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The purpose of this study is to develop statistical methodology to facilitate indirect estimation of the concentration of antiretroviral drugs and viral loads in the prostate gland and the seminal vesicle. The differences in antiretroviral drug concentrations in these organs may lead to suboptimal concentrations in one gland. Suboptimal levels of the antiretroviral drugs may not be able to fully suppress the virus in that gland, leading to a source of sexually transmissible virus and increasing the chance of selecting for a drug-resistant virus. This information may be useful for selecting an antiretroviral drug regimen that will achieve optimal concentrations in the genital tract glands. Using fractionally collected semen ejaculates, Lundquist (Acta Physiol. Scand. 1949; 19:1-95) measured levels of surrogate markers in each fraction that are uniