RESUMEN
AIM OF THE WORK: The study was conducted to evaluate the influence of theophylline pre-treatment on serum pharmacokinetics and milk elimination of tylosin following single intramuscular (IM) administrations in lactating goats. METHODS AND RESULTS: In a cross-over study, tylosin was injected via intramuscular (IM) at a single dose of 15 mg/kg b.wt. After a one-month washout period goats received theophylline at a daily IM dose of 2 mg/kg b.wt. for seven consecutive days then tylosin was injected IM dose of 15 mg/kg b.wt. two hours after the last theophylline dosing. Blood samples were collected before and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, and 24 h post-injection. Samples were left to clot and then centrifuged to yield serum. Milk samples were collected before and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h post-injection from each goat by hand milking. Tylosin serum concentrations were determined by high-performance liquid chromatography (HPLC). Tylosin concentrations versus time were analyzed by a noncompartmental method. Tylosin Cmax significantly declined from 1.73 ± 0.10 to 1.01 ± 0.11 µg/ml, and attained Tmax values of 2 and 1 h, respectively in theophylline-pretreated goats. Moreover, theophylline pretreatment significantly shortened the elimination half-life (t1/2el) from 6.94 to 1.98 h, t1/2ka from 0.62 to 0.36 h and the mean residence time (MRT) from 8.02 to 4.31 h, also Vz/F and AUCs decreased from 11.91 to 7.70 L/kg and from 12.64 to 4.57 µg*h/ml, respectively, consequently, theophylline enhanced the clearance (Cl/F) of tylosin from the body. Similarly, tylosin milk concentrations were significantly lower in theophylline-pretreated goats than in goats that received tylosin alone and were detected up to 24 and 72 h in both groups, respectively. Moreover, the t1/2el and AUCs were significantly decreased from 14.68 ± 1.97 to 4.72 ± 0.48 h, and from 181 to 67.20 µg*h/ml, respectively. CONCLUSIONS: The withdrawal period for tylosin in goat milk is at least 72 h. Theophylline pretreatment significantly decreases serum and milk tylosin concentrations to subtherapeutic levels, which could have serious clinical consequences such as failure of therapy. This means that after administering tylosin to goats, milk from these animals should not be consumed for at least 96 h to ensure that the milk is free from residues of the antibiotic.
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Antibacterianos , Estudios Cruzados , Cabras , Lactancia , Leche , Teofilina , Tilosina , Animales , Cabras/metabolismo , Teofilina/farmacocinética , Teofilina/administración & dosificación , Teofilina/sangre , Tilosina/farmacocinética , Tilosina/administración & dosificación , Tilosina/sangre , Inyecciones Intramusculares/veterinaria , Leche/química , Femenino , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Semivida , Área Bajo la CurvaRESUMEN
Theophylline is commonly used for the treatment of asthma and has a low hepatic clearance. The changes in plasma albumin concentration occurring in asthma may affect the exposure of theophylline. The aim of the presented work was to predict theophylline pharmacokinetics (PK) after incorporating the changes in plasma albumin concentration occurring in patients with asthma into a physiologically based pharmacokinetic (PBPK) model to see whether these changes can affect the systemic theophylline concentrations in asthma. The PBPK model was developed following a systematic model building approach using Simcyp. The predictions were performed initially in healthy adults after intravenous and oral drug administration. Only when the developed adult PBPK model had adequately predicted theophylline PK in healthy adults, the changes in plasma albumin concentrations were incorporated into the model for predicting drug exposure in patients with asthma. After evaluation of the developed model in the adult population, it was scaled to children on physiologic basis. The model evaluation was performed by using visual predictive checks and comparison of ratio of observed and predicted (Robs/Pre) PK parameters along with their 2-fold error range. The developed PBPK model has effectively described theophylline PK in both healthy and diseased populations, as Robs/Pre for all the PK parameters were within the 2-fold error limit. The predictions in patients with asthma showed that there were no significant changes in PK parameters after incorporating the changes in serum albumin concentration. The mechanistic nature of the developed asthma-PBPK model can facilitate its extension to other drugs. SIGNIFICANCE STATEMENT: Exposure of a low hepatic clearance drug like theophylline may be susceptible to plasma albumin concentration changes that occur in asthma. These changes in systemic albumin concentrations can be incorporated into a physiologically based pharmacokinetic model to predict theophylline pharmacokinetics in adult and pediatric asthma populations. The presented work is focused on predicting theophylline absorption, distribution, metabolism, and elimination in adult and pediatric asthma populations after incorporating reported changes in serum albumin concentrations to see their impact on the systemic theophylline concentrations.
