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1. The neuropharmacokinetics of antipyrine, a readily dialysable drug, in rat frontal cortex were studied and the effect of sampling time and contribution of period sampling and dialysate dead volume investigated in relation to tmax, Cmax, AUC and t1/2 values. 2. After i.p. administration, antipyrine (35 mg kg-1, n = 5) concentrations rose rapidly in rat frontal cortex (tmax, 12 min) and then declined exponentially tmax, Cmax, AUC and t1/2 values were determined after 2 min dialysate sampling and compared to values obtained from simulated sampling times of 4, 6, 8, 10 and 20 min. 3. Antipyrine tmax and Cmax values were directly dependent on sampling frequency. Thus, mean 2 min sampling tmax and Cmax values were 63% lower and 27% higher, respectively, compared to 20 min sampling values. AUC and t1/2 values were unaffected. 4. Adjustment for dialysate dead volume (the volume of dialysate within the dialysis probe and sampling tube) reduced tmax values significantly but did not affect the other neuropharmacokinetic parameters. 5. Contribution of period sampling on neuropharmacokinetic parameters were investigated by comparing plots of antipyrine concentration data at midpoint and at endpoint of sampling time interval. Only tmax values were affected with values decreasing with increasing sampling time interval. 6. In conclusion, although microdialysis is a useful method for monitoring events at the extracellular level and for kinetic studies, it is important to understand its inherent characteristics so that data can be interpreted appropriately. Sampling frequency, particularly during monitoring of periods of rapid change, is very important since Cmax and tmax values will be significantly underestimated and overestimated respectively, if sampling time is longer rather than shorter. These considerations are particularly important in relation to microdialysis studies of pharmacokinetic-pharmacodynamic interrelationships and modelling.

Most anaesthetists using target-controlled infusion systems will have observed that the calculated effect-site concentration at loss of consciousness is usually higher than the concentration at emergence. Inertia is the ability of biological systems to keep a functional state at rest or in activity and is an active process of resistance to change in state. Hysteresis is a phenomenon whereby the value of a physical property lags behind changes in the effect that is causing it and this is also seen in anaesthesia pharmacology. Recently, a phenomenon called neuronal inertia has been proposed when trying to explain the resistance observed to changes in consciousness induced by general anaesthesia, independent of drug kinetics. This review discusses the existence of this phenomenon and the conceptual and practical impact it may have on induction and recovery from general anaesthesia.

Some pharmacodynamic (PD) models, called K-PD models, have been developed for the description of drug action kinetics in the absence of drug concentration measurements. Because blood samples for drug measurements are not needed, these models may be very useful in pediatric studies, by reducing their invasiveness. In addition, a number of PD measurements are also non-invasive and specific devices exist for measures in children. Therefore, the kinetics of drug action may be characterized with minimal invasiveness. A brief description of the key features of these models is given, and a number of examples of application are presented. K-PD models are expected to be most useful when the drug kinetics is simple (i.e. when the one-compartment model is a reasonable description), or when the response kinetics is slow compared with drug kinetics. K-PD models have already demonstrated their usefulness in animal and adult studies. They are very attractive for pediatric studies and they should facilitate the assessment of drug efficacy and safety.

A workshop was conducted on November 18?19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

Splenectomy does not influence the ESF-response in erythraemic mice after a single i.v. administration of less than 2.0 IRP-units of ESF. A significantly smaller response, however, is observed in splenectomized mice than in sham operated animals when ESF-doses larger than 2.0 IRP-units are administered. Comparison of the ESF-dose-response in ESF-prestimulated, splenectomized or sham operated mice with that of non-prestimulated controls indicates that ESF leads to an increase in the number of primitive erythropoietin-responding cells, and that this increase mainly, if not exclusively, takes place in the spleen. Although the number of primitive erythropoietin-responding cells does not increase in splenectomized mice following stimulation with ESF, divided administration of large ESF-doses to such animals causes a moderate but significant increase in the dose-response as compared to that of un-divided administration. As ESF is eliminated exponentially, divided administration of a large ESF-dose will increase the ‘stimulation time’, i.e. the time during which the dose is effective. A mathematical expression for the ‘stimulation time’ as a function of the dose and the number of fractions used for administration of the dose is advanced. It is suggested that an extension of the ‘stimulation time’ explains the enhanced response observed after fractionated administration of ESF to splenectomized animals. It is concluded that the substantial increase in ESF-response obtained by fractionated administration of ESF to erythraemic mice with intact spleen is caused partly by an extension of the ESF-stimulation-time and partly by an increase in the number of erythropoietin-responding cells induced by the first fraction of the dose.

Summary 1 Utilizing a general stochastic theory of drug kinetics we have demonstrated that from the serum concentration curve derived from a single dose of lithium, it is possible to predict the steady state concentration, the time required to reach steady state, the dependency of these quantities on the time interval between drug administrations and the fluctuations in plasma level under steady state conditions. 2 It has been shown in general that the more frequently the drug is administered the higher is the steady state level, the shorter is the time required to reach steady state, and the smaller are the fluctuations.

Although approximately 10%-15% of patients with idiopathic generalized epilepsy (IGE)/genetic generalized epilepsy remain drug-resistant, there is no consensus or established concept regarding the underlying mechanisms and prevalence. This review summarizes the recent data and the current hypotheses on mechanisms that may contribute to drug-resistant IGE. A literature search was conducted in PubMed and Embase for studies on mechanisms of drug resistance published since 1980. The literature shows neither consensus on the definition nor a widely accepted model to explain drug resistance in IGE or one of its subsyndromes. Large-scale genetic studies have failed to identify distinct genetic causes or affected genes involved in pharmacokinetics. We found clinical and experimental evidence in support of four hypotheses: (1) "network hypothesis"-the degree of drug resistance in IGE reflects the severity of cortical network alterations, (2) "minor focal lesion in a predisposed brain hypothesis"-minor cortical lesions are important for drug resistance, (3) "interneuron hypothesis"-impaired functioning of γ-aminobutyric acidergic interneurons contributes to drug resistance, and (4) "changes in drug kinetics"-genetically impaired kinetics of antiseizure medication (ASM) reduce the effectiveness of available ASMs. In summary, the exact definition and cause of drug resistance in IGE is unknown. However, published evidence suggests four different mechanisms that may warrant further investigation.

Background Prescription information for many drugs entering the market lacks dosage guidance for hepatic impairment. Dedicated studies for assessing the fate of drugs in hepatic impairment commonly stratify patients using Child-Pugh score. Child-Pugh is a prognostic clinical score with limitations in reflecting the liver's metabolic capacity. Aims To demonstrate the need for better drug dosing approaches in hepatic impairment, summarise the current status, identify knowledge gaps related to drug kinetic parameters in hepatic impairment, propose solutions for predicting the liver disease impact on drug exposure and discuss barriers to dosing guidance in those patients. Methods Relevant reports on dosage adjustment in hepatic impairment were analysed concerning the prediction of the impairment impact on drug kinetics using physiologically-based pharmacokinetic (PBPK) modelling. Results PBPK models are suggested as a potential framework to understand drug clearance changes in hepatic impairment. Quantifying changes in abundance and activity of drug-metabolising enzymes and transporters, understanding the impact of shunting, and accounting for interindividual variations in drug absorption could help in extending the success of these models in hepatically-impaired populations. These variables might not correlate with Child-Pugh score as a whole. Therefore, new metabolic activity markers, imaging techniques and other scoring systems are proposed to either support or substitute Child-Pugh score. Conclusions Many physiological changes in hepatic impairment determining the fate of drugs do not necessarily correlate with Child-Pugh score. Quantifying these changes in individual patients is essential in future hepatic impairment studies. Further studies assessing Child-Pugh alternatives are recommended to allow better prediction of drug exposure.

The interpretation of acute abuse liability studies and drug interaction studies would be importantly strengthened by the routine inclusion of drug concentration measurements at appropriate sampling times. Reliance on mean kinetic data misrepresents the variation in drug kinetics and fails to take experimental advantage of the natural differences in the population which may represent the extremes of abuse risk. Pharmacokinetic-pharmacodynamic studies to better understand the relationship of plasma drug concentration, drug concentration in the receptor biophase and specific drug reinforced behaviour will ensure proper study design and yield useful theoretic information. Multi- and poly-drug abuse (including heavy smoking and heavy ethanol use) are very common. Such patterns of use can have quite large effects on drug kinetics. Because of the potentially large qualitative and quantitative differences in drug metabolism and kinetics between pre-clinical species and the human, data should be gathered at the earliest possible time with respect to human metabolic rates, patterns, and identification of inhibitors. The availability of human liver microsomes facilitates such studies.

