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BACKGROUND: Prednisolone (PLN) is a widely used corticosteroid in a variety of immune-mediated diseases. Treatment regimes generally consist of empirically derived treatment doses, whereas therapeutic response among patients is highly variable. Drug monitoring of serum PLN levels might support a more rational approach to dose selection, yet is invasive and laborious. In analogy to cortisol, salivary PLN may offer a good alternative for serum PLN, being a representative approximation of free serum PLN. The aims of this study were to evaluate the correlation between free serum and salivary PLN levels and to quantify this relationship within a population pharmacokinetic model. METHODS: PLN and prednisone (PN) concentrations were measured in 396 samples from 19 healthy volunteers after oral ingestion of 80 mg PLN. Measurements in serum, ultrafiltrate, and saliva were performed with a recently validated liquid chromatography tandem mass spectrometry method. Population pharmacokinetic analysis was performed with nonlinear mixed effect modeling using NONMEM. RESULTS: Salivary PLN levels correlated well with free serum PLN levels (r = 0.931, P < 0.01). A weaker correlation was found for PN (r = 0.318, P < 0.01), which may be explained by the finding that salivary PN levels mainly seemed to consist of PLN enzymatically converted to PN. Total and free serum PLN concentrations decreased over time after drug administration and showed a nonlinear mutual relationship, consistent with concentration-dependent protein binding. Modeled PLN pharmacokinetics corresponded with previous reports. Low to moderate interindividual variability was found for V/F and CL/F (coefficients of variation were 13.8% and 14.6%, respectively). Free and salivary PLN showed a nonlinear relationship with total PLN. An equation predicting free serum levels from salivary levels was successfully derived from the data. CONCLUSIONS: This study is the first to describe the relationship between salivary and (free) serum PLN using a population pharmacokinetic model. Salivary PLN was found to be a reliable predictor of free and total serum PLN in healthy volunteers. The results of this study encourage further exploration of the use of saliva as a noninvasive and feasible method for drug monitoring of PLN.
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Prednisolona/farmacocinética , Prednisona/farmacocinética , Saliva/química , Saliva/metabolismo , Administración Oral , Adulto , Cromatografía Liquida/métodos , Monitoreo de Drogas/métodos , Femenino , Voluntarios Sanos , Humanos , Masculino , Espectrometría de Masas/métodos , Persona de Mediana Edad , Prednisolona/sangre , Prednisona/sangre , Adulto JovenRESUMEN
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: ⢠Cannabis based medicines are registered as a treatment for various indications, such as pain and spasms in multiple sclerosis (MS) patients, and anorexia and nausea in patients with HIV or receiving cancer treatment. ⢠the pharmacokinetics of the various administration routes of cannabis and cannabis based medicines are variable and dosing is hard to regulate. WHAT THIS STUDY ADDS: ⢠Namisol is a new tablet containing pure THC (>98%) that has a beneficial pharmacokinetic profile after oral administration. ⢠Namisol gives a quick onset of pharmacodynamic effects in healthy volunteers, which implies a rapid initiation of therapeutic effects in patients. AIMS: Among the main disadvantages of currently available Δ(9) -tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®. METHODS: This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed. RESULTS: Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t(1/2) was 72-80 min, t(max) was 39-56 min and C(max) 2.92-4.69 ng ml(-1) . THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (-2.7 mm, 95% CI -4.5, -0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min(-1) , 95% CI 2.7, 6.5). Namisol® was well tolerated. CONCLUSIONS: Oral Namisol® showed promising PK and PD characteristics. Variability and t(max) of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.