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Asma/tratamiento farmacológico , Cálculo de Dosificación de Drogas , Albúmina Sérica Humana/análisis , Teofilina/farmacocinética , Administración Intravenosa , Administración Oral , Adulto , Factores de Edad , Área Bajo la Curva , Asma/sangre , Niño , Preescolar , Simulación por Computador , Conjuntos de Datos como Asunto , Relación Dosis-Respuesta a Droga , Femenino , Voluntarios Sanos , Eliminación Hepatobiliar , Humanos , Lactante , Masculino , Modelos Biológicos , Teofilina/administración & dosificación , Distribución TisularRESUMEN
Doxophylline (DOXO) and theophylline are widely used as bronchodilators for treating asthma and chronic obstructive pulmonary disease, and DOXO has a better safety profile than theophylline. How DOXO's metabolism and disposition affect its antiasthmatic efficacy and safety remains to be explored. In this study, the metabolites of DOXO were characterized. A total of nine metabolites of DOXO were identified in vitro using liver microsomes from human and four other animal species. Among them, six metabolites were reported for the first time. The top three metabolites were theophylline acetaldehyde (M1), theophylline-7-acetic acid (M2), and etophylline (M4). A comparative analysis of DOXO metabolism in human using liver microsomes, S9 fraction, and plasma samples demonstrated the following: 1) The metabolism of DOXO began with a cytochrome P450 (P450)-mediated, rate-limiting step at the C ring and produced M1, the most abundant metabolite in human liver microsomes. However, in human plasma, the M1 production was rather low. 2) M1 was further converted to M2 and M4, the end products of DOXO metabolism in vivo, by non-P450 dismutase in the cytosol. This dismutation process also relied on the ratio of NADP+/NADPH in the cell. These findings for the first time elucidated the metabolic sites and routes of DOXO metabolism in human. SIGNIFICANCE STATEMENT: We systematically characterized doxophylline metabolism using in vitro and in vivo assays. Our findings evolved the understandings of metabolic sites and pathways for methylxanthine derivatives with the aldehyde functional group.
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Acetaldehído/metabolismo , Broncodilatadores/farmacocinética , Hígado/enzimología , Teofilina/análogos & derivados , Teofilina/metabolismo , Acetaldehído/química , Adulto , Animales , Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Voluntarios Sanos , Humanos , Macaca fascicularis , Ratones , Microsomas Hepáticos , Oxidación-Reducción , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Conejos , Ratas , Teofilina/administración & dosificación , Teofilina/química , Teofilina/farmacocinéticaRESUMEN
BACKGROUND: Theophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies. METHODS: A population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5 mg/kg intravenous (i.v.) load then 1.8 mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10 mg/L) associated with clinical response was examined. RESULTS: Birth weight was a significant predictor of theophylline clearance and volume of distribution (p < 0.05). The median half-life was 39.5 h (range 27.2-50.4). An aminophylline loading dose of 7 mg/kg followed by 1.6 mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates. CONCLUSIONS: In neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population. IMPACT: Theophylline is a potential renal-protective therapy in neonates with HIE undergoing therapeutic hypothermia; however, the pharmacokinetics and dose needs in this population are not known. Theophylline clearance was low in neonates with HIE undergoing therapeutic hypothermia with a 50% longer half-life compared to full-term normothermic neonates without HIE. As theophylline is advanced in clinical development, dosing strategies will need to consider the unique pharmacokinetic needs of neonates with HIE undergoing therapeutic hypothermia.
