The plasma concentration-time profile of a drug is essential to explain the relationship between the administered dose and the kinetics of drug action. However, in some cases such as in pre-clinical pharmacology or phase-III clinical studies where it is not always possible to collect all the required PK information, this relationship can be difficult to establish. In these circumstances several authors have proposed simple models that can analyse and simulate the kinetics of the drug action in the absence of PK data. The present work further develops and evaluates the performance of such an approach. A virtual compartment representing the biophase in which the concentration is in equilibrium with the observed effect is used to extract the (pharmaco)kinetic component from the pharmacodynamic data alone. Parameters of this model are the elimination rate constant from the virtual compartment (KDE), which describes the equilibrium between the rate of dose administration and the observed effect, and the second parameter, named EDK(50) which is the apparent in vivo potency of the drug at steady state, analogous to the product of EC(50), the pharmacodynamic potency, and clearance, the PK "potency" at steady state. Using population simulation and subsequent (blinded) analysis to evaluate this approach, it is demonstrated that the proposed model usually performs well and can be used for predictive simulations in drug development. However, there are several important limitations to this approach. For example, the investigated doses should extend from those producing responses well below the EC(50) to those producing ones close to the maximum response, optimally reach steady state response and followed until the response returns to baseline. It is shown that large inter-individual variability on PK-PD parameters will produce biases as well as large imprecision on parameter estimates. It is also clear that extrapolations to dosage routes or schedules other than those used to estimate the parameters should be undertaken with great caution (e.g., in case of non-linearity or complex drug distribution). Consequently, it is advised to apply this approach only when the underlying structural PD and PK are well understood. In any case, K-PD model should definitively not be substituted for the gold standard PK-PD model when correct full model can and should be identified.

An integrated model for the regulation of glucose and insulin concentrations following intravenous glucose provocations in healthy volunteers and type 2 diabetic patients was developed. Data from 72 individuals were included. Total glucose, labeled glucose, and insulin concentrations were determined. Simultaneous analysis of all data by nonlinear mixed effect modeling was performed in NONMEM. Integrated models for glucose, labeled glucose, and insulin were developed. Control mechanisms for regulation of glucose production, insulin secretion, and glucose uptake were incorporated. Physiologically relevant differences between healthy volunteers and patients were identified in the regulation of glucose production, elimination rate of glucose, and secretion of insulin. The model was able to describe the insulin and glucose profiles well and also showed a good ability to simulate data. The features of the present model are likely to be of interest for analysis of data collected in antidiabetic drug development and for optimization of study design.

An integrated model for the glucose-insulin system describing oral glucose tolerance test data was developed, extending on a previously introduced model for intravenous glucose provocations. Model extensions comprised the description of glucose absorption by a chain of transit compartments with a mean transit time of 35 minutes, a bioavailability of 80%, and a representation of the incretin effect, expressed as a direct effect of the glucose absorption rate on insulin secretion. The ability of the model to predict the incretin effect was assessed by simulating the observed difference in insulin response following an oral glucose tolerance test compared with an isoglycemic glucose infusion mimicking an oral glucose tolerance test profile. The extension of the integrated glucose-insulin model to gain information from oral glucose tolerance test data considerably expands its range of applications because the oral glucose tolerance test is one of the most common glucose challenge experiments for assessing the efficacy of hypoglycemic agents in clinical drug development.