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Analgésicos no Narcóticos/farmacocinética , Sistema Nervioso Central/efectos de los fármacos , Dronabinol/farmacocinética , Frecuencia Cardíaca/efectos de los fármacos , Dolor/tratamiento farmacológico , Equilibrio Postural/efectos de los fármacos , Adolescente , Adulto , Analgésicos no Narcóticos/farmacología , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Dronabinol/análogos & derivados , Dronabinol/farmacología , Femenino , Humanos , Masculino , Dimensión del Dolor , Adulto JovenRESUMEN
Dose selection for "first in children" trials often relies on scaling of the pharmacokinetics from adults to children. Commonly used approaches are physiologically-based pharmacokinetic modeling (PBPK) and allometric scaling (AS) in combination with maturation of clearance for early life. In this investigation, a comparison of the two approaches was performed to provide insight into the physiological meaning of AS maturation functions and their interchangeability. The analysis focused on the AS maturation functions established using paracetamol and morphine paediatric data after intravenous administration. First, the estimated AS maturation functions were compared with the maturation functions of the liver enzymes as used in the PBPK models. Second, absolute clearance predictions using AS in combination with maturation functions were compared to PBPK predictions for hypothetical drugs with different pharmacokinetic properties. The results of this investigation showed that AS maturation functions do not solely represent ontogeny of enzyme activity, but aggregate multiple pharmacokinetic properties, as for example extraction ratio and lipophilicity (log P). Especially in children younger than 1 year, predictions using AS in combination with maturation functions and PBPK were not interchangeable. This highlights the necessity of investigating methodological uncertainty to allow a proper estimation of the "first dose in children" and assessment of its risk and benefits.
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Acetaminofén/farmacocinética , Descubrimiento de Drogas/tendencias , Morfina/farmacocinética , Acetaminofén/administración & dosificación , Adolescente , Factores de Edad , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas/métodos , Humanos , Lactante , Recién Nacido , Tasa de Depuración Metabólica/efectos de los fármacos , Tasa de Depuración Metabólica/fisiología , Morfina/administración & dosificaciónRESUMEN
The application of model-based drug development in special populations becomes increasingly important for clinical trial optimization, mostly by providing a rationale for dose selection and thereby aiding risk-benefit assessment. In this article, a semiphysiological approach is presented, enabling the extrapolation of the pharmacokinetics from healthy subjects to patients with different disease conditions. This semiphysiological approach was applied to solifenacin, using clinical data on total and free plasma and urine concentrations in healthy subjects. The analysis was performed using nonlinear mixed-effects modeling and relied on the use of a general partitioning framework to account for binding to plasma proteins and to nonplasma tissues together with principles from physiology that apply to the main pharmacokinetic process, i.e., bioavailability, distribution, and elimination. Application of these physiology principles allowed quantification of the impact of key physiological parameters (i.e., body composition, glomerular function, liver enzyme capacity, and liver blood flow) on the pharmacokinetics of solifenacin. The prediction of the time course of the drug concentration in liver- and renal-impaired patients only required adjustment of the physiological parameters that are known to change upon liver and renal dysfunction without modifying the pharmacokinetic model structure and/or its respective parameter estimates. Visual predictive checks showed that the approach applied was able to adequately predict the pharmacokinetics of solifenacin in liver- and renal-impaired patients. In addition, better insight into the pharmacokinetic properties of solifenacin was obtained. In conclusion, the proposed semiphysiological approach is attractive for prediction of altered pharmacokinetics of compounds influenced by liver and renal disease conditions.
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Enfermedades Renales/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Modelos Biológicos , Farmacocinética , HumanosRESUMEN
INTRODUCTION: Understanding the effect of oxycodone pharmacokinetics (PK) on µ-opioid receptor binding benefits from an integrated approach to compiling the results of multiple studies. The current pharmacokinetic/pharmacodynamic (PK/PD) model analysis brings together various studies to support the interpretation of newly collected PK/PD data, putting the new results into the perspective of the full concentration-effect curve. METHODS: A two-step modeling approach was applied to characterize the PK of oxycodone and its PK/PD relationship for the pupil diameter as a biomarker for µ-opioid receptor binding in recreational opioid users. First, a model-based meta-analysis (MBMA) was used to quantify the state-of-the-art knowledge from seven published studies, each of which contained part of the data needed for full characterization. Subsequently, the estimated parameters with uncertainty from the MBMA were used as prior information for a model developed on newly collected clinical data after intranasal administration in a clinical abuse potential trial. RESULTS: The inclusion of intravenous data in the MBMA showed that the PK of oxycodone can be described by a two-compartmental model, and allowed for the estimation of absolute bioavailability after intranasal and oral administration. A hysteresis loop was observed when plotting plasma concentrations and pupil constriction, which was approximated using an effect compartment. The totality of literature data enabled the identification of a Hill equation for the drug effect. The model with prior information fitted successfully to the newly collected data, where most parameter estimates had their confidence intervals overlapping with the prior distribution. The new data led to a slightly lower intranasal absorption rate constant, explaining the longer apparent half-life of oxycodone in the newly collected data. The PK/PD model parameters were confirmed by the new data, leading to the following estimates: half maximal inhibitory concentration (IC50) of 26.5 ng/mL, maximum pupil restriction of 66.0% from baseline, and a Hill factor of 1.05. CONCLUSIONS: The new data confirmed the PK profile and the PK/PD relationship identified using the MBMA, resulting in similar parameter estimates except for the intranasal absorption rate constant. The latter was lower than in the MBMA and explained the slightly longer apparent half-life of oxycodone in the newly collected data.