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Hipotermia Inducida/métodos , Hipoxia-Isquemia Encefálica/terapia , Riñón/efectos de los fármacos , Teofilina/administración & dosificación , Teofilina/farmacocinética , Aminofilina/administración & dosificación , Peso al Nacer , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hipotermia Inducida/efectos adversos , Hipoxia-Isquemia Encefálica/complicaciones , Recién Nacido , Recien Nacido Prematuro , Masculino , Método de Montecarlo , Farmacocinética , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Theophylline, a xanthine derivative drug, is used for the treatment of respiratory diseases, such as asthma, and is primarily eliminated by hepatic metabolism. There is marked interindividual variability in theophylline clearance. Therefore, the aim of this study was to evaluate the influence of chronic hepatitis (CH), liver cirrhosis (LC), and other covariates on theophylline clearance by population pharmacokinetic (PPK) analysis. METHODS: The authors retrospectively obtained 496 trough concentrations of theophylline at steady state from 226 adult patients with bronchial asthma. The liver functions of the patients were classified into 3 categories: normal hepatic function, CH, and LC. The PPK analysis was performed using the NONMEM program. CH, LC, age, smoking status, coadministration of clarithromycin (CAM), and sex were considered as covariates that affected theophylline clearance. RESULTS: Theophylline clearance (CL/F per kg) was significantly influenced by CH, LC, smoking, and CAM. The final model of theophylline clearance was as follows: CL/F (L/h·kg) = 0.0484 × 1.40 × 0.861 × 0.889 × 0.557. Smoking is a well-known factor that markedly enhances CL/F through the induction of CYP1A enzymes, whereas CAM has been reported to inhibit CYP3A4. The final model for hepatic function showed that CL/F in CH and LC patients was 0.043 and 0.027 L/h/kg, respectively, and it was lower than that in patients with normal hepatic function. As theophylline clearance depends on intrinsic hepatic clearance, lower CL/F in patients with LC than in those with CH may be due to a decrease in the metabolic enzymatic capability of LC patients. CONCLUSIONS: Differences exist in theophylline clearance between CH and LC patients as per the PPK analysis.
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Hepatitis Crónica , Cirrosis Hepática , Teofilina , Adulto , Hepatitis Crónica/metabolismo , Humanos , Cinética , Cirrosis Hepática/metabolismo , Estudios Retrospectivos , Teofilina/farmacocinéticaRESUMEN
A full Bayesian statistical treatment of complex pharmacokinetic or pharmacodynamic models, in particular in a population context, gives access to powerful inference, including on model structure. Markov Chain Monte Carlo (MCMC) samplers are typically used to estimate the joint posterior parameter distribution of interest. Among MCMC samplers, the simulated tempering algorithm (TMCMC) has a number of advantages: it can sample from sharp multi-modal posteriors; it provides insight into identifiability issues useful for model simplification; it can be used to compute accurate Bayes factors for model choice; the simulated Markov chains mix quickly and have assured convergence in certain conditions. The main challenge when implementing this approach is to find an adequate scale of auxiliary inverse temperatures (perks) and associated scaling constants. We solved that problem by adaptive stochastic optimization and describe our implementation of TMCMC sampling in the GNU MCSim software. Once a grid of perks is obtained, it is easy to perform posterior-tempered MCMC sampling or likelihood-tempered MCMC (thermodynamic integration, which bridges the joint prior and the posterior parameter distributions, with assured convergence of a single sampling chain). We compare TMCMC to other samplers and demonstrate its efficient sampling of multi-modal posteriors and calculation of Bayes factors in two stylized case-studies and two realistic population pharmacokinetic inference problems, one of them involving a large PBPK model.
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Variación Biológica Poblacional , Modelos Biológicos , Acetaminofén/administración & dosificación , Acetaminofén/farmacocinética , Algoritmos , Teorema de Bayes , Humanos , Cadenas de Markov , Método de Montecarlo , Programas Informáticos , Teofilina/administración & dosificación , Teofilina/farmacocinéticaRESUMEN
Nonlinear mixed-effects models are being widely used for the analysis of longitudinal data, especially from pharmaceutical research. They use random effects which are latent and unobservable variables so the random-effects distribution is subject to misspecification in practice. In this paper, we first study the consequences of misspecifying the random-effects distribution in nonlinear mixed-effects models. Our study is focused on Gauss-Hermite quadrature, which is now the routine method for calculation of the marginal likelihood in mixed models. We then present a formal diagnostic test to check the appropriateness of the assumed random-effects distribution in nonlinear mixed-effects models, which is very useful for real data analysis. Our findings show that the estimates of fixed-effects parameters in nonlinear mixed-effects models are generally robust to deviations from normality of the random-effects distribution, but the estimates of variance components are very sensitive to the distributional assumption of random effects. Furthermore, a misspecified random-effects distribution will either overestimate or underestimate the predictions of random effects. We illustrate the results using a real data application from an intensive pharmacokinetic study.