The late 1950s and early 1960s witnessed a dramatic change in the practice of medicine. At this time many drugs were introduced into the clinic which for the first time allowed the effective treatment of many common diseases such as hypertension, angina pectoris, depression, schizophrenia, carcinomas and leukaemias to name only a few. Right from the beginning of modern drug therapy, it was observed that there was substantial variability among patients both in therapeutic efficacy and the occurrence of side-effects. The realization that dose was a poor predictor of therapeutic response raised the curiosity of clinicians and pharmacologists in elucidating the mechanisms responsible. This was the starting point for the development of clinical pharmacology. Of great importance for clinical pharmacology was the work carried out by the groups of R. T. Williams at St Mary's Hospital and B. B. Brodie in the Laboratory of Chemical Pharmacology at the NIH who pioneered the work on drug metabolism. The discovery of drug-metabolizing enzymes and realizing that their activity determined the rate at which drugs were eliminated from the body was instrumental for our understanding of why patients respond differently to the same dose of a drug. In a number of elegant studies, B. B. Brodie and coworkers showed that species differences in the duration of hexobarbitone action after administration of the same dose were not due to differences in sensitivity but a consequence of pronounced species differences in the rate of biotransformation of hexobarbitone. Moreover, he showed that the blood concentration at the time of awakening was very similar among the various species and in man. It is still worth reading his famous Toral Sollmann Award lecture Of Mice, Microsomes and Man at the ASPET Meeting (August 13, 1963 In this lecture, many principles that can account for variability in drug response between animals and humans were put forward. The concept that drug effects are not related to the dose administered but rather the plasma concentration achieved, and that in analogy to species differences, patient-to-patient variability in response can be explained by different plasma concentrations, was instrumental for clinical pharmacology. Rather than giving a detailed account on the progress being made, I would like to focus on Alasdair Breckenridge's contribution to the field of drug metabolism. It is in the area of drug metabolism and especially in understanding the various factors that could affect the activity of drug-metabolizing enzymes where Alasdair Breckenridge has made substantial contributions to clinical pharmacology throughout his professional career. His interest was not restricted to the experimental findings but to explore the consequences of his results for drug action and side-effects in patients. It is a persistent feature of his work that observation of a clinical problem led him to carry out experimental work to understand the mechanisms responsible and then to test the hypothesis generated in his laboratory experiments in the clinical setting. His initial work in the area focused on the importance of drug metabolism for interindividual differences in drug kinetics as this was identified at this time as a major source of variability in response [4, 7, 11]. This work was consequently extended to the clinical setting when the role of pathophysiological factors influencing drug kinetics was studied [8]. At the same time that all the new drugs were introduced into clinical medicine, it was realized that coadministration of two or more drugs could result either in an increased or a diminished drug action, a phenomenon termed drug interaction. It was soon realized that changes in drug metabolism were a major mechanism due to either inhibition or induction of drug-metabolizing enzymes [4, 10]. Particularly in the case of the oral anticoagulant warfarin, these metabolic interactions had detrimental consequences for the patients. It was Alasdair Breckenridge and his coworkers who were at the forefront, and made major contributions to our understanding of warfarin interactions [1, 4]. In addition, in work carried out together with Edgar Ohnhaus, Alasdair not only explored the role of rifampicin in the induction of drug-metabolizing enzymes but also its physiological functions. They demonstrated for the first time that induction by rifampicin increased liver blood flow substantially [13]. Although the clinical importance of drug interactions have been recognized and the principal mechanism elucidated many years ago, they continue to be a relevant problem. Every year drug interactions lead to the withdrawal of medicines from the market. In the 1980s, chirality of drug action and disposition became a big issue in clinical pharmacology, industry and regulatory agencies. It was the late pharmacologist E. J. Ariens who questioned the use of racemates by phrasing it this way: ‘Consumers have long been asking for clean water and clean food. Next they will ask for clean drugs’. He was referring to the situation that, in contrast to drugs derived from natural sources which are usually administered as pure enantiomers, most of the drugs produced by chemical synthesis are racemates, e.g. a 50 : 50 mixture of two enantiomers. Because the enantiomers contained in racemates quite often differ both in qualitative and quantitative terms in their pharmacological activity and kinetic behaviour two drugs are in fact being administered. Thus in the case were one enantiomer is much less potent then the other, Ariens considered this enantiomeric ballast,which was responsible for adverse effects of racemates [1]. This two-faced nature of racemates and its consequences for drug action and disposition, especially in the context of drug interactions with warfarin, was already realized by Alasdair and his group in the early 1970s. In 1973, in a classical work with warfarin they studied the kinetics and dynamics of R- and S-warfarin demonstrating that they behaved quite differently [6]. Moreover they showed that the R and S enantiomer were metabolized by different routes. By applying this knowledge, they could explain the paradoxical observation that there were drug interactions with warfarin that caused a dramatic increase in the anticoagulatory effect without affecting the drug concentrations. Based on a careful analysis of the kinetics and of the metabolites formed from R- and S-warfarin, the hypothesis was put forward that phenylbutazone affected the metabolism of R- and S-warfarin in opposite directions, i.e. inhibition of S- and induction of R-warfarin clearance. They also realized and demonstrated that changes in protein binding, which at that time were considered as the mechanism responsible for the phenylbutazone–warfarin interaction, were unlikely [9, 12]. In the late 1970s and early 1980s our understanding of drug metabolism and its contribution to presystemic elimination changed. At this time it was increasingly recognized that in addition to the liver, gut wall was an important site of drug metabolism. Again Alasdair Breckenridge was active in the field right from the beginning, studying the contribution of gut wall to the presystemic metabolism of ethinyloestradiol and norethindrone. In these studies he and his coworkers showed that there was substantial conjugation by the gut wall of these drugs and outlined that this accounted for the rather low oral bioavailability of this class of compounds [2, 3, 10]. Since that time, our understanding of the processes involved in the absorption, distribution, metabolism and elimination of drugs has advanced substantially, especially in the area of drug absorption, which until recently had been considered a passive process depending on dissolution of the drug preparation, particle size, physical chemical properties such as lipophilicity and the pKa of the drug. It is now known that this process is controlled by active transport. In summary, this brief overview demonstrates the progress that has been made in drug metabolism during Alasdair Breckenridge's professional career. It shows the constant progress that has been made over the years by adding more and more details to give a very complex picture that at the beginning was a rather simple sketch. Clinical pharmacology owes Alasdair Breckenridge much for the many valuable pieces he has contributed in creating this picture.

