RESUMEN
INTRODUCTION: Mibefradil was approved as a novel calcium antagonist in Switzerland in 1996. Following its launch as an antihypertensive and anti-anginal agent, there were reports about serious pharmacokinetic and pharmacodynamic interactions occurring with other drugs frequently administered to patients with cardiovascular diseases. Despite appropriate modifications of the prescribing information, such interactions continued to occur. The drug was finally withdrawn after a study in patients with congestive heart failure showed a trend to higher mortality with mibefradil. This increase in mortality could again be due to multiple interactions between mibefradil and other drugs. In retrospect, it can be concluded that several of the interactions, including the theoretical risk of severe toxicity in some patients, could have been and in fact were predicted on the basis of the data available before introduction to the market. Depending on the benefits, these problems would however not necessarily represent an unacceptable risk for a new active compound. RESULTS AND CONCLUSION: The most important points revealed by this analysis were: (1) when interpreting the results of interaction studies, it is important to consider not only the mean of the interaction effect but also the observed and the theoretically conceivable extreme effects in individual subjects and (2) a drug with a high interaction potential may represent a high risk even if an adequate warning is included in the product information. The need for specific pharmacokinetic and pharmacodynamic interaction studies with new drugs and the limitations of the pivotal clinical efficacy and safety studies during phase III in order to reveal such interactions are discussed.
Asunto(s)
Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/farmacología , Mibefradil/efectos adversos , Mibefradil/farmacología , Aprobación de Drogas , Interacciones Farmacológicas , Humanos , Vigilancia de Productos Comercializados , SuizaRESUMEN
To answer the question of the benefit and the cost/benefit ratio of the activities of a drug regulatory agency, the most important, clinically relevant "products" of a licensing authority in general, and the Swiss licensing authority (IKS) in particular are discussed. The activities of the medicines licensing authority assure that: For all new substances the efficacy and a positive benefit/risk ratio have been demonstrated before a marketing authorisation. For all marketed medicines an information for professionals and patients is available that has been evaluated and approved by an independent and competent reviewer. An independent post marketing surveillance of the side effects profile continues after a medicine has been put on the market. All clinical trials investigating medicinal products are performed according to GCP rules corresponding to international ethical and scientific standards. An international comparison of the time needed for the evaluation of a marketing authorisation application for a new medicine reveals that the IKS is one of the most efficient agencies. This is illustrated with an example showing the evaluation times of the EMEA and the IKS for products approved in 1997.
Asunto(s)
Control de Medicamentos y Narcóticos/legislación & jurisprudencia , Control de Medicamentos y Narcóticos/tendencias , Humanos , SuizaRESUMEN
The predictive value of a two-compartment Bayesian feedback program for tobramycin dose optimization was retrospectively evaluated in 199 hospitalized patients and compared with that of a simple non-Bayesian one-compartment model. Before dose adjustment, 64% of the patients were underdosed indicating that tobramycin monitoring is still necessary to avoid ineffective antibiotic therapy. When physicians adhered to the dose instructions calculated with the Bayesian method, 90% of the patients had optimal concentration-time profiles as opposed to only 53% of the 43 patients in whom dose recommendations were not followed. In young patients with normal renal function, precision and accuracy of the Bayesian feedback and the one-compartment method were well correlated, whereas in elderly patients (> 60 years) and patients with impaired renal function (estimated creatinine clearance < 60 ml/minute), the Bayesian method was significantly more precise. Multiple regression analysis revealed that renal function was the only independent variable predicting the performance of the Bayesian program. The results of this study indicate that the Bayesian feedback method is a reliable method for the therapeutic tobramycin monitoring under clinical conditions and in particular, elderly patients in whom renal impairment is frequent.
