT(1B/1D) agonist widely used in the treatment of migraine; the effectiveness of the intranasal formulation (20mg) has been well established in several clinical studies. This article reviews the pharmacokinetics of intranasal sumatriptan and includes comparisons with oral and subcutaneous administration. After intranasal administration, sumatriptan is directly and rapidly absorbed, with 60% of the maximum plasma concentration (C(max)) occurring at 30 minutes after administration of a single 20mg dose. Following intranasal administration, approximately 10% more sumatriptan is absorbed probably via the nasal mucosa when compared with oral administration. Mean C(max) after a 20mg intranasal dose is approximately 13.1 to 14.4 ng/mL, with median time to C(max) approximately 1 to 1.75 hours. When given as a single dose, intranasal sumatriptan displays dose proportionality in its extent of absorption and C(max) over the dose range 5 to 10mg, but not between 5 and 20mg for C(max). The elimination phase half-life is approximately 2 hours, consistent with administration by other routes. Sumatriptan is metabolised by monoamine oxidase (MAO; predominantly the A isozyme, MAO-A) to an inactive metabolite. Coadministration with a MAO-A inhibitor, moclobemide, leads to a significant increase in sumatriptan plasma concentrations and is contraindicated. Single-dose pharmacokinetics in paediatric and adolescent patients following intranasal sumatriptan were studied to determine the effect of changes in nasal morphology during growth, and of body size, on pharmacokinetic parameters. The pharmacokinetic profile observed in adults was maintained in the adolescent population; generally, factors such as age, bodyweight or height did not significantly affect the pharmacokinetics. In children below 12 years, C(max) is comparable to that seen in adolescents and adults, but total exposure (area under the concentration-time curve from zero to infinity) was lower in children compared with older patients, especially in younger children treated with 5mg. Clinical experience suggests that intranasal sumatriptan has some advantages over the tablet (more rapid onset of effect and use in patients with gastrointestinal complaints) or subcutaneous (noninvasive and fewer adverse events) formulations.