Aims One barrier contributing to the lack of pharmacokinetic (PK) data in paediatric populations is the need for serial sampling. Analysis of clinically obtained specimens and data may overcome this barrier. To add evidence for the feasibility of this approach, we sought to determine PK parameters for fentanyl in children after cardiac surgery using specimens and data generated in the course of clinical care, without collecting additional blood samples. Methods We measured fentanyl concentrations in plasma from leftover clinically-obtained specimens in 130 paediatric cardiac surgery patients and successfully generated a PK dataset using drug dosing data extracted from electronic medical records. Using a population PK approach, we estimated PK parameters for this population, assessed model goodness-of-fit and internal model validation, and performed subset data analyses. Through simulation studies, we compared predicted fentanyl concentrations using model-driven weight-adjusted per kg vs. fixed per kg fentanyl dosing. Results Fentanyl clearance for a 6.4 kg child, the median weight in our cohort, is 5.7 l h–1 (2.2–9.2 l h–1), similar to values found in prior formal PK studies. Model assessment and subset analyses indicated the model adequately fit the data. Of the covariates studied, only weight significantly impacted fentanyl kinetics, but substantial inter-individual variability remained. In simulation studies, model-driven weight-adjusted per kg fentanyl dosing led to more consistent therapeutic fentanyl concentrations than fixed per kg dosing. Conclusions We show here that population PK modelling using sparse remnant samples and electronic medical records data provides a powerful tool for assessment of drug kinetics and generation of individualized dosing regimens.

The mechanisms of absorption, distribution, metabolism and elimination of small and large molecule therapeutics differ significantly from one another and can be explored within the framework of a physiologically based pharmacokinetic (PBPK) model. This paper briefly reviews fundamental approaches to PBPK modeling, in which drug kinetics within tissues and organs are explicitly represented using physiologically meaningful parameters. The differences in PBPK models applied to small/large molecule drugs are highlighted, thus elucidating differences in absorption, distribution and elimination properties between these two classes of drugs in a systematic manner. The absorption of small and large molecules differs with respect to their common extravascular routes of delivery (oral versus subcutaneous). The role of the lymphatic system in drug distribution, and the involvement of tissues as sites of elimination (through catabolism and target mediated drug disposition) are unique features of antibody distribution and elimination that differ from small molecules, which are commonly distributed into the tissues but are eliminated primarily by liver metabolism. Fundamental differences exist in the ability to predict human pharmacokinetics based upon preclinical data due to differing mechanisms governing small and large molecule disposition. These differences have influence on the evolving utilization of PBPK modeling in the discovery and development of small and large molecule therapeutics.

Obtaining pharmacokinetic data from the intravenous route for drugs intended for oral administration has traditionally been expensive and time consuming because of the toxicology requirements and challenges in intravenous formulations. Such studies are necessary, however, particularly when regulator agencies request absolute bioavailability data. A method has emerged whereby the drug administered intravenously is isotopically labeled and dosed at a maximum of 100 µg concomitantly with an oral administration given at a therapeutically relevant level. The intravenous administration has been termed a microtracer and obviates intravenous toxicology requirements as well as simplifying formulations. The study design also essentially removes issues of nonlinear pharmacokinetics that may occur when oral and intravenous doses are administered separately. This review examines the methodology and the literature to date, including those studies intended for regulatory submission. The method has been extended to the study of prodrug-to-active drug kinetics and to obtaining clearance, volume of distribution, and absolute bioavailability at steady-state conditions.

Dichloroacetate (DCA) is biotransformed by glutathione transferase zeta 1 (GSTZ1), a bifunctional enzyme that, as maleylacetoacetate isomerase (MAAI), catalyzes the penultimate step in tyrosine catabolism. DCA inhibits GSTZ1/MAAI, leading to delayed plasma drug clearance and to accumulation of potentially toxic tyrosine intermediates. Haplotype variability in GSTZ1 influences short-term DCA kinetics in healthy adults, but the impact of genotype in children treated chronically with DCA is unknown. Drug kinetics was studied in 17 children and adolescents with congenital mitochondrial diseases administered 1,2-(13) C-DCA. Plasma drug half-life and trough levels varied 3-6-fold, depending on GSTZ1/MAAI haplotype and correlated directly with urinary maleylacetone, a substrate for MAAI. However, chronic DCA exposure did not lead to progressive accumulation of plasma drug concentration; instead, kinetics parameters plateaued, consistent with the hypothesis that equipoise is established between the inhibitory effect of DCA on GSTZ1/MAAI and new enzyme synthesis. GSTZ1/MAAI haplotype variability affects DCA kinetics and biotransformation. However, these differences appear to be stable in most individuals and are not associated with DCA plasma accumulation or drug-associated toxicity in young children.