Asunto(s)
Antibacterianos/sangre , Teorema de Bayes , Monitoreo de Drogas/métodos , Cómputos Matemáticos , Modelos Biológicos , Modelos Estadísticos , Tobramicina/sangre , Absorción , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Estudios de Cohortes , Simulación por Computador , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Análisis de Regresión , Estudios Retrospectivos , Programas Informáticos , Tobramicina/administración & dosificación , Tobramicina/efectos adversosRESUMEN
Currently, there is an increasing focus on the implementation of pharmacokinetic-pharmacodynamic (PK-PD) studies and modelling as essential tools for drug development. Strategies involving specifically the population approach, which are based on relatively recent statistical methodology (e.g. nonlinear mixed effects modelling, NONMEM) have been advocated for investigating pharmacokinetic and pharmacodynamic variability as well as dose-concentration-effect relationships. The present article outlines this approach, and discusses how it can be implemented within the framework of the studies currently performed as part of the clinical phases of new drug development. It also considers study design and performance, based on real-life experiences. Population approaches, if designed carefully and early, as part of the planning of the drug development programme, are expected to play a significant role at every phase of the programme and to contribute to providing information that is valuable for registration purposes. Statistical methodology and software are now widely available. However, practical issues such as integration of the population approach within existing protocols, quality control of the data, timing of laboratory and statistical analyses, as well as resource allocation, remain legitimate concerns to be considered in prospective studies.
Asunto(s)
Diseño de Fármacos , Farmacocinética , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Estudios de Cohortes , Simulación por Computador , Guías como Asunto , Humanos , Estudios Multicéntricos como Asunto , Estadística como AsuntoRESUMEN
An expert meeting to discuss issues relating to the design of population pharmacokinetic/pharmacodynamic (PK/PD) studies was held in Brussels in March 1995, under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. The purpose of the meeting was to discuss the experts' experience in designing and performing population PK/PD studies. The topics discussed were current practice, logistical issues, ensuring the accuracy of data, covariate assessment, communication, and protocol design.
Asunto(s)
Farmacocinética , Proyectos de Investigación , Bélgica , Ensayos Clínicos como AsuntoRESUMEN
An expert meeting to discuss population pharmacokinetic/pharmacodynamic software was held in Brussels in November 1993 under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. Recently developed statistical methods offer the possibility of gaining integrated information on pharmacokinetics and response from relatively sparse observational data obtained directly in patients who are being treated with the drug under development. These methods can minimize the need to exclude patient groups and also allow analysis of a variety of unbalanced designs that frequently arise in the evaluation of the relationships between dose or concentration on the one hand and efficacy or safety on the other relationships that do not readily lend themselves to other forms of statistical analysis. The purpose of the Brussels meeting was to evaluate the state of both existing software and software under development, and to specify the needs and wishes of potential users of such software. It was apparent from the meeting that software development for population data analysis is currently a very active area of investigation and that several very good packages are already available, with more in development. The general consensus of the meeting was that well validated, easy to use software was essential to the implementation of the population approach to drug development.
Asunto(s)
Farmacocinética , Farmacología , Programas Informáticos , Humanos , Población , Estadística como AsuntoRESUMEN
Netilmicin pharmacokinetics were studied in neonates of 27 to 42 weeks' gestational age and 0.8 to 5.0 kg body weight in their first 2 weeks of life by the population pharmacokinetic approach. The data were best described by a two-compartment model. Clearance depends on body weight, gestational age, and postnatal age. Volume of distribution of the central and peripheral compartments was also related to body weight. Including these patient characteristics in the population pharmacokinetic regression model resulted in a marked reduction of the unexplained interindividual variability. This enabled us to derive dosage recommendations that result in peak and average concentrations within the desired range for 95% of the neonates with gestational age above 31 weeks, thus avoiding the need for individual drug-level monitoring in a well-defined large group of patients. Only for infants with gestational age less than 31 weeks who are less than 6 days old is individual dose adjustment based on serum concentration measurements required.