After reports from Japan of neuropsychiatric adverse events (NPAEs) in children taking oseltamivir phosphate (hereafter referred to as oseltamivir [Tamiflu; F. Hoffmann-La Roche Ltd, Basel, Switzerland]) during and after the 2004--5 influenza season, Roche explored possible reasons for the increase in reporting rate and presented regular updates to the US FDA and other regulatory authorities. This review summarizes the results of a comprehensive assessment of the company's own preclinical and clinical studies, post-marketing spontaneous adverse event reporting, epidemiological investigations utilizing health claims and medical records databases and an extensive review of the literature, with the aim of answering the following questions: (i) what the types and rates of neuropsychiatric abnormalities reported in patients with influenza are, and whether these differ in patients who have received oseltamivir compared with those who have not; (ii) what levels of oseltamivir and its active metabolite, oseltamivir carboxylate are achieved in the CNS; (iii) whether oseltamivir and oseltamivir carboxylate have pharmacological activity in the CNS; and (iv) whether there are genetic differences between Japanese and Caucasian patients that result in different levels of oseltamivir and/or oseltamivir carboxylate in the CNS, differences in their metabolism or differences in their pharmacological activity in the CNS. In total, 3051 spontaneous reports of NPAEs were received by Roche, involving 2466 patients who received oseltamivir between 1999 and 15 September 2007; 2772 (90.9%) events originated from Japan, 190 (6.2%) from the US and 89 (2.9%) from other countries. During this period, oseltamivir was prescribed to around 48 million people worldwide. Crude NPAE reporting rates (per 1,000,000 prescriptions) in children (aged < or =16 years) and adults, respectively, were 99 and 28 events in Japan and 19 and 8 in the US. NPAEs were more commonly reported in children (2218 events in 1808 children aged < or =16 years vs 833 in 658 adults) and generally occurred within 48 hours of the onset of influenza illness and initiation of treatment. After categorizing the reported events according to International Classification of Diseases (9th edition) codes, abnormal behaviour (1160 events, 38.0%) and delusions/perceptual disturbances (661 events, 21.7%) were the largest categories of events, and delirium or delirium-like events (as defined by the American Psychiatric Association) were very common in most categories. No difference in NPAE reporting rates between oseltamivir and placebo was found in phase III treatment studies (0.5% vs 0.6%). Analyses of US healthcare claims databases showed the risk of NPAEs in oseltamivir-treated patients (n = 159,386) was no higher than those not receiving antivirals (n = 159,386). Analysis of medical records in the UK General Practice Research Database showed that the adjusted relative risk of NPAEs in influenza patients was significantly higher (1.75-fold) than in the general population. Based on lite...

The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.

AimsIbandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation. Methods and resultsUsing selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accurately described the P K of i.v. ibandronate in plasma and urine and urinary excretion of the C-telopeptide of the a chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK-PD model was simplified using a 'kinetics of drug action' or kinetic (K)-PD model (i.e. a dose-response model as opposed to a dose-concentration-response model). The performance of the K-PD model was evaluated by fitting data simulated with the PK-PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK-PD model. The K-PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the P D response and validated by retrospectively simulating the uCT X response in a prior Phase III and Phase II/III study of i.v. ibandronate, given once every 3 months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K-PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K-PD model adequately described the uCTX response after oral dosing. ConclusionsThis validated K-PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.

1Interaction between alcohol and bretazenil (a benzodiazepine partial agonist in animals) was studied with diazepam as a comparator in a randomized, double‐blind, placebo controlled six‐way cross over experiment in 12 healthy volunteers, aged 19−26 years. 2Bretazenil (0.5 mg), diazepam (10 mg) and matching placebos were given as single oral doses after intravenous infusion of alcohol to a steady target‐blood concentration of 0.5 g l−1 or a control infusion of 5% w/v glucose at 1 week intervals. 3CNS effects were evaluated between 0 and 3.5 h after drug administration by smooth pursuit and saccadic eye movements, adaptive tracking, body sway, digit symbol substitution test and visual analogue scales. 4Compared with placebo all treatments caused significant decrements in performance. Overall, the following sequence was found for the magnitude of treatment effects: bretazenil+alcohol>diazepam+alcohol≥bretazenil> diazepam>alcohol>placebo. 5There were no consistent indications for synergistic, supra‐additive pharmacodynamic interactions between alcohol and bretazenil or diazepam. 6Bretazenil with or without alcohol, and diazepam+alcohol had marked effects. Because subjects were often too sedated to perform the adaptive tracking test and the eye movement tests adequately, ceiling effects may have affected the outcome of these tests. 7No significant pharmacokinetic interactions were found. 8Contrary to the results in animals, there were no indications for a dissociation of the sedative and anxiolytic effects of bretazenil in man.

Disease-onset time (DOT) and disease trajectory concepts were applied to derive an Alzheimer's disease (AD) progression population model using the clinical dementia rating scale—sum of boxes (CDR-SOB) from the AD neuroimaging initiative (ADNI) database. The model enabled the estimation of a DOT and a disease trajectory for each patient. The model also allowed distinguishing fast and slow-progressing subpopulations according to the functional assessment questionnaire, normalized hippocampal volume, and CDR-SOB score at study entry. On the basis of these prognostic factors, 81% of the mild cognitive impairment (MCI) subjects could correctly be assigned to slow or fast progressers, and 77% of MCI to AD conversions could be predicted whereas the model described correctly 84% of the conversions. Finally, synchronization of the biomarker-time profiles on estimated individual DOT virtually expanded the population observation period from 3 to 8 years. DOT-disease trajectory model is a powerful approach that could be applied to many progressive diseases.