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Analgésicos Opioides , Oxicodona , Administración Intranasal , Constricción , Humanos , Modelos Biológicos , PupilaRESUMEN
This paper presents an example of how optimal design methodology was used to help design a phase II clinical study. The planned analysis would relate the clinical endpoint to exposure (measured via the area under the curve (AUC)), rather than dose. Optimal design methodology was used to compare a number of candidate phase II designs, and an algorithm for finding optimal designs was employed. The sigmoidal E(max) with baseline (E0) model was used to relate the clinical endpoint to individual subject AUCs, and the primary metrics were D optimality and the standard error (SE) of the AUC required to yield a clinically relevant change in the clinical endpoint. The performance of the candidate designs were compared across four different 'true' exposure response relationships (determined from the analysis of an earlier proof of concept (PoC) study). The results suggested the total sample size should be increased from the planned 540 individuals, and that the optimal design with 700 individuals would be equivalent to 812 individuals with the reference design (a 16% gain). The performance with this design was considered acceptable, although all designs performed poorly if the true exposure response relationship was very flat. This work allowed a prospective assessment of the likely performance and precision from the exposure response modelling prior to the start of the phase II study, and hence allowed the design to be revised to ensure the subsequent analysis would be of most value.
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Ensayos Clínicos Fase II como Asunto , Proyectos de Investigación , Algoritmos , Área Bajo la Curva , Simulación por Computador , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Determinación de Punto Final , Humanos , Modelos Biológicos , Tamaño de la MuestraRESUMEN
OBJECTIVE: The main aim of this analysis was to characterize the pharmacokinetics (PK) of tapentadol in pediatric patients from birth to <18 years old who experience acute pain, requiring treatment with an opioid analgesic. PATIENTS AND METHODS: Data from four clinical trials and 148 pediatric patients who received a single dose of tapentadol oral or intravenous solution were included. Population PK analysis was performed to determine the contribution of size-related (bodyweight) and function-related (maturation) factors to the changes in oral bioavailability (F), volume of distribution (V), and clearance (CL) with age. Simulations were carried out to compare pediatric exposures to reference adult values. RESULTS: A one-compartment model with allometric scaling on disposition parameters (using theoretical or estimated exponents) and maturation functions on CL and F best described tapentadol PK. The estimated allometric exponents for CL (0.603) and V (0.820) differed slightly from the theoretical values of 0.75 for CL and 1 for V. A maximum in CL/F was observed at about 2-3 years when expressed on a bodyweight basis. Results for younger children as well as the F estimate were sensitive to the scaling approach, but CL/F and V/F as a function of age for the two scaling approaches led to similar curves within the bioequivalence range except below 5 weeks of age. Model-based simulations indicated that the doses used in the included clinical trials lead to exposures within the lower half of the targeted adult exposure. CONCLUSION: The development of tapentadol is one of the first examples following a systematic approach for analgesic drug development for children. Our analysis enabled a full characterization and robust understanding of tapentadol PK in children from birth to <18 years, including preterm infants, and showed the importance of evaluating the sensitivity of the inferences of the PK parameters to the selected scaling approach.
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OBJECTIVE: The main aim of this analysis was to characterize the pharmacokinetics (PK) of the strong analgesic tapentadol in 2-year-old to <18-year-old patients with acute pain and to inform the optimal dosing strategy for a confirmatory efficacy trial in this patient population. METHODS: The analysis dataset included tapentadol concentrations obtained from 92 pediatric patients receiving a single tapentadol oral solution (OS) dose of 1.0 mg/kg bodyweight in two single-dose PK clinical trials. Population PK analysis was performed using nonlinear mixed effects modeling. Simulations were performed to identify tapentadol OS doses in pediatric subjects (2 to <18 years) that would produce exposures similar to those in adults receiving safe and efficacious doses of tapentadol IR (50-100 mg every 4 hrs). RESULTS: Tapentadol PK in children aged from 2 to <18 years was best described by a one-compartment model. Mean population apparent clearance and apparent volume of distribution for a typical subject weighing 45 kg were 170 L/h and 685 L, respectively. Clearance, expressed in bodyweight units as L/h/kg, decreased with increasing age whereas total clearance (L/h) increased with increasing age. Model-based simulations suggested that a tapentadol OS dose of 1.25 mg/kg to children and adolescents aged 2 to <18 years would result in efficacious tapentadol exposures similar to those in adults receiving tapentadol immediate release 50-100 mg every 4 hrs. The proposed tapentadol OS dose was subsequently applied in a confirmatory efficacy trial in 2 to <18-year-old patients suffering from acute postsurgical pain. CONCLUSION: This analysis provides an example of a model-based approach for a dose recommendation to be used in an efficacy trial in the pediatric population. Uniform dosing based on bodyweight was proposed for the treatment of acute pain in children aged from 2 to <18 years.
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The aim of this study was the development of an agonist-antagonist interaction model to estimate the in vivo affinity of S(-)-atenolol for the beta(1)-adrenoreceptor. Male Wistar-Kyoto (WKY) rats were used to characterize the interaction between the model drugs isoprenaline (to induce tachycardia) and S(-)-atenolol. Blood samples were taken to determine plasma pharmacokinetics. Reduction of isoprenaline-induced tachycardia was used as a pharmacodynamic endpoint. The pharmacokinetic-pharmacodynamic relationship of isoprenaline was first characterized with the operational model of agonism using the literature value for the affinity (K(A)) of isoprenaline (3.2 x 10(-8) M; left atria WKY rats). Resulting estimates for baseline (E(0)), maximal effect (E(max)), and efficacy (tau) were 374 (1.9%), 130 (5.9%), and 247 (33%) beats per minute, respectively. In addition, the interaction between isoprenaline and S(-)-atenolol was characterized using a pharmacodynamic interaction model based on the operational model of agonism that describes the heart rate response based on the affinity of the agonist (K(A)), the affinity of the antagonist (K(B)), the efficacy (tau), the maximal effect (E(max)), the Hill coefficient (n(H)), the concentrations of isoprenaline and atenolol, and the displacement of the endogenous agonist adrenaline. The estimated in vivo affinity (K(B)) of S(-)-atenolol for the beta(1) -receptor was 4.6 x 10(-8) M. The obtained estimate for in vivo affinity of S(-)-atenolol (4.6 x 10(-8) M) is comparable to literature values for the in vitro affinity in functional assays. In conclusion, a meaningful estimate of in vivo affinity for S(-)-atenolol could be obtained using a mechanism-based pharmacodynamic modeling approach.
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Agonistas Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/metabolismo , Atenolol/química , Atenolol/metabolismo , Modelos Biológicos , Receptores Adrenérgicos beta 1/metabolismo , Agonistas de Receptores Adrenérgicos beta 1 , Antagonistas de Receptores Adrenérgicos beta 1 , Animales , Masculino , Unión Proteica/fisiología , Ratas , Ratas Endogámicas WKY , Estadística como Asunto , EstereoisomerismoRESUMEN
A mechanistic model is proposed to predict the time course of the concentrations of 5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) in rat frontal cortex following acute administration of SSRIs. In the model, SSRIs increase synaptic 5-HT concentrations by reversible blockade of the SERT in a direct concentration-dependent manner, while the 5-HT response is attenuated by negative feedback via 5-HT autoreceptors. In principle, the model allows for the description of oscillatory patterns in the time course of 5-HT and 5-HIAA concentrations in brain extracellular fluid. The model was applied in a pharmacokinetic-pharmacodynamic (PK/PD) investigation on the time course of the microdialysate 5-HT and 5-HIAA response in rat frontal cortex following a 30-min intravenous infusion of 3.7 and 7.3mg/kg fluvoxamine. Directly after administration of fluvoxamine, concentrations of 5-HT were increased to approximately 450-600% of baseline values while 5-HIAA concentrations were decreased. Thereafter 5-HT and 5-HIAA concentrations gradually returned to baseline values in 6-10h, respectively. The PK/PD analysis revealed that inhibition of 5-HT reuptake was directly related to the fluvoxamine concentration in plasma, with 50% inhibition of 5-HT reuptake occurring at a plasma concentration of 1.1ng/ml (EC50). The levels of 5-HT at which 50% of the inhibition of the 5-HT response was reached (IC50) amounted to 272% of baseline. The model was unable to capture the oscillatory patterns in the individual concentration time curves, which appeared to occur randomly. The proposed mechanistic model is the first step in modeling of complex neurotransmission processes. The model constitutes a useful basis for prediction of the time course of median 5-HT and 5-HIAA concentrations in the frontal cortex in behavioral pharmacology studies in vivo.