Asunto(s)
Netilmicina/farmacocinética , Peso Corporal , Simulación por Computador , Femenino , Edad Gestacional , Humanos , Técnicas para Inmunoenzimas , Recién Nacido , Masculino , Netilmicina/administración & dosificación , Netilmicina/sangre , Estudios Prospectivos , Radioinmunoensayo , Análisis de RegresiónRESUMEN
To evaluate the pharmacologic activity of 5-hydroxypropafenone, electrocardiographic changes (PQ and QRS duration) and blood pressure levels were measured in 6 healthy extensive metabolizers of debrisoquine after a single oral dose of 300 mg of this metabolite as a solution in a placebo-controlled, double-blind crossover study. Well-absorbed, with a lag time of 4.4 to 9.8 minutes, 5-hydroxypropafenone reached peak concentrations of 153 to 337 ng/ml after 20 to 51 minutes. The terminal half-life was 506 to 963 minutes. To describe the temporal aspects of the concentration-effect relation, a pharmacokinetic-pharmacodynamic model with a hypothetical effect compartment was applied. The relation between electrocardiographic changes and drug concentration at the effect site could be described by a linear regression model. Significant prolongations of PQ and QRS duration were found in 5 of 6 subjects. There were no changes in QTc interval, blood pressure measurements and heart rate in the supine position. However, blood pressure measurements in the upright position revealed a greater percent decrease of systolic blood pressure than with placebo (mean +/- standard deviation -25.6 +/- 13.8% vs -3.4 +/- 13.1%, p less than 0.05). It is concluded that 5-hydroxypropafenone exerts significant pharmacologic activity in humans as well as animals. Because QRS prolongation in patients treated with class IC antiarrhythmic drugs correlates with the antiarrhythmic effect, our data suggest that 5-hydroxypropafenone may contribute to the therapeutic activity of propafenone in humans.
Asunto(s)
Antiarrítmicos/farmacología , Propafenona/análogos & derivados , Administración Oral , Adulto , Antiarrítmicos/farmacocinética , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Electrocardiografía/efectos de los fármacos , Femenino , Semivida , Humanos , Masculino , Postura/fisiología , Propafenona/efectos adversos , Propafenona/farmacocinética , Propafenona/farmacología , Valores de ReferenciaRESUMEN
1. Population pharmacokinetic parameters of quinidine were determined based on 260 serum drug concentration measurements in 60 patients treated for arrhythmias with quinidine sulphate or quinidine bisulphate (Kinidin duriles) orally. 2. Quinidine kinetics were best described by a two compartment model with zero order absorption from the gastrointestinal tract. The pharmacokinetics are influenced by severe heart or liver failure and renal function impairment. No effect was found for mild or moderate heart failure, for age, for body weight or for coadministration of nifedipine. 3. Population pharmacokinetic parameters of quinidine (assuming 100% bioavailability of oral quinidine sulphate) were: nonrenal clearance for patients without severe heart and liver failure 12.6 l h-1, reduction in patients with severe heart or liver failure to 6.8 l h-1, renal clearance (l h-1) related to creatinine clearance (ml min-1), proportionality constant 0.0566, volume of distribution of the central compartment 161 l, maximum serum drug concentration 1.4 h after administration of quinidine sulphate and 6.0 h after administration of quinidine bisulphate. 4. The results were validated by predicting the serum drug concentration in a separate group of 30 patients. The model reliably predicted both the population average and the variability of the serum concentration of quinidine. 5. Using Monte Carlo computer simulations, an a priori dosing regimen was derived that should maximize the proportion of patients having quinidine serum concentrations within the recommended range (2-5 mg l-1): initial dose of 600 mg quinidine sulphate in all patients, 3 h later first maintenance dose of quinidine bisulphate.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Quinidina/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Peso Corporal/fisiología , Simulación por Computador , Femenino , Insuficiencia Cardíaca/metabolismo , Humanos , Hepatopatías/metabolismo , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Modelos Biológicos , Método de Montecarlo , Población , Análisis de RegresiónRESUMEN
The effect of propafenone and its major metabolite 5-hydroxy-propafenone on ECG intervals was investigated in eight healthy extensive metabolizers after single oral (300 to 450 mg) and intravenous (35 to 50 mg) doses of propafenone in a single-blind randomized trial. Peak serum concentrations were 278 +/- 233 ng/ml (oral) and 295 +/- 131 ng/ml (intravenous). After oral administration peak 5-hydroxy-propafenone levels were 194 +/- 65 ng/ml, whereas after intravenous dosing no metabolite was detected, except in one subject. Serum concentrations were related to effects by linear regression including a hypothetical effect-site compartment in a pharmacokinetic-pharmacodynamic model. Significant prolongations of ECG intervals were found in both sequences. Comparison of the two concentration-effect data sets (intravenous, oral) revealed an additive effect of 5-hydroxy-propafenone in four of eight subjects for PQ interval and seven of eight subjects for QRS duration. We conclude that 5-hydroxy-propafenone exerts pharmacologic activity and could thus contribute to the antiarrhythmic effect of propafenone.
