Therapeutic drug monitoring databases for postmarketing surveillance of drug-drug interactions.

Drug-drug interactions can be associated with patient morbidity due to either increased toxicity or a potentially ineffective concentration. Because interactions cannot always be anticipated during drug development and actual patients receiving a drug for therapeutic use often differ from those included in clinical trials, postmarketing surveillance is essential. Therapeutic drug monitoring (TDM) databases offer a unique opportunity in this respect. Prerequisites for TDM databases to provide valid information in a pharmacoepidemiological perspective include the following: precise description of exposure to the potentially interacting drugs; measurement of parent compound and active metabolites through accurate and precise analytical techniques; documentation of relevant patient characteristics that may act as confounding factors (e.g. gender, age, smoking habits); repeated assessments over time if possible; and sound pharmacokinetic framework for data selection, analysis and interpretation. The contribution of TDM to the documentation of drug-drug interactions takes advantage of different possible study designs, discussed on the basis of recently published studies. The single case report plays an important role as an alert signal. It is illustrated for a patient on long-term treatment, who displayed an unexpectedly high clozapine concentration after the introduction of ciprofloxacin comedication. The prospective on and off comedication panel study shows advantages in terms of carefully selected inclusion criteria and control of treatment modalities. A study of the thioridazine-fluvoxamine interaction is presented, with patients followed on thioridazine monotherapy, after introduction of fluvoxamine and after its discontinuation. The main advantage of the retrospective large-scale TDM database screen is representativeness of patients actually treated, whereas drawbacks are related to quality of data and suitability for valid interpretation. Such an approach is illustrated by a review of data collected over 10 years of routine TDM that allowed documenting induction of nortriptyline metabolism by carbamazepine and inhibition by several phenothiazines. Finally, population pharmacokinetics is well suited to observational data collected for TDM purpose, provided quality is ascertained. Focus is placed on interindividual variability and relationship between pharmacokinetic parameters and patient characteristics, including comedication. The population approach is discussed with respect to a study that documented a 32% increase of haloperidol clearance associated with anticonvulsant comedication, in addition to effects of age and bodyweight. Among factors to consider for improved effectiveness in the use of TDM databases for postmarketing surveillance of drug-drug interactions, integration of efficacy and safety data in future studies and communication of expert recommendations to prescribing physicians are essential.

Population pharmacokinetics of clomipramine, desmethylclomipramine, and hydroxylated metabolites in patients with depression receiving chronic treatment: model evaluation.

Because metabolites play a major role in the clinical response to clomipramine, the objective of the current study was to develop a population model and evaluate its performance to describe the pharmacokinetic profiles of clomipramine (C) and its active metabolites desmethylclomipramine (DC), 8-hydroxy-clomipramine (OHC) and 8-hydroxy-desmethylclomipramine (OHDC). A first sample of 14 patients served for development of a 2-molecule C and DC model, which was shown to provide reasonable estimates of AUC-based clearances, as well as precise estimation of interindividual variability. Simulated data, generated to mimic a semi-rich sampling design and chronic treatment with clomipramine, indicated that clearance estimation was feasible under routine treatment conditions. A second sample of 30 patients, recruited prospectively and followed for a median 4-week period, was used to extend the 2-molecule model to a 4-molecule model. Goodness-of-fit assessment revealed that model-predicted concentrations were reasonably close to observed concentrations for a majority of patients. Interindividual variability was 50% to 60% for hydroxylation and desmethylation clearances, and residual variability was 30%. The proposed model incorporates much of what is known about the metabolism of clomipramine and may valuably integrate the influence of genetic and environmental factors on each metabolic pathway.

Modelling during drug development.

With the advancement of both biological and computer sciences, new drug development faces the challenge to integrate a huge amount of knowledge accumulated from the very early quantitative structure-activity relationship investigations of the candidate molecule to the large scale clinical trials in patients. Whereas pharmacokinetics and pharmacodynamics are fields in which modelling has long demonstrated its value, its potential in many other areas of drug development has recently been the object of intensive scientific activity. The present review places emphasis on these newer applications; it includes the opinion of many experts in often highly specialised areas such as in vitro to in vivo extrapolation, toxicokinetics, non-continuous response models, population approaches and computer assisted simulation of clinical trials. It is most probable that in the near future many of these areas of research will be the objects of intensive and interesting developments. This will undoubtedly lead to improve developmental strategies for new drugs as well as more individualised pharmacological strategies for patients.

Cultural differences: implications on drug therapy and global drug development.

INTRODUCTORY REMARKS: Discussing the "inter-ethnicity" of kinetics and actions of drugs is fraught with terminology problems. It is, however, generally accepted that "ethnicity" covers the influences of factors genetically and culturally transmitted. The study of inter-ethnic variability in drug response addresses the problem of distinguishing variability factors that are common to one particular group of individuals from those which are not specifically shared. DIFFERENCES IN DAILY DOSES BETWEEN DIFFERENT GEOGRAPHIC REGIONS: It is well known that for a number of drugs, the daily dose prescribed in Japan is lower than in the US and Europe. Presently, independent surveys strongly indicate that for a majority of drugs dose differences are not the result of pharmacokinetic differences. In addition, they indicate that inter-ethnic differences do not seem to be larger than intra-ethnic variations. The differences observed for daily doses must thus be found elsewhere than in pharmacogenetic traits. DIFFERENCES IN DIAGNOSES: The most important impediments encountered in the evaluation of minority patients include differences with respect to language, communication style, cultural belief. The same problems arise if studies performed in different geographic areas are compared, socio-economic aspects play then an even greater role. Language problems arise differently if minorities are evaluated and compared to a majority of patients living in the same country or if clinical studies are performed in different regions. Communication styles also differ markedly between cultures. As an example, certain gestures may be considered as disrespectful or insulting by some ethnic groups and constitute normal behavior in others. RATING SCALES: Ethnicity clearly plays a role on the cross-cultural use of rating scales. Sophisticated rating scales established and validated in Western culture must undergo culturally sensitive revision and rigorous evaluation before their use in non-Western culture. EFFICACY-SAFETY ASSESSMENT: As an example, the assessment of risk and benefit is different in Japan, Europe and the United States. In Japan, safety is given a greater weighting relative to efficacy than in the two other regions. PLACEBO/NOCEBO EFFECTS: Placebo and nocebo effects are difficult to study, even in the absence of any cultural difference. They are even more so if ethnicity is concerned. PATIENT COMPLIANCE: Clinicians treating cross-cultural patients must carefully explore the beliefs held by their patient regarding illness causality and treatment expectations. CONCLUDING REMARKS: There are many unanswered questions in the field of inter-ethnic variability in drug response. The present overview will not pretend to have given specific answers, but it is hoped that it will point to some areas where more research is needed, in particular in the area of methodologies to take inter-ethnicity into account during drug development.

Clomipramine concentration as a predictor of delayed response: a naturalistic study.

OBJECTIVES: The aim of the present study was to characterise onset of response to clomipramine treatment in a naturalistic setting and to investigate the relationship between concentration and delayed response, postulated to reflect drug-specific response to antidepressant therapy. METHODS: Ninety-eight depressed patients were prescribed clomipramine in an open flexible manner and followed for depressive symptoms (Montgomery-Asberg depression scale) over a maximum 12 weeks follow-up period. All patients had at least one concentration measurement for therapeutic drug monitoring purpose. RESULTS: Firstly, survival analysis revealed a probability of 15.4% for patients not to show 50% improvement over baseline by week 12, and thus to be considered as non-responders. Median time to onset of response was 31 days for responders, indicating a relatively high probability of delayed response under routine treatment. Secondly, pattern analysis indicated a significant association between early and abrupt response on the one hand and delayed and gradual response on the other. A tendency towards an association between delayed and persistent response was also observed. Finally, receiver operating characteristics analysis allowed identification of a highly significant lower threshold of 230 ng x ml(-1) for the sum of clomipramine and desmethyl-clomipramine, as measured at week 3, with respect to response from week 3 onward. Predictive values were 68.8% and 81.0% for concentrations above and below this threshold to predict delayed response and non-response, respectively. Thresholds were 55 ng x ml(-1) for parent compound and 180 ng x ml(-1) for metabolite. CONCLUSION: This approach supports the hypothesis that delayed response may be concentration dependent and thus may reflect true drug effect. As a consequence, monitoring clomipramine concentration about 3 weeks after initiation of therapy may valuably contribute to help clinicians decide about the adequacy of ongoing therapy.

Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: reappraisal of interindividual variability factors.

Because of the enormous gap between premarketing studies in physically healthy subjects and clinical practice in patients, the present study reconsidered interindividual variability factors affecting risperidone concentrations under routine therapeutic drug monitoring conditions. The study included 92 patients, 27% of whom were 70 years or older. The patients received risperidone orally (dose range, 0.5-11 mg per day) and had concentrations of risperidone and the active metabolite 9-hydroxyrisperidone measured at steady state by a new, rapid, and sensitive method of high-performance liquid chromatography (HPLC). After normalization to a dose of 4 mg/day, median concentrations were 2.9 ng/ml (80% range, 0.9-27.9 ng/ml) for the parent compound and 24.1 ng/ml (80% range, 12.0-57.6 ng/ml) for the metabolite. When considering linear regression models, age was identified as a major source of interindividual variability, with expected increases of 340% and 220% for concentrations of parent compound and metabolite, with age increasing from 20 to 80 years. Body weight provided an additional significant contribution to the variability of 9-hydroxyrisperidone concentration, a 20-kg higher body weight associated with a concentration decrease of 23%. Serotonin-specific reuptake inhibitor (SSRI) comedication (fluoxetine, two patients; citalopram, two patients; paroxetine, one patient; fluvoxamine, one patient) was significantly associated with 4.6-fold higher concentrations of parent compound, in keeping with an inhibitory action on CYP2D6 enzyme. Significantly higher concentrations of 9-hydroxy-risperidone (+ 29%) were also observed in the 17 patients with biperiden comedication. Therapeutic drug monitoring data, collected in patients representative of the population for which the drug was intended, allowed us to quantify the dose reduction needed in elderly patients and thus provided valuable information in addition to the one collected during premarketing studies performed with strict inclusion and exclusion criteria.

Optimized release of dexamethasone and gentamicin from a soluble ocular insert for the treatment of external ophthalmic infections.

In the case of external ophthalmic infections, repeated instillations of antibiotics are required to reach therapeutic level, above the minimal inhibitory concentration (MIC). An additional administration of a corticosteroid is often needed, in order to limit the precorneal damages caused by the infection. However, repeated administration of a corticosteroid can increase intraocular pressure and thus lead to glaucoma. To overcome the disadvantages of separated and repeated instillations of two products and to avoid the side effects of dexamethasone, a soluble insert containing gentamicin sulfate and dexamethasone phosphate was developed. The new system ensures the concomitant release of the two drugs during the first 10 h of treatment, followed by an adequate concentration of gentamicin sulfate, above the MIC of 4.0 microgram ml-1, during 50 h, due to a combination of gentamicin sulfate with cellulose acetate phthalate, which reduces the solubility of gentamicin.

Therapeutic drug monitoring databases for postmarketing surveillance of drug-drug interactions: evaluation of a paired approach for psychotropic medication.

The present study investigated the potential of therapeutic drug monitoring data to document pharmacokinetic drug interactions with psychotropic medication, both in terms of methodology and applicability. It focused on 105 patients exposed to one of five agents known for their capacity to induce (phenytoine, phenobarbital, and carbamazepine) or to inhibit (thioridazine and levomepromazine) the metabolism of psychotropic drugs. These patients were matched by gender, age, and monitored psychotropic medication to 105 patients randomly selected from a pool of subjects nonexposed to target comedication. Such a paired approach was shown to be effective in reducing variability for a majority of substances. Power analysis suggested that eight to 10 pairs of exposed and nonexposed patients would effectively allow the detection of twofold effects of interacting substances. In keeping with the literature, analysis of the ratios of dose-normalized exposed to nonexposed concentrations indicated that phenothiazine comedication led to significantly higher concentrations of desmethylated metabolites but not parent compounds, when clomipramine, imipramine, or amitriptyline were administered. A similar, as yet undocumented interaction was observed for the tetracyclic antidepressant mianserine. In contrast, the present study revealed that maprotiline concentrations were increased, but its metabolite was largely unaffected by phenothiazine comedication. Increased concentrations were also observed for moclobemide, but not citalopram or its metabolite. In addition to its long recognized capacity to decrease haloperidol concentrations, carbamazepine was shown to induce the metabolism of clopenthixol and possibly flupenthixol. The consistency of such a picture substantiates the need to consider therapeutic drug monitoring databases as cost-effective and reliable tools for postmarketing surveillance.

Drug metabolism as a confounding factor in PK/PD population approaches.

Pharmacokinetic/pharmacodynamic population approaches aim at establishing relationships between dose, drug concentration of active principles and clinical response, accounting for factors responsible for inter-individual variability. Additional difficulties in the presence of metabolites include the need to decide a priori which metabolites should be monitored according to their respective role in efficacy and/or toxicity, the need to select appropriate selective analytical methods, and the requirement for more complex pharmacokinetic and/or pharmacodynamic models. These points are discussed more extensively for psychotropic drugs, and in particular for the active metabolites of phenothiazines, for reduced haloperidol, for the desmethylated and hydroxylated metabolites of tricyclic antidepressants, and for the desmethyl metabolites of the serotonin-specific reuptake inhibitors fluoxetine and citalopram.

Therapeutic drug monitoring and drug-drug interactions: a pharmacoepidemiological perspective.

The present study investigates the potential of therapeutic drug monitoring databases to document co-medication as a possible risk factor for subtherapeutic or excessively high concentrations of psychotropic drugs. Exposure was defined with respect to co-medication including one of five agents known for their capacity to induce (phenytoin, phenobarbital and carbamazepine) or to inhibit (thioridazine and levomepromazine) the metabolism of psychotropic drugs. 87 patients exposed to such co-medication were matched by sex, age and monitored psychotropic medication with 87 patients randomly selected from a pool of subjects whose co-medication did not include any substance known to interact. Outcome was defined with respect to dose-normalized concentrations being below or above therapeutic range. When taking all psychotropic drugs together, the estimated relative risk to reach concentrations above the therapeutic range was 7.8 for patients exposed to phenothiazine co-medication. The relative risk to remain at subtherapeutic level was 2.7 for patients with inducers. When considering the different psychotropic drugs separately, a coherent picture was observed, with increased risk ratios for all substances.

Investigation of xenobiotic metabolism by CYP2D6 and CYP2C19: importance of enantioselective analytical methods.

Investigations into the genetic polymorphism of drug metabolism have involved specific models to screen poor and extensive metabolisers of xenobiotics. Debrisoquine, sparteine, S-mephenytoin and dextromethorphan are particularly well known. They have been extensively described in the literature and are used to phenotype human subjects before performing investigations with new drugs which are believed to be under the control of a genetic polymorphism. Dextromethorphan, debrisoquine and sparteine are good substrates for CYP2D6, whereas the S-enantiomer of mephenytoin is a good substrate for CYP2C19, both being two isozymes of cytochrome P-450. In many drugs, the hepatic microsomal oxidative metabolism involving stereogenic centres congregates either with CYP2D6 or with CYP2C19 or, in certain cases, with both of them. The availability of both CYP2D6 from poor and extensive metabolisers and an enantioselective assay would allow genetic polymorphism in drug biotransformation to be investigated in vitro ex vivo at an early stage of drug development before the IND (investigational new drug). Single-dose investigations in vivo can also be performed when only minimal pre-clinical toxicological data are available and produce more reliable results than in vitro studies. This paper focuses on the problem of genetic polymorphism in drug development and specifically discusses some relevant knowledge gained in the last two decades on enantioselective bioassays. Specific examples are given.

New alterations of serum glycoproteins in alcoholic and cirrhotic patients revealed by high resolution two-dimensional gel electrophoresis.

Plasma protein are synthesized and secreted by the liver. Several reports have shown that excessive consumption of ethanol interferes with the hepatic protein synthesis and/or secretion. This study was undertaken to identify the plasma/serum proteins altered in two groups of patients with different alcohol-related diseases: actively drinking alcoholic patients group without liver disease and alcohol cirrhotic patients group. Two-dimensional gel electrophoresis was used to separate proteins with high resolution. Proteins were detected by silver staining and glycoproteins were specifically visualized and analyzed after lectin blotting followed by chemiluminescence detection. Different protein alterations were identified in each group of patients. In the alcoholic group, two new glycosylation modifications of serum proteins were identified. An abnormal microheterogeneity of haptoglobin and alpha1-antitrypsin was detected in the serum of all alcoholic patients. We also characterized by two-dimensional gel electrophoresis the carbohydrate deficient transferrin. The modifications of haptoglobin, alpha1-antitrypsin and transferrin present a similar change of charge and molecular weight in the two-dimensional gel electrophoresis pattern. These qualitative estimations support the hypothesis of a general mechanism of liver glycosylation alteration of serum proteins induced by excessive alcohol consumption. The immunoglobulin alterations were easily visualized and identified for the cirrhotic and the alcoholic patients. And finally, the decrease of haptoglobin and albumin spots for cirrhotic patients was confirmed.

The use of population pharmacokinetics in drug development.

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.

Antidepressants and drug-metabolizing enzymes--expert group report.

Antidepressant drugs are extensively metabolized. Consequently, the biotransformation pattern of antidepressants has an important influence on their clinical properties, i.e., pharmacokinetics, toxicity, drug-drug interactions, side-effect profile and last but not least therapeutic efficacy. It was against this background that a multidisciplinary group of experts discussed the clinical relevance of the rapidly increasing body of knowledge of antidepressant-metabolizing enzymes. The variability of the response of a given individual to an antidepressant is determined genetically and by the environment. Genetic polymorphism of drug-metabolizing enzymes and inhibition by other substrates may affect the enzymatic biotransformation of antidepressants. In vitro assay techniques allow an estimation of the potential variability in clinical response to antidepressants and a reasonable prediction of the drug-drug interaction patterns. The results of in vitro tests should therefore be considered early in the development of an antidepressant as a background for designing clinical studies (treatment schedules and dosing). Physicians should have an understanding of the relevance of genetic polymorphism for clinical practice. Education is needed in order to fill the existing gaps in knowledge about antidepressant-enzyme interactions and their application in daily treatment practice. The information on potential drug interactions determined by genetic polymorphism and based on studies with enzymes should be increasingly contained in drug compendia.

Practical experience and issues in designing and performing population pharmacokinetic/pharmacodynamic studies.

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.

Metabolic interaction between fluoxetine and clomipramine: a case report.

An 83-year-old patient suffering from a depressive episode was treated with a combination of clomipramine and fluoxetine. As no marked improvement was observed and cardiac side-effects were observed, a blood sample was taken for therapeutic drug monitoring. The result showed that the concentrations of clomipramine and desmethylclomipramine were very high (i.e. in the subtoxic range). A metabolic interaction was suspected and both antidepressants were immediately discontinued. Over time, concentrations of clomipramine and its metabolite decreased slowly and, simultaneously, the mood improved and side-effects disappeared. When clomipramine and desmethylclomipramine concentrations reached the lower limit of the optimal therapeutic range, monotherapy was restarted with clomipramine, and the patient improved enough to be discharged from the hospital.

Ocular availability of gentamicin in small animals after topical administration of a conventional eye drop solution and a novel long acting bioadhesive ophthalmic drug insert.

PURPOSE: Gentamicin eye drop solutions have a short precorneal residence time. The present study investigates the effect of gentamicin using a new long acting delivery Bioadhesive Ophthalmic Insert (BODI) in healthy dogs and rabbits and compares the results with a conventional regimen using an eye drop solution. METHODS: In vivo assays were performed on animals after deposition of one BODI and instillations of an eye drop solution. Tear samples were collected over 72 hours and 60 minutes, in the case of inserts and eye drop solution respectively. The gentamicin concentration profiles in tear fluid (determined by a fluorescent polarization immunoassay technique) was individually analyzed, in each animal, in relation with the minimum inhibitory concentration observed in vitro against some bacteria. A non classical pharmacokinetic approach was used for the analysis of the topically applied drug substance, involving two parameters: the efficacy area under the curve (AUCeff) and the efficacy time (teff). RESULTS: In the case of the eye drop solution, the AUCeff were higher in dogs (2.80 10(3) - 3.64 10(3) [micrograms ml-1 h]) than in rabbits (0.64 x 10(3) - 0.95 x 10(3) [micrograms ml-1 h]); the teff had a similar behavior: 6-15 [h] in dogs and 2-6 [h] in rabbits. In the case of BODIs, the AUCeff and the teff were quite similar between dogs and rabbits: 190 10(3) - 205 10(3) [micrograms ml-1 h] and 70-76 [h], respectively. The AUCeff and the teff were always much higher in the case of BODIs than for the eye drop solution both in dogs and rabbits. CONCLUSIONS: This study shows that topical administration of gentamicin using BODIs can improve treatment due to the decreasing number of applications while ensuring an effective level of antibiotic in tears controlled by the device.

Human blood platelet protein map established by two-dimensional polyacrylamide gel electrophoresis.

Two-dimensional (2-D) maps of cytosol and enriched-membrane platelet proteins has allowed the identification of more than 25 spots by three different methods: matching of the platelet gels with other 2-D reference maps, immunoblotting with chemiluminescence detection, and N-terminal sequencing. Different G protein (guanosine triphosphate-binding protein) subunits, cytoskeletal proteins, and proteins common to the human liver, red blood cells and plasma were identified. The two platelet protein maps presented here contribute to the project of identification of human cell and body fluid proteins. They may serve as working tools since platelets are popular models for the study of central nervous system neurotransmitter systems and stimulus-response coupling mechanisms.

Potential of concentration monitoring data for a short half-life drug: analysis of pharmacokinetic variability for moclobemide.

The pharmacokinetic variability of moclobemide, a new short half-life reversible selective inhibitor of monoamine oxidase (MAO) was investigated through analysis of concentrations measured during early open clinical use. Eighty-nine depressed patients, aged 21-96 years, were included in the present study. Doses ranged from 200 to 900 mg/day, and the time interval between blood sampling and last drug intake on the previous day was between 8 and 23 h. Intraindividual variability was generally moderate, with a few patients displaying consistently high concentrations despite moderate doses. Interindividual variability for measured concentrations was approximately 300-fold. After concentration decrease with time was taken into account (average half-life estimate of 4.6 h), age was identified as a major factor responsible for between-patient variability. Average concentration increase per decade of age was 38%. Neither gender, weight, height, smoking, nor alcohol intake explained a significant additional part of the variance. Analysis of residuals also suggested that phenytoin co-medication may induce moclobemide metabolism. The present study indicates that concentration monitoring of a newly marketed drug can contribute to gaining insight into its pharmacokinetic behavior and to enhancing its rational use in clinical practice.

Bioequivalence. An updated reappraisal addressed to applications of interchangeable multi-source pharmaceutical products.

This paper reviews study procedures for bioequivalence trials, mainly addressed to the New Drug Application (NDA) of generic drugs, strictly referring to EU and USA guidelines on this matter. Specific attention is devoted to the most appropriate experimental designs, the size of the volunteer sample, the ethical issues involved, statistics to assess bioequivalence and the accepted standard format for final research reports. Some aspects which create serious problems in bioequivalence trials, most of which not fully covered by the EU and USA specific guidelines, are comprehensively discussed. These include a) drugs with elevated variability; b) endogeneous substances and the management of baseline value; c) modified release formulations; d) prodrugs; e) restrictions to be contained in forthcoming guidelines on chiral medicinal products; f) superbioavailability; g) drugs with elevated half-life and h) cases in which bioequivalence trials should not be needed. As generic drugs cost less than the innovator product, agencies have facilitated their NDA procedures by requiring a dossier on chemistry and pharmacy and a pivotal bioequivalence study to demonstrate that the generic formulation is fully interchangeable with the innovator product. Bioequivalence is thus the key requirement for an NDA of a generic drug, and trials should be planned, conducted and reported in the most appropriate way. With this in mind, this review is an up-to-date reappraisal that should stimulate the attention of scientists and regulatory authorities on some open questions on bioequivalence.