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Modelos Estadísticos , Dinámicas no Lineales , Proyectos de Investigación/estadística & datos numéricos , Administración Oral , Antiasmáticos/administración & dosificación , Antiasmáticos/farmacocinética , Variación Biológica Poblacional , Interpretación Estadística de Datos , Humanos , Funciones de Verosimilitud , Estudios Longitudinales , Teofilina/administración & dosificación , Teofilina/farmacocinética , Factores de TiempoRESUMEN
Age is known as one of influencing factor for theophylline (TP)-metabolizing capacity. In a previous our study, the ratio of TP and its major metabolite 1,3-dimethyluric acid (DMU) in serum (DMU/TP) is a useful index to estimate TP-metabolizing capacity, and this value markedly increased by influencing factor, such as the history of smoking. However, it is unknown whether DMU/TP values in serum reflect age-associated changes of TP-metabolizing capacity. In this study, the effect of age on the DMU/TP values in serum were investigated using mice of different age due to the limited blood sampling in human. The concentrations of TP and its metabolites in mouse serum were simultaneously measured using HPLC. As observed in human serum, serum TP concentrations were closely correlated with DMU concentration in mice, which indicates that the DMU/TP ratio is a good indicator of TP metabolic ability in mice. When TP was administered subcutaneously in 2-28-week-old mice, age-associated changes in the DMU/TP ratio in mice were observed. In conclusion, age-associated changes in TP-metabolizing capacity can be estimated by the DMU/TP ratio in serum.
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Envejecimiento/sangre , Teofilina/sangre , Ácido Úrico/análogos & derivados , Envejecimiento/metabolismo , Animales , Masculino , Ratones Endogámicos ICR , Teofilina/farmacocinética , Ácido Úrico/sangreRESUMEN
The combination of acebrophylline (ABP), levocetirizine (LCZ) and pranlukast (PRN) is used to treat allergic rhinitis, asthma, hay-fever and other conditions where patients experience difficulty in breathing. This study was carried out with the aim of developing and validating a reverse-phase high-performance liquid chromatographic bioanalytical method to simultaneously quantitate ABP, LCZ and PRN in rat plasma. The objective also includes determination of the pharmacokinetic interaction of these three drugs after administration via the oral route after individual and combination treatment in rat. Optimum resolution between the analytes was observed with a C18 Kinetex column (250 mm × 4.6 mm × 5 µm). The chromatography was performed in a gradient elution mode with a 1 mL/min flow rate. The calibration curves were linear over the concentration range of 100-1600 ng/mL. The intra- and inter-day precision and accuracy were found to be within acceptable limits as specified in US Food and Drug Administration guideline for bioanalytical method validation. The analytes were stable on the bench-top (8 h), after three freeze-thaw cycles, in the autosampler (8 h) and as a dry extract (-80°C for 48 h). The statistical results of the pharmacokinetic study in Sprague-Dawley rats showed a significant change in pharmacokinetic parameters for PRN upon co-administration of the three drugs.
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Ambroxol/análogos & derivados , Cetirizina , Cromonas , Teofilina/análogos & derivados , Ambroxol/sangre , Ambroxol/química , Ambroxol/farmacocinética , Animales , Cetirizina/sangre , Cetirizina/química , Cetirizina/farmacocinética , Cromatografía Líquida de Alta Presión , Cromonas/sangre , Cromonas/química , Cromonas/farmacocinética , Límite de Detección , Modelos Lineales , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Teofilina/sangre , Teofilina/química , Teofilina/farmacocinéticaRESUMEN
Theophylline is a commonly used bronchodilator drug for treatment of chronic canine bronchitis, but no formulations validated in dogs are currently available. An oral, modified and compounded theophylline product (MCT), which could fulfil this need, is available through a USP-compliant, veterinary compounding pharmacy; however, its pharmacokinetic properties are unknown. The aim of this study was to determine the pharmacokinetics of MCT. Plasma drug concentrations were measured in seven healthy, fed dogs after single doses of intravenous aminophylline (8.6 mg/kg theophylline equivalent) and oral MCT (10 mg/kg). Systemic bioavailability of the MCT was 96.2 ± 32.9%. MCT times to maximum concentration, mean absorption time and terminal half-life were 8.85 ± 3.63, 6.95 ± 3.42, and 8.67 ± 1.62 hr, respectively. Based on simulations of 10 mg/kg and 12-hr dosing, steady-state plasma theophylline concentrations are expected to exceed the minimum therapeutic concentration for 71.7 ± 35.6% of the dosing interval. Overall, the MCT product investigated showed similar pharmacokinetic characteristics compared to previously validated extended-release theophylline products. An oral dose of 10 mg/kg q 12 hr is likely an appropriate dosage to begin therapy; however, therapeutic drug monitoring may be warranted because of inter-individual variation.