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Fluvoxamina/farmacocinética , Lóbulo Frontal/metabolismo , Ácido Hidroxiindolacético/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Serotonina/metabolismo , Animales , Fluvoxamina/sangre , Masculino , Modelos Biológicos , Ratas , Ratas Wistar , Inhibidores Selectivos de la Recaptación de Serotonina/sangreRESUMEN
The objective of this investigation is to characterize the role of complex biophase distribution kinetics in the pharmacokinetic-pharmacodynamic correlation of a wide range of opioids. Following intravenous infusion of morphine, alfentanil, fentanyl, sufentanil, butorphanol and nalbuphine the time course of the EEG effect was determined in conjunction with blood concentrations. Different biophase distribution models were tested for their ability to describe hysteresis between blood concentration and effect. In addition, membrane transport characteristics of the opioids were investigated in vitro, using MDCK:MDR1 cells and in silico with QSAR analysis. For morphine, hysteresis was best described by an extended-catenary biophase distribution model with different values for k1e and keo of 0.038+/-0.003 and 0.043+/-0.003 min(-1), respectively. For the other opioids hysteresis was best described by a one-compartment biophase distribution model with identical values for k1e and keo. Between the different opioids, the values of k1e ranged from 0.04 to 0.47 min(-1). The correlation between concentration and EEG effect was successfully described by the sigmoidal Emax pharmacodynamic model. Between opioids significant differences in potency (EC50 range 1.2-451 ng/ml) and intrinsic activity (alpha range 18-109 microV) were observed. A statistically significant correlation was observed between the values of the in vivo k1e and the apparent passive permeability as determined in vitro in MDCK:MDR1 monolayers. It can be concluded that unlike other opioids, only morphine displays complex biophase distribution kinetics, which can be explained by its relatively low passive permeability and the interaction with active transporters at the blood-brain barrier.
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Analgésicos Opioides/farmacología , Analgésicos Opioides/farmacocinética , Electroencefalografía/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Algoritmos , Animales , Línea Celular , Difusión , Perros , Masculino , Modelos Estadísticos , Permeabilidad , Relación Estructura-Actividad Cuantitativa , Ratas , Ratas Wistar , Distribución TisularRESUMEN
The pharmacokinetic-pharmacodynamic (PK-PD) correlation of the effect of fluvoxamine on para-chloroamphetamine (PCA)-induced behavior was determined in the rat. Rats (n=66) with permanent arterial and venous cannulas received a 30-min intravenous infusion of 1.0, 3.7 or 7.3 mg kg(-1) fluvoxamine. At various time points after the start of fluvoxamine administration, a single dose of PCA (2.5 mg kg(-1)) was injected in the tail vein and resulting behavioral effects, excitation (EXC), flat body posture (FBP) and forepaw trampling (FT), were immediately scored (scores: 0, 1, 2 or 3) over a period of 5 min. In each individual animal the time course of the fluvoxamine plasma concentration was determined up to the time of PCA administration. Observed behavioral effects were related to fluvoxamine plasma concentrations. Fluvoxamine pharmacokinetics was described by a population three-compartment pharmacokinetic model. The effects of fluvoxamine on PCA-induced behavior (probability of EXC, FBP and FT) were directly related to fluvoxamine plasma concentration on the basis of the proportional odds model. For EXC, EC(50) values for the cumulative probabilities P(Y<1), P(Y<2), P(Y<3) were 237+/-39, 174+/-28 and 100+/-20 ng ml(-1), respectively. Slightly higher EC(50) values were obtained for the corresponding effects on FBP and FT. This investigation demonstrates the feasibility of PK-PD modeling of categorical drug effects in animal behavioral pharmacology. This constitutes a basis for the future development of a mechanism-based PK-PD model for fluvoxamine in this paradigm.