Asunto(s)
Propafenona/farmacología , Administración Oral , Adulto , Evaluación de Medicamentos , Electrocardiografía/efectos de los fármacos , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Propafenona/análogos & derivados , Propafenona/farmacocinética , Distribución AleatoriaRESUMEN
Serum concentration measurements represent a tool that can help the physician to choose the optimal dose in an individual patient. Its application has been recommended for several drugs that show a narrow therapeutic range and for which the dose cannot be individually adjusted directly on the basis of the therapeutic effect. For an effective use of his therapeutic tool, it is important to observe the following three points: 1. The dosage history must be known, including patient's compliance. 2. Whenever possible, the measurement should be obtained after steady-state has been reached on a constant dosing regimen (four half-lives of the drug). The dose adjustment in steady-state is very simple: The concentration changes are for most drugs proportional to the changes in dose rate. 3. The dose adjustment should never be performed on the basis of the concentration measurement alone, but always in the context of the clinical conditions and the patient's response.
Asunto(s)
Quimioterapia , Farmacocinética , Semivida , Humanos , Cooperación del Paciente , Preparaciones Farmacéuticas/metabolismoRESUMEN
The application of population pharmacokinetic analysis has received increasing attention in the last few years. The main goal of this report is to make investigators aware of the necessity of independent evaluation of the results obtained from a population analysis based on observational studies. We also describe with the help of a specific example (a new synthetic opiate Alfentanil) how such evaluation can be performed for parameter estimates obtained with the software system NONMEM. The method differs depending on the type of serum concentration data that are used for the evaluation. A general method is described, based on the regression model used in NONMEM, that can test for bias in the estimates of fixed and random effects independent of the number of observations per patient and dosing. Since the procedure for testing for statistically significant bias in the prediction of the average concentration and its variability can be relatively complex, we propose that generally available program packages performing estimation of the pharmacokinetic parameters from observational data should contain the necessary software to evaluate the reliability of the parameter estimates on a second data set.
Asunto(s)
Interpretación Estadística de Datos , Farmacocinética , Programas Informáticos , Alfentanilo/farmacocinética , Análisis de Varianza , Estudios de Evaluación como Asunto , Humanos , Matemática , Valor Predictivo de las PruebasRESUMEN
The predictability and intraindividual variability of serum theophylline concentrations (STC) after different dosing schedules were investigated in 24 patients with chronic obstructive lung disease (COLD). Three oral regimens were compared in 3 groups of 8 randomly assigned patients. Group I:Drug A once daily in the evening; Group II: Drug A b.d.; Group III: Drug B b.d. The doses for each patient were estimated by Bayesian forecasting aiming at an STC of 10-15 mg/l. STC and FEV1 were measured on two consecutive days at steady-state. The day-to-day variability of STC was less than 20% in all three groups. The within-day fluctuation in Group I amounted to 259% (median) compared to 57% and 38% in Groups II and III, respectively. Dose adjustment by Bayesian forecasting resulted in a therapeutic STC in most patients with a b.d. regimen, whereas for the once daily dose the prediction was not satisfactory. No difference in lung function was found between the 24-h and 12-h dosing, probably because of the large intersubject variability in FEV1. Therefore, the question whether the differences in STC profile are of clinical importance in COLD can only be investigated in a larger group of patients.