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Bronquitis Crónica/veterinaria , Enfermedades de los Perros/tratamiento farmacológico , Teofilina/farmacocinética , Teofilina/uso terapéutico , Animales , Área Bajo la Curva , Bronquitis Crónica/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Broncodilatadores/sangre , Broncodilatadores/farmacocinética , Broncodilatadores/uso terapéutico , Perros , Femenino , Semivida , Inyecciones Intravenosas , Masculino , Teofilina/administración & dosificación , Teofilina/sangreRESUMEN
Transdermal administration of drugs that penetrate, in this case directly into the blood circulation, has many advantages and is promising for many drugs thanks to its easy application and good patient compliance. (S)-8-Methyl-6,9-diazaspiro[4.5]decan-7,10-dione (alaptide), has been studied as a potential chemical permeation enhancer. Based on its structure, four selected piperazine-2,5-diones were synthesized by means of multi-step synthetic pathways. All the compounds were investigated on their ability to enhance the permeation of the model drug theophylline from the hydrophilic medium propylene glycol:water (1:1). In vitro experiments were performed using vertical Franz diffusion cells at constant temperature 34 ± 0.5 °C and using full-thickness pig (Sus scrofa f. domestica) ear skin. Withdrawn samples were analyzed by RP-HPLC for determination of the permeated amount of theophylline. All the compounds were applied in ratio 1:10 (w/w) relative to the amount of theophylline. One hour after application, the permeated amount of theophylline from formulations with alaptide and (3S,6S)-3,6-dimethylpiperazine-2,5-dione, was ca. 15- and 12-fold higher, respectively, than from the formulation without the tested compounds. Despite the enhancement ratio of both enhancers in a steady state was ca. 2.3, the pseudo-enhancement ratio in the time range from 1 to 3 h was 4.4. These enhancement ratios indicate that the compounds are able to enhance the permeation of agents through the skin; however, the short-term application of both compound formulations seems to be more advantageous. In addition, the screening of the cytotoxicity of all the prepared compounds was performed using three cell lines, and the compounds did not show any significant toxic effect.
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Piperazina/farmacocinética , Absorción Cutánea , Teofilina/farmacocinética , Línea Celular Tumoral , Humanos , Estructura Molecular , Permeabilidad , Piperazina/química , Teofilina/químicaRESUMEN
Certain xenobiotics, such as paraquat, are sequestered into the lungs from the systemic circulation by the polyamine transporter system (PTS). The aim of this study was to investigate whether ion-pairing a drug (theophylline) with a PTS substrate (spermine) provides a means of using this active transport mechanism to target drug delivery to the lungs. Fourier transform infrared spectroscopy showed that two of the amine groups of spermine interact with C-N7 and C6âO of theophylline, leaving two free amines to interact with the PTS. In A549 cells, which possess a functional PTS (spermidine Km and Vmax, 0.6 ± 0.3 µM and 1.8 ± 0.3 pmol·min-1 per 105 cells, respectively), uptake of the theophylline-spermine ion-pair was increased 1.8-fold compared to free theophylline at 37 °C, but not at 4 °C. In an isolated perfused rat lung model (IPL) a 3.6-fold increase in lung theophylline concentration was observed after vascular administration of the ion-pair compared to free theophylline. Theophylline was cleared from the IPL with similar kinetics irrespective of whether it was delivered as the free drug or an ion-pair, although lung levels remained elevated after washout following delivery as an ion-pair. In vitro simulation of the theophylline-spermine break down demonstrated that a drop in pH from 9.6 to 7.4, such as that undergone by the ion-pair in biological matrices, induces rapid and almost complete dissociation of the ion-paired species. However, infusion of the ion-pair formulations via the vasculature provides almost immediate delivery to the pulmonary capillary bed permitting PTS-mediated active sequestering of ion-paired theophylline into the lungs.