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Conducta Animal/efectos de los fármacos , Fluvoxamina/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Serotoninérgicos/farmacología , p-Cloroanfetamina/farmacología , Animales , Estudios de Factibilidad , Fluvoxamina/administración & dosificación , Fluvoxamina/sangre , Infusiones Intravenosas , Inyecciones Intravenosas , Masculino , Modelos Biológicos , Dinámicas no Lineales , Ratas , Ratas Wistar , Serotoninérgicos/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , p-Cloroanfetamina/administración & dosificaciónRESUMEN
The limitations of blood sampling in pharmacokinetic (PK)/pharmacodynamic (PD) studies in behavioral animal models could in part be overcome by a mixed effects modeling approach. This analysis characterizes and evaluates the population PK of fluvoxamine in rat plasma using nonlinear mixed effects modeling. The model is assessed for its utility in animal behavioral PK/PD studies. In six studies with a different experimental setup, study site and/or sampling design, rats received an intravenous infusion of 1, 3.7 or 7.3mg/kg fluvoxamine. A population three-compartment PK model adequately described the fluvoxamine plasma concentrations. Body weight was included as a covariate and mean population PK parameters for CL, V(1), V(2), Q(2), V(3) and Q(3) were 25.1 ml/min, 256 ml, 721 ml, 30.3 ml/min, 136 ml and 1.0 ml/min, respectively. Inter-individual variability was identified on CL (39.5%), V(1) (43.5%), V(2) (50.1%) and Q(2) (25.7%). A predictive check and bootstrap analysis confirmed the predictive ability, model stability and precision of the parameter estimates. Body weight was identified as a significant covariate of the inter-compartmental clearance Q(2). The pharmacokinetics was independent of factors such as dose, surgery (for instrumentation) and study site. The utility of the model in animal behavioral studies was demonstrated in a PK/PD analysis of the effects on REM sleep in which a sparse PK sampling design was used. By using the pertinent information from the population PK model, individual PK profiles and the PK/PD correlation could be adequately described.
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Conducta Animal/efectos de los fármacos , Fluvoxamina , Modelos Biológicos , Inhibidores Selectivos de la Recaptación de Serotonina , Animales , Fluvoxamina/farmacocinética , Fluvoxamina/farmacología , Infusiones Intravenosas , Masculino , Ratas , Ratas Wistar , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sueño REM/efectos de los fármacosRESUMEN
The psychomimetic effects that occur after acute administration of ketamine can constitute a model of psychosis and antipsychotic drug action. However, the optimal dose/concentration has not been established and there is a large variety in outcome measures. In this study, 36 healthy volunteers (21 males and 15 females) received infusions of S(+)-ketamine or placebo to achieve pseudo-steady state concentrations of 180 and 360 ng/mL during two hours. The target of 360 ng/mL induced increasingly more intensive effects than expected, and the targets were subsequently reduced to 120 and 240 ng/mL, which were considered tolerable. There was a clear, concentration-dependent psychomimetic effect as shown on all subscales of the positive and negative syndrome scale (e.g. positive subscale +43.7%, 95%CI 34.4-53.7%, p < 0.0001 for 120 ng/mL and +70.5%, 95%CI 59.0-82.8%, p < 0.0001 for 240 ng/mL) and different visual analogue scales. The startle reflex was inhibited (prepulse inhibition) by both main target concentrations to a similar extent, suggesting a maximum effect. Ketamine was found to constitute a robust model for induction of psychomimetic symptoms and the optimal concentration range for a drug interaction study would be between 100 and 200 ng/mL.
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Antagonistas de Aminoácidos Excitadores/farmacología , Ketamina/farmacología , Psicosis Inducidas por Sustancias/etiología , Reflejo de Sobresalto/efectos de los fármacos , Adolescente , Adulto , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Femenino , Humanos , Ketamina/administración & dosificación , Masculino , Escalas de Valoración Psiquiátrica , Psicosis Inducidas por Sustancias/psicología , Adulto JovenRESUMEN
Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.