Asunto(s)
Enfermedades Pulmonares Obstructivas/tratamiento farmacológico , Teofilina/sangre , Adulto , Anciano , Teorema de Bayes , Preparaciones de Acción Retardada , Esquema de Medicación , Femenino , Humanos , Enfermedades Pulmonares Obstructivas/sangre , Enfermedades Pulmonares Obstructivas/epidemiología , Masculino , Flujo Espiratorio Máximo , Persona de Mediana Edad , Teofilina/administración & dosificación , Teofilina/efectos adversosRESUMEN
The pharmacokinetics of oral and i.v. propafenone and its major metabolites have been investigated in 8 healthy subjects. The total body clearance of propafenone was 963 ml/min, the terminal half-life 198 min and its absolute bioavailability was 15.5%. The two active metabolites (5-hydroxypropafenone and N-depropylpropafenone) showed non-linear kinetics in that both the dose-corrected area under the serum concentration-time curve and the amount excreted in the urine were larger after oral dosing. This resulted in considerably higher serum concentrations of the metabolites despite comparable serum concentrations of the parent compound. Thus, the concentration-effect relationship in the same patient may differ after oral and intravenous doses if concentrations of the active metabolite(s) are not taken into consideration. Although the mechanism of the nonlinearity is not clear, the data indicate that it may be due to saturable biliary excretion of the metabolites.
Asunto(s)
Propafenona/farmacocinética , Biotransformación , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Propafenona/análogos & derivados , Propafenona/metabolismoRESUMEN
We used isolated rat hearts subjected to coronary artery ligation and reperfusion to study the antiarrhythmic activity of 5-hydroxypropafenone (5OHP) and N-depropylpropafenone (NDPP), major metabolites of propafenone (P) in humans, and of the two enantiomers (R)- and (S)-propafenone. 5OHP suppressed reperfusion arrhythmias similar to the parent drug in a concentration-dependent manner. The concentration of 5OHP needed to prevent ventricular fibrillation in 50% of experiments (EC50) was significantly higher than that of P (0.186 +/- 0.05 vs. 0.153 +/- 0.005 mg/L, mean +/- SEM, p less than 0.05). 5OHP had a relative potency of 80% compared to P. When 5OHP and P were administered together, their antiarrhythmic effect appeared to be supra-additive. The NDPP metabolite showed very little antiarrhythmic potency and was about four times less active than P. The two enantiomers (R) and (S) were equipotent and showed antiarrhythmic activities similar to racemic P.
Asunto(s)
Arritmias Cardíacas/fisiopatología , Daño por Reperfusión Miocárdica/fisiopatología , Propafenona/farmacología , Animales , Biotransformación , Cromatografía Líquida de Alta Presión , Masculino , Propafenona/análogos & derivados , Propafenona/metabolismo , Ratas , Ratas Endogámicas , EstereoisomerismoRESUMEN
1. Population pharmacokinetic parameters of tobramycin were determined in a heterogenous group of 97 patients using serum samples drawn for the routine monitoring of tobramycin concentrations, following multiple dosing regimens. 2. To describe the accumulation kinetics of tobramycin a two-compartment pharmacokinetic model was required. The best fit to the data was obtained when drug clearance (1 h-1) was related linearly to creatinine clearance (proportionality constant: 0.059 +/- 0.002 x CLcr (ml min-1)) and initial volume of distribution (1) was related linearly to body weight (proportionality constant: 0.327 +/- 0.014 x body weight (kg)). The intersubject variability in these two parameters was 32% and 3%, respectively, whilst the residual or intrasubject variability amounted to 21% of the tobramycin concentration. The terminal half-life of tobramycin, 26.6 +/- 9.4 h, was appreciably shorter than previously reported. 3. The population pharmacokinetic model was validated against data obtained from 34 independent patients and the predicted and observed concentrations were found to be in good agreement. The population pharmacokinetic model was used to design a priori dosing recommendations for tobramycin.