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Broncodilatadores/administración & dosificación , Proteínas de Transporte de Catión/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Pulmón/metabolismo , Teofilina/administración & dosificación , Células A549 , Animales , Broncodilatadores/farmacocinética , Humanos , Concentración de Iones de Hidrógeno , Iones/química , Masculino , Poliaminas/metabolismo , Ratas , Ratas Wistar , Espermina/química , Espermina/metabolismo , Teofilina/farmacocinética , Distribución TisularRESUMEN
BACKGROUND: In population pharmacokinetic modeling, bodyweight is often incorporated as an important covariate using fixed (0.75) or single-exponent model. In recent years, several variations of allometric models have been suggested for the prediction of drug clearance across a wide age range. The objective of this study is to develop and evaluate single-exponent, bodyweight-dependent allometric exponent (BDE), age-dependent exponent (ADE), and segmented regression models for predicting clearance and maintenance dose of theophylline. METHODS: The BDE model was described by the following equation: (Equation is included in full-text article.), where L × BW defines the BDE for clearance. The coefficient and the exponents L and M were estimated. The ADE model consisted of several empirical exponents based on age and ranged from 0.75 (children >5 years and adults) to 1.2 (premature neonates). Data for model development and validation were based on 52 subjects each. RESULTS: All structural and statistical parameters were estimated with acceptable precision for single-exponent and BDE models (<30%); however, the BDE model was superior in describing theophylline clearance across a wide age range for the training data. The segmented regression model on log-transformed data also adequately described theophylline clearance. When models were evaluated with validation data, a single-exponent model overpredicted clearance and dosing rate in premature neonates and adults with a mean prediction error of ≥50%. For premature neonates and adults, mean clearance and dosing rate were predicted within a 30% prediction error using the BDE, ADE, and segmented models. CONCLUSIONS: This study demonstrates that the BDE, ADE, and segmented models performed better than a single-exponent model for predicting clearance and dose of theophylline across a wide age range.
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Envejecimiento , Peso Corporal , Cálculo de Dosificación de Drogas , Modelos Biológicos , Teofilina/administración & dosificación , Teofilina/farmacocinética , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
The aim of this paper is to provide an overview of pharmacometric models that involve some latent process with Markovian dynamics. Such models include hidden Markov models which may be useful for describing the dynamics of a disease state that jumps from one state to another at discrete times. On the contrary, diffusion models are continuous-time and continuous-state Markov models that are relevant for modelling non observed phenomena that fluctuate continuously and randomly over time. We show that an extension of these models to mixed effects models is straightforward in a population context. We then show how the forward-backward algorithm used for inference in hidden Markov models and the extended Kalman filter used for inference in diffusion models can be combined with standard inference algorithms in mixed effects models for estimating the parameters of the model. The use of these models is illustrated with two applications: a hidden Markov model for describing the epileptic activity of a large number of patients and a stochastic differential equation based model for describing the pharmacokinetics of theophyllin.
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Cadenas de Markov , Modelos Biológicos , Farmacología/métodos , Administración Oral , Algoritmos , Simulación por Computador , Epilepsia/diagnóstico , Epilepsia/fisiopatología , Humanos , Distribución de Poisson , Teofilina/administración & dosificación , Teofilina/farmacocinética , Distribución TisularRESUMEN
The objective of this study was to develop an authentic ionic-driven osmotic pump system and investigate the release mechanism, simultaneously exploring the in vitro and in vivo correlation of the ionic-driven osmotic pump tablet. A comparison of the ionic-driven and conventional theophylline osmotic pump, the influence of pH and the amount of sodium chloride on drug release, the relationship between the ionic osmotic pressure and the drug release, and the pharmacokinetics experiment in beagle dogs were investigated. Consequently, the similarity factor (f 2 ) between the novel and conventional theophylline osmotic pump tablet was 60.18, which indicated a similar drug-release behavior. Also, the release profile fitted a zero-order kinetic model. The relative bioavailability of the ionic-driven osmotic pump to the conventional osmotic pump calculated from the AUC (0-∞) was 93.6% and the coefficient (R = 0.9945) confirmed that the ionic-driven osmotic pump exhibited excellent IVIVC. The driving power of the ionic-driven osmotic pump was produced only by ions, which was strongly dependent on the ion strength, and a novel formula for the ionic-driven osmotic pump was derived which indicated that the drug-release rate was proportional to the ionic osmotic pressure and the sodium chloride concentration. Significantly, the formula can predict the drug-release rate and release characteristics of theophylline ionic-driven osmotic pumps, guiding future modification of the ionic osmotic pump.