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Dronabinol/administración & dosificación , Dronabinol/farmacocinética , Psicotrópicos/administración & dosificación , Psicotrópicos/farmacocinética , Administración por Inhalación , Administración Intravenosa , Administración Oral , Adolescente , Adulto , Ensayos Clínicos como Asunto , Simulación por Computador , Femenino , Semivida , Humanos , Masculino , Adulto JovenRESUMEN
The mycotoxin, deoxynivalenol (DON), is produced world-wide by the Fusarium genus in different cereal crops. We derived a provisional TDI of 1.1 microg/kg body weight (bw) and proposed a concentration limit of 129 microg DON/kg wheat based on this TDI and a high wheat consumption of children. In the period September 1998-January 2000, the average DON concentration in wheat was 446 microg/kg (n = 219) in The Netherlands. During this period, the dietary intake of DON exceeded the provisional TDI, especially in children. Eighty percent of the one-year-olds showed a DON intake above the provisional TDI and 20% of these children exceeded twice the provisional TDI. Our probabilistic effect assessment shows that at these exposure levels, health effects may occur. Suppressive effects on body weights and relative liver weight were estimated at 2.2 and 2.7%. However, the large confidence intervals around these estimates indicated that the magnitudes of these effects are uncertain.
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Contaminación de Alimentos/legislación & jurisprudencia , Tricotecenos/efectos adversos , Animales , Dieta , Análisis de los Alimentos , Humanos , Ratones , Modelos Estadísticos , Países Bajos , Medición de Riesgo , Tricotecenos/toxicidad , TriticumRESUMEN
First-dose-in-children relies on the prediction of clearance from adults for which little information is available on the accuracy of the scaling-approaches applied. For CYP3A-metabolized compounds, scaling of clearance is further challenged by different isoforms and by the CYP3A7 to CYP3A4 switch at young ages. This investigation aimed to evaluate the accuracy of two frequently used scaling approaches and to gain insights into the ontogeny of CYP3A. Hence, a literature database was compiled containing 203 clearance values from term-neonates to adults for 18 CYP3A-metabolized compounds. The clearances in adults were scaled to children using (i) allometric scaling plus maturation function and (ii) a mechanistic approach based on the well-stirred model. Three maturation functions were separately evaluated. In children >3 months, all approaches were interchangeable heeding the maturation function applied and biases were mostly observed in children <3 months. The results from a sensitivity analysis indicate that these biases are possibly caused by disregarding the CYP3A7 activity which could account for up to 86% of the metabolism in term-neonates. Only the mechanistic approach using an overall-CYP3A maturation function led to unbiased predictions of clearances across all ages. The current investigation adds to the predictions of the first-dose-in-children of compounds (partially) metabolized by CYP3A.
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Envejecimiento/metabolismo , Citocromo P-450 CYP3A/metabolismo , Modelos Biológicos , Preparaciones Farmacéuticas/metabolismo , Adolescente , Adulto , Algoritmos , Peso Corporal , Niño , Preescolar , Arteria Hepática/fisiología , Humanos , Lactante , Recién Nacido , Hígado/irrigación sanguínea , Preparaciones Farmacéuticas/sangre , Farmacocinética , Vena Porta/fisiología , Flujo Sanguíneo RegionalRESUMEN
The subjective effects of cannabis and its main psychoactive component Δ(9) -tetrahydrocannabinol (THC) have played an important part in determining the therapeutic potential of cannabinoid agonists and antagonists. The effects mainly consist of feeling high, changes in perception, feelings of relaxation and occasionally dysphoric reactions. These effects are captured by two of the most frequently used visual analogue scales (VASs) in clinical (pharmacologic) research to measure subjective effects: VAS Bond and Lader (alertness, calmness and mood) and VAS Bowdle (psychedelic effects). In this analysis, the effects of THC on these VASs were compared within a total of 217 subjects who participated in 10 different studies. Not surprisingly, the item feeling high was found to be the best predictor for the effect of THC. Three separate clusters that describe the spectrum of subjective effects of THC were identified using different statistical methods, consisting of VAS "time", "thoughts" and "high" ("perception"), VAS "drowsy", "muzzy", "mentally slow" and "dreamy" ("relaxation") and VAS "voices", "meaning" and "suspicious" ("dysphoria"). These results provide experimental evidence that THC can evoke different classes of effects. These distinct subjective clusters could represent effects on various systems in the brain, which can be used to further differentiate the involvement of endocannabinoid systems in health and disease.