Cefotaxime powder was diluted with sterile water to a concentration of 100 mg/mL. The volume of solution was adjusted for each experimental horse to provide a total dose of 15, 20, and 25 mg/kg and was administered by infusion through a jugular vein catheter over a 10-min period. All three doses were administered to each of the six experimental horses at three different times. Cefotaxime concentrations in plasma and synovial fluid samples were measured by high-performance liquid chromatography (HPLC). Standard compartmental analysis techniques and the WINSAAM modeling program were used to determine standard pharmacokinetic parameters for cefotaxime. The plasma and synovial fluid data from the five horses administered the 2 5 mg/kg dose was analyzed. Plasma cefotaxime concentrations appeared to be linearly related to dose infused and declined in parallel, suggesting linear drug kinetics. Moreover, cefotaxime concentrations declined monotonically suggesting that its disposition kinetics could essentially be described by a one-compartment model rather than the fact that sampling occurred after the infusion was discontinued. Maximum concentration of cefotaxime in plasma occurred immediately after cessation of the infusion. Minimum inhibitory concentrations were determined for Staphylococcus aureus. Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, common isolates from septic arthritis in horses. Based on our pharmacokinetic data, a regimen of 25 mg/kg administered i.v. every 6 h appears appropriate for susceptible joint infections in adult horses.

SUMMARY 1. An acute in vivo hindlimb skeletal muscle preparation was developed in anaesthetized sheep in order to facilitate studies of the effects of altered blood flow states on drug kinetics in skeletal muscle. 2. A continuous index of blood flow was recorded via ultrasonic Doppler probes on the femoral artery and vein. Skeletal muscle effluent blood was sampled via a catheter in the femoral vein proximal to the probe. Low- and high-blood flow states were achieved by direct femoral artery infusion of adrenaline (0.002–0.006 mg/min) or magnesium (0.4–1 mmol/min), which produced mean (±SD) stable flow states of 25±12 and 185±56% (both n = 5) of baseline, respectively. The correlation coefficients between arterial and venous Doppler frequency shifts in five sheep during and after adrenaline infusion were 0.96 (indicating these vessels probably supplied and drained common tissue). 3. The venous Doppler frequency shifts were calibrated against timed collections of the femoral vein outflow to provide estimates of the low and normal blood flow states (mean flows of 2.8±1.7 and 9.3±5.7 mL/100 g per min; both n = 3) and against an indirect Kety–Schmidt method during low- and high-blood flow states (mean flows of 2.2±1.3 and 18.2±7.0 mL/100 g per min; both n = 5). There was a generally good agreement between the two methods. 4. The tissue was neither hypoxic nor acidotic in the low- or high-flow states and altering the flow produced no change in muscle oxygen consumption, suggesting the flow changes were largely due to changes in resistance vessel tone. 5. Postmortem femoral artery dye injection and dissection of stained tissues showed the artery supplied 657±96 g (n = 5) of skeletal muscle and 42±20 g (n = 5) of other tissues. 6. It is concluded that the method is suitable for sampling predominantly muscle effluent blood at low- or high-blood flow states according to experimental requirements.

In an ideal world, photodynamic therapy (PDT) of abnormal tissue would reliably spare the surrounding normal tissue. Normal tissue responses set the limits for light and drug dosimetry. The threshold fluence for necrosis (TFN) was measured in normal skin following intravenous infusion with a photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA) Verteporin as a function of drug dose (0.25-2.0 mg/kg), wavelength of irradiation (458 and 690 nm) and time interval (0-5 h) between drug administration and irradiation. The BPD-MA levels were measured in plasma and skin tissue to elucidate the relationship between TFN, drug kinetics and biodistribution. The PDT response of normal skin was highly reproducible. The TFN for 458 and 690 nm wavelengths was nearly identical and the estimated quantum efficiency for skin response was equal at these two wavelengths. Skin phototoxicity, quantified in terms of 1/TFN, closely correlated with the plasma pharmacokinetics rather than the tissue pharmacokinetics and was quadratically dependent on the plasma drug concentration regardless of the administered drug dose or time interval between drug and light exposure. This study strongly suggests that noninvasive measurements of the circulating drug level at the time of light treatment will be important for setting optimal light dosimetry for PDT with liposomal BPD-MA, a vascular photosensitizer.