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Sistemas de Liberación de Medicamentos , Animales , Disponibilidad Biológica , Preparaciones de Acción Retardada , Perros , Liberación de Fármacos , Iones , Ósmosis , Presión Osmótica , Cloruro de Sodio/química , Solubilidad , Comprimidos , Teofilina/administración & dosificación , Teofilina/farmacocinéticaRESUMEN
Fetal exposure to drugs cannot be readily estimated from single time point cord blood sampling at the time of delivery. Therefore, we developed a physiologically based pharmacokinetic (PBPK) model to estimate fetal drug exposure throughout pregnancy. In this study, we report verification of this novel maternal-fetal PBPK (m-f-PBPK) model for drugs that passively diffuse across the placenta and are not metabolized/transported there. Our recently built m-f-PBPK model was populated with gestational age-dependent changes in maternal drug disposition and maternal-fetal physiology. Using midazolam as an in vivo calibrator, the transplacental passive diffusion clearance of theophylline and zidovudine was first estimated. Then, for verification, the predicted maternal plasma (MP) and umbilical venous (UV) plasma drug concentrations by our m-f-PBPK were compared against those observed at term. Overall, our m-f-PBPK model well predicted the maternal and fetal exposure to the two verification drugs, theophylline and zidovudine, at term, across a range of dosing regimens, with nearly all observed MP and UV plasma drug concentrations falling within the 90% prediction interval [i.e., 5th-95th percentile range of a virtual pregnant population (n = 100)]. Prediction precision and bias of theophylline MP and UV were 14.5% and 12.4%, and 9.4% and 7.5%, respectively. Furthermore, for zidovudine, after the exclusion of one unexpectedly low MP concentration, prediction precision and bias for MP and UV were 50.3% and 30.2, and 28.3% and 15.0%, respectively. This m-f-PBPK should be useful to predict fetal exposure to drugs, throughout pregnancy, for drugs that passively diffuse across the placenta.
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Intercambio Materno-Fetal/fisiología , Midazolam/farmacocinética , Placenta/metabolismo , Teofilina/farmacocinética , Zidovudina/farmacocinética , Femenino , Feto/metabolismo , Humanos , Cinética , Modelos Biológicos , Permeabilidad , EmbarazoRESUMEN
Hypoxemia can be life-threatening, both acutely and chronically. Because hypoxemia causes vascular dysregulation that further restricts oxygen availability to tissue, it can be pharmacologically addressed. We hypothesized that theophylline can be safely combined with the ß2-adrenergic vasodilator bambuterol to improve oxygen availability in hypoxemic patients. Ergogenicity and hemodynamic effects of bambuterol and theophylline were measured in rats under hypobaric and normobaric hypoxia (12% O2). Feasibility in humans was assessed using randomized, double-blind testing of the influence of combined slow-release theophylline (300 mg) and bambuterol (20 mg) on adverse events (AEs), plasma K+, pulse, blood pressure, and drug interaction. Both drugs and their combination significantly improved hypoxic endurance in rats. In humans, common AEs were low K+ (<3.5 mmol/L; bambuterol: 12, theophylline: 4, combination: 13 episodes) and tremors (10, 0, 14 episodes). No exacerbation or serious AE occurred when drugs were combined. A drop in plasma K+ coincided with peak bambuterol plasma concentrations. Bambuterol increased heart rate by approximately 13 bpm. Drug interaction was present but small. We report promise, feasibility, and relative safety of combined theophylline and bambuterol as a treatment of hypoxemia in humans. Cardiac safety and blood K+ will be important safety endpoints when testing these drugs in hypoxemic subjects.
Asunto(s)
Hipoxia/tratamiento farmacológico , Terbutalina/análogos & derivados , Teofilina/farmacología , Adulto , Animales , Disponibilidad Biológica , Interacciones Farmacológicas , Femenino , Semivida , Hemodinámica/efectos de los fármacos , Humanos , Hipoxia/sangre , Hipoxia/fisiopatología , Masculino , Condicionamiento Físico Animal , Ratas , Seguridad , Terbutalina/efectos adversos , Terbutalina/farmacocinética , Terbutalina/farmacología , Terbutalina/uso terapéutico , Teofilina/efectos adversos , Teofilina/farmacocinética , Teofilina/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
The aim of the present work was to better understand the drug-release mechanism from sustained release matrices prepared with two new polyurethanes, using a novel in silico formulation tool based on 3-dimensional cellular automata. For this purpose, two polymers and theophylline as model drug were used to prepare binary matrix tablets. Each formulation was simulated in silico, and its release behavior was compared to the experimental drug release profiles. Furthermore, the polymer distributions in the tablets were imaged by scanning electron microscopy (SEM) and the changes produced by the tortuosity were quantified and verified using experimental data. The obtained results showed that the polymers exhibited a surprisingly high ability for controlling drug release at low excipient concentrations (only 10% w/w of excipient controlled the release of drug during almost 8 h). The mesoscopic in silico model helped to reveal how the novel biopolymers were controlling drug release. The mechanism was found to be a special geometrical arrangement of the excipient particles, creating an almost continuous barrier surrounding the drug in a very effective way, comparable to lipid or waxy excipients but with the advantages of a much higher compactability, stability, and absence of excipient polymorphism.