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Analgésicos no Narcóticos/farmacología , Dronabinol/farmacología , Dimensión del Dolor/efectos de los fármacos , Escala Visual Analógica , Analgésicos no Narcóticos/uso terapéutico , Bases de Datos Factuales/estadística & datos numéricos , Relación Dosis-Respuesta a Droga , Dronabinol/uso terapéutico , Análisis Factorial , Femenino , Voluntarios Sanos , Humanos , Masculino , Análisis de Componente PrincipalRESUMEN
BACKGROUND: Prediction of pharmacokinetics in humans is essential for translating preclinical data to humans and planning safe and efficient clinical studies. The performance of various methods in extrapolation of preclinical pharmacokinetic data to humans is usually benchmarked by the fraction of predictions falling within a predefined interval that is centred on the value observed clinically. Recently, such an approach was used to compare physiologically based pharmacokinetic (PBPK) modelling and allometry in predicting the pharmacokinetics of a set of compounds in humans. Here, we present an analysis of the same dataset, focusing on predictions falling outside such a relatively narrow and centrally located interval. These are the main risk determinants in extrapolation of preclinical pharmacokinetic data to humans and should therefore be thoroughly understood in a risk mitigation approach to the design of early-phase human studies. METHODS: Values that had been previously predicted by allometry and by PBPK modelling in terms of the apparent total clearance after oral administration, apparent volume of distribution, area under the plasma concentration-time curve, maximum plasma drug concentration, time to reach the maximum plasma concentration and terminal elimination half-life in humans were used to generate a log-transformed dataset of predicted/observed ratios. The probabilities of mispredicting the values of these pharmacokinetic parameters using PBPK modelling and allometry were estimated by a bootstrap procedure on this set of ratios. RESULTS: Our results, albeit from a limited dataset, indicated that although PBPK modelling yielded higher fractions of satisfactory predictions than allometry, both methodologies were associated with a significant and occasionally high probability of obtaining mispredictions of pharmacokinetic parameters by factors of >2, >3 and >10. In line with recent proposals to extend the goals of early-phase human studies beyond safety and tolerability, and considering the need to mitigate risks in studies dealing with novel and highly potent drug candidates, we discuss these results in a pharmacological context. CONCLUSIONS: Concise recommendations are given regarding the use of allometric and PBPK extrapolation methodologies in the translation process. The results presented here should alert clinical investigators to the limitations inherent in all approaches to prediction of human pharmacokinetics from preclinical data. We propose an adaptive approach to the design of early-phase clinical studies, particularly when dealing with compounds that are characterized by novel and only partially understood pharmacological profiles.
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Evaluación Preclínica de Medicamentos , Farmacocinética , Medición de Riesgo , Animales , Humanos , Modelos BiológicosRESUMEN
INTRODUCTION: A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine. MATERIALS AND METHODS: Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.3 mg.kg(-1) of fluvoxamine. ANALYSIS: With increasing dose a disproportional increase in brain concentrations was observed. The kinetics of brain distribution was estimated by simultaneous analysis of plasma, free brain ECF and total brain tissue concentrations. The PK model consists of three compartments for fluvoxamine concentrations in plasma in combination with a catenary two compartment model for distribution into the brain. In this catenary model, the mass exchange between a shallow perfusion-limited and a deep brain compartment is described by a passive diffusion term and a saturable active efflux term. RESULTS: The model resulted in precise estimates of the parameters describing passive influx into (k in) of 0.16 min(-1) and efflux from the shallow brain compartment (k out) of 0.019 min(-1) and the fluvoxamine concentration at which 50% of the maximum active efflux (C 50) is reached of 710 ng.ml(-1). The proposed brain distribution model constitutes a basis for precise characterization of the PK-PD correlation of fluvoxamine by taking into account the non-linearity in brain distribution.