Population pharmacokinetics can be defined as a study of the basic features of drug disposition in a population, accounting for the influence of diverse pathophysiological factors on pharmacokinetics, and explicitly estimating the magnitude of the interindividual and intraindividual variability. It is used to identify subpopulations of individuals that may present with differences in drug kinetics or in kinetic/dynamic responses. Rooted in procedures used in engineering systems, population pharmacokinetics methods were conceived as a means to determine the pharmacokinetic profile in populations in which a sparse number of samples were obtained per individual, such as those in late stage human clinical trials. This is the situation commonly encountered in all aspects of veterinary medicine. The exploratory nature of this technique allows one to probe relationships between clinical factors (such as age, gender, renal function, etc.) and drug disposition and/or effect. Similarly, the utilization of these techniques in the clinical research phases of drug development optimize the determination of efficacy and safety of drugs. Given the observational nature of most studies published so far, statistical methods to validate the population models are necessary. Simulation studies may be conducted to explore data collection designs that maximize information yield with a minimum expenditure of resources. The breadth of this approach has allowed population studies to be more commonly employed in all areas of drug therapy and clinical research. Finally, in veterinary medicine, there is an additional field in which population studies are potentially ideally suited: the application of this methodology to the study of tissue drug depletion and drug residues in production animals, and the establishment of withdrawal times tailored to the clinical or production conditions of populations or individuals. Such application would provide a major step toward assuring a safe food supply under a wide variety of dose and off-label clinical uses. Population pharmacokinetics is an ideal method for generating data in support of the implementation of flexible labelling policies and extralabel drug use recently approved under AMDUCA (Animal Medicinal Drug Use Clarification Act. 21 CFR Part 530).

Six healthy volunteers and six patients with asymptomatic duodenal ulcer disease received placebo or 300 mg nizatidine once at night or twice daily (morning and evening) for a week in a random, cross-over fashion. Steady-state serum nizatidine concentrations and gastric pH were measured over a 24-hour period. No significant differences in the pharmacokinetic indices were observed between the healthy volunteers and patients with duodenal ulcer disease. In patients with duodenal ulcers, significantly lower peak serum concentrations, longer half-life (t1/2) and larger volume of distribution (Vd) were observed after the night doses compared with the daytime doses. The diurnal variation in drug kinetics between the nighttime and daytime doses in the twice daily regimen may be caused by a slower absorption rate, paralleled with a higher extent of distribution. Despite lower serum nizatidine concentrations, gastric pH was higher in the evening than in the daytime; it is speculated that this was due to a time-dependent enhanced distribution of the H2-receptor blocker into the site of action.

This report studies the importance of passive exposure of medical personnel to cocaine hydrochloride and its impact on urine screening testing. Eleven medical staff members were exposed to cocaine hydrochloride by means of aerosol and cutaneous application, similar to that which may occur in medical practice. Urine drug screening tests were negative for everyone tested. This finding is supported by known drug kinetics. It is unlikely that a single passive exposure of medical staff to cocaine hydrochloride will produce a positive urine screening test. In all cases of positive urine tests, contaminants should be tested for which may indicate a source of the drug. The routine use of gloves and masks--which is recommended to prevent HIV infection--should further decrease medical personnel's passive exposure to cocaine hydrochloride.