Asunto(s)
Poliuretanos , Teofilina , Broncodilatadores/química , Broncodilatadores/farmacocinética , Simulación por Computador , Preparaciones de Acción Retardada , Liberación de Fármacos , Excipientes/química , Excipientes/farmacocinética , Microscopía Electrónica de Rastreo/métodos , Poliuretanos/química , Poliuretanos/farmacocinética , Solubilidad , Comprimidos , Teofilina/química , Teofilina/farmacocinéticaRESUMEN
The small intestine represents the region where the majority of drug and nutrient absorption transpires. Among adults, small intestinal transit kinetics is well delineated; however, the applicability of these values toward children remains unclear. This article serves to examine the relationship between age and mean small intestinal transit time (SITT) based on the available literature. In addition, the influence of alterations in intestinal transit time was explored among children using a model-based approach. Primary literature sources depicting SITT from children to adults were ascertained via the PubMed database. Data were limited to subjects without pathologies that could influence intestinal motility. Random-effect meta-regression models with between-study variability were employed to assess the influence of age on SITT. Three separate models with age as a linear or higher-order (i.e., second- and third-order polynomial) regressor were implemented to assess for the potential of both linear and curvilinear relationships. Examination of the influence of altered intestinal transit kinetics on the absorption of a sustained release theophylline preparation was explored among children between 8 and 14 years using physiologically based pharmacokinetic (PBPK) modeling. Age was not found to be a significant modulator of small intestinal transit within either the linear or higher-order polynomial meta-regression models. PBPK simulations indicated a lack of influence of variations in SITT on the absorption of theophylline from the examined sustained release formulation in older children. Based on the current literature, there is no evidence to suggest that mean SITT differs between children and adults.
Asunto(s)
Envejecimiento , Tránsito Gastrointestinal , Absorción Intestinal , Teofilina/farmacocinética , Administración Oral , Adolescente , Adulto , Factores de Edad , Niño , Preparaciones de Acción Retardada , Humanos , Intestino Delgado , Modelos Lineales , Modelos Biológicos , Dinámicas no Lineales , Teofilina/administración & dosificaciónRESUMEN
The drug, theophylline is frequently used as an additive to medications for people suffering from chronic obstructive pulmonary diseases (COPD). We studied the effect of theophylline in bone cells, skeleton and parameters related to systemic calcium homeostasis. Theophylline induced osteoblast apoptosis by increasing reactive oxygen species production that was caused by increased cAMP production. Bone marrow levels of theophylline were higher than its serum levels, indicating skeletal accumulation of this drug. When adult Sprague-Dawley rats were treated with theophylline, bone regeneration at fracture site was diminished compared with control. Theophylline treatment resulted in a time-dependent (at 4- and 8 weeks) bone loss. At 8 weeks, a significant loss of bone mass and deterioration of microarchitecture occurred and the severity was comparable to methylprednisone. Theophylline caused formation of hypomineralized osteoid and increased osteoclast number and surface. Serum bone resorption and formation marker were respectively higher and lower in the theophylline group compared with control. Bone strength was reduced by theophylline treatment. After 8 weeks, serum 25-D3 and liver 25-hydroxylases were decreased in theophylline group than control. Further, theophylline treatment reduced serum 1, 25-(OH)2 vitamin D3 (1,25-D3), and increased parathyroid hormone and fibroblast growth factor-23. Theophylline treated rats had normal serum calcium and phosphate but displayed calciuria and phosphaturia. Co-administration of 25-D3 with theophylline completely abrogated theophylline-induced osteopenia and alterations in calcium homeostasis. In addition, 1,25-D3 protected osteoblasts from theophylline-induced apoptosis and the attendant oxidative stress. We conclude that theophylline has detrimental effects in bone and prophylactic vitamin D supplementation to subjects taking theophylline could be osteoprotective.