COST is the acronym for European Cooperation in the Field of Scientific and Technical Research. This comprises a framework for cooperative research amongst the member countries of the European Community and other members of EFTA. Project COST B1 was the first biomedical research programme within COST. It was initiated in 1985 and was entitled ‘Criteria for the choice and definition of healthy volunteers and patients for Phase I and Phase II studies in drug development’. The project was renewed twice and came to a close in 1998. (More information on COST B1 can be obtained from the website http://europa.eu.int/communication/dg12/rtdinf18/18e06.html). COST B15 is a new action set up towards the end of 1998, entitled ‘Modelling during drug development’. To date 12 countries (Belgium, Czech Republic, Denmark, Finland, Germany, Italy, Norway, Slovak Republic, Spain, Sweden, Switzerland and the United Kingdom) have signed the Memorandum of Understanding (Doc. COST 299/98) and two others (France and the Netherlands) have indicated their intention of signing. The present note is meant to briefly describe the purpose of COST B15. The present action focuses on the current status and future possibilities of modelling methods in the development of new drugs. This is an area where models have been tested extensively and where present activities are very promising for new modelling methods. Modelling may also be used in the context of human safety assessment of industrial chemicals not intended for deliberate administration to humans. They may thus represent health hazards, in the same way that medicinal products may display undesirable effects in addition to their therapeutic effect. The transfer of technology and methodology between these two related areas will be one of the objectives of this new Action. Drug development can be broken down to a number of interconnected stages: (1) theoretically derived physico-chemical properties; (2) in vitro methods; (3) animal experimentation; (4) studies in healthy subjects; (5) phase 2 clinical trials; (6) phase 3 clinical trials; and (7) postmarketing studies. For chemicals the considerations in stages (1), (2) and (3) are identical with the considerations for drugs as far as toxicological aspects are concerned. However, experimental intended exposure in humans is not possible for ethical reasons. Predictability of models including physico-chemical properties, in vitro and animal experiments thus represent key (and often unique) bases for health hazard assessment in humans. Some form of modelling is performed at each of the stages defined above. However, as often demonstrated in practice, information is not necessarily available to scientists working on stages which are more than one level apart. For example, it is not uncommon that clinicians responsible for phase 3 clinical trials have very little knowledge of important facts observed during in vitro testing or animal studies. Another example is to be found in the often minimal feedback that medicinal chemists receive when the development of a new drug has to be interrupted on the basis of a NOGO decision. For chemicals, presently fixed safety factors are used to scale up from animal data to human. This approach is scientifically not well based and does not take all the information into consideration which is or could be made available: for example data from animal and human recombinant expressed enzyme systems. The aim of the new action is to promote communication between scientists active at all levels of drug development and use. The action would also involve scientists active in the assessment of human toxic properties of industrial chemicals. The tool of communication to be developed will be the ‘modelling approach’. The primary goal to be reached at the end of this new action is to define a comprehensive picture of all modelling methods used at all stages of drug development and a proposal of strategies aimed at combining these methods more efficiently. The duration of this concerted action is 4 years. It is clear that in such a short duration, a fully integrated modelling approach cannot be achieved. However, it will be possible to lay down the scientific bases and create links between research groups that should allow the acceptance of such integrative modelling by the scientific community, regulatory bodies and the pharmaceutical industry. Three working groups have been established: in vitro/in vivo extrapolation; biomarkers; and clinical modelling. The in vitro/in vivo group has identified three key areas for further investigation. These are: (1) the effect of permeation, absorption and membrane translocation on drug kinetics and interactions; (2) in vivo validation of in vitro interaction models; and (3) the use of genomics and proteomics in the identification of potential biomarkers for assessing safety and efficacy. The biomarker group has identified mechanism-based PK/PD modelling and clinical trial design as the basis for the development, evaluation and validation of biomarkers as areas of interest. Finally the clinical modelling group identified modelling in phase I, II and III of drug development and the transfer of information between the phases as important areas of interest. Activity in these areas will take the form of expert meetings and international conferences. It is the remit of COST to publish the findings from these meetings as widely as possible. Further information on COST B15 can be obtained from the authors of this article. See also http://www.sdu.dk/med/homepages/costb15/ which includes a list of national representatives.

The pharmacokinetics of the new angiotensin converting enzyme (ACE) inhibitor benazepril.HCl were evaluated in healthy male volunteers. The single dose kinetics were established from data of 62 subjects receiving an oral 10 mg dose of the drug. The steady state kinetics were investigated in 15 subjects after once-daily oral doses of 5, 10 or 20 mg. The compound is a prodrug which, on absorption, is hydrolysed to the pharmacologically active metabolite benazeprilat. Thus, plasma concentrations and urinary excretion of parent compound and active metabolite were determined. Benazepril.HCl was rapidly absorbed (tmax = 0.5 h) and rapidly eliminated from plasma (t1/2 = 0.6 h). Only trace amounts were excreted unchanged in urine. The drug was rapidly metabolized to benazeprilat (tmax = 1.5 h). The elimination of the metabolite from plasma was biphasic. About 80 per cent of benazeprilat formed was eliminated within 24 h (t 1/2 = 2.7 h), whereas the terminal phase (t1/2 = 22.3 h) controlled a minor amount of elimination. About 17 per cent of dose was excreted in the 24-h urine as benazeprilat. The drug disposition did not change during repeated oral dosing and only small accumulation of the metabolite occurred. The accumulation ratio was 1.20 for AUC and 1.24 for urinary excretion. The effective half-life for accumulation was estimated at about 10-11 h. The comparison with other ACE inhibitors showed similarities but also marked differences with respect to the drug kinetics and excretion.

1. Healthy young and elderly volunteers received 20 mg nifedipine (slow release) orally for 2 weeks with concomitant dosing of atenolol 50 mg orally during the second week. 2. Drug kinetics and dynamics were compared between the groups after a single dose of nifedipine (day 1), after chronic dosing for 1 week (day 8), and following concomitant daily dosing of atenolol (day 15). 3. Plasma profiles of nifedipine were similar within each group on each of the 3 sampling days. The elderly group had higher plasma concentrations from about 6 h but there was no difference in the maximum concentrations achieved. The half-life in the elderly was significantly longer (8.8 +/- 0.9 h) compared with that in the young (5.8 +/- 1.1 h) (P less than 0.01). 4. Blood concentrations of atenolol were higher in the elderly at 12 and 24 h post-dose (P less than 0.001) and the AUC was greater than in the young (P less than 0.001). 5. Systolic blood pressure was reduced by nifedipine in both groups but to a greater extent in the elderly (P less than 0.01); differences in diastolic blood pressure were not significant. Blood pressure was reduced further by the addition of atenolol. Atenolol reduced the heart rate in all subjects.

Differences in drug kinetics between supine rest and ambulation have been reported, but the relative contribution of postural changes and changes in the level of physical activity has not been evaluated. Ampicillin pharmacokinetics, glomerular filtration rate (GFR) and renal plasma flow (RPF) were studied in six male volunteers at rest in the sitting and lying position with an interval of 1 week. After intravenous administration ampicillin kinetics, analyzed according to a two-compartment open model, demonstrated significant changes in drug distribution when the position was changed from lying to sitting: alpha-increased by 50%, V1 and V beta increased by 19% and 22% respectively. Ampicillin clearance, the fraction of dose recovered from urine, GFR and RPF were, however, not influenced by the change in posture. Our data on effects of posture in resting subjects suggest that previously reported differences in drug elimination and RPF between lying and ambulatory subjects are largely due to differences in the level of physical activity.

The purpose of this study was to investigate the disposition of two aminopenicillins and their intra- and inter-individual variation in pharmacokinetic parameters in healthy, elderly volunteers. Two groups, each of 12 active, community-dwelling volunteers between 69 and 83 years of age participated. One group was given 500 mg of amoxycillin, the other group 500 mg of ampicillin as single i.v. infusions. Within the drug groups each volunteer was given the infusion at two different occasions separated by a time-period of 1 week. Amoxycillin and ampicillin were determined in plasma and urine by modern column liquid chromatographic methods. The mean plasma clearance was about 200 ml min-1 1.73 m-2 for both drugs and renal clearance accounted for approximately 80% of this. As expected, drug clearance was correlated to renal function as determined by 51Cr-EDTA. The volume of distribution at steady-state (Vss) was about 0.3 l kg-1 for both drugs. Compared to our previous results in younger subjects, plasma and renal clearances were essentially similar in this study, but slightly longer half-lives and higher Vss were seen for amoxycillin and ampicillin. The intra-individual variation, expressed as the error of a single determination (CV), was small, for plasma clearance 3.7% and 6.4% after amoxycillin and ampicillin. The corresponding inter-individual variation in clearance was higher, 14.4% after amoxycillin, and 11.9% after ampicillin. The results confirm a higher relative efficiency of a crossover vs a completely randomized parallel groups design in parenteral studies of these penicillins. In our elderly subjects there was only an approximately 30% decrease in renal function. This was not enough to reduce the drug clearance and offers an explanation for the similarity between our present results in the elderly and our previous results in younger subjects. Elderly volunteers may be different from patients with disease as a confounding factor. Studies on elderly active and community-dwelling volunteers, as in this study, may therefore be more representative as to the effect of age per se on drug kinetics.

Kinetics of a single 100-mg dose of nortriptyline were studied in 10 normal men who took this dose at 9 A.M. in the morning and on another occasion at 9 P.M. Only minimal differences in kinetic parameters were observed, none enough to be of any clinical consequence. A rather high first-pass metabolism of the drug was evident by high plasma concentrations of 10-hydroxynortriptyline. It is thus unlikely that the recent custom of giving single daily doses of tricyclic antidepressants in the evening excludes regimens with more favorable drug kinetics.

This paper investigates the properties of reachable sets of discrete-time compartmental systems. The discrete-time compartmental system is characterized by the non-negativeness of all coefficients of its system state equations and its inputs. The paper first deals with the properties of reachable sets at finite sampling times of general ordinary linear discrete-time systems with simple non-negative input, and the n.a.s.c. under which the reachable set coincides with the maximal reachable set at finite sampling times. Then, it deals with the characteristic polynomial representation of state transition matrix and the properties of the maximal reachable set. After showing the properties of reachable sets of compartmental systems, the paper discusses the drug kinetics problem as an example of the analysis of reachable sets.

1 Ranitidine oral kinetics and plasma concentration-effect relationships upon meal-induced gastric secretion were investigated in normal subjects. Four oral doses of ranitidine (50, 100, 150 or 200 mg) and placebo were tested. 2 Oral ranitidine showed a terminal half-life of about 2 h 25 min. Maximal plasma level was about 240 ng/ml for a 100 mg dose, and occurred about 1 h after dose. From the range of 50 to 200 mg dose, no indication of non-linearity was observed in the drug kinetics. 3 Ranitidine administration resulted in a dose-related reduction in meal-stimulated acid secretion reaching, 46, 70, 82 and 92%, respectively. Mean ranitidine plasma concentrations producing 50 and 80% inhibition of acid secretion were 73 and 180 ng/ml, respectively, with great inter-individual variability. 150 and 200 mg ranitidine oral doses maintained IC50 for at least 4.5 and 5.5 h, respectively. Upon oral administration, ranitidine exerted no effect on gastric emptying of the meal but slightly decreased the gastrin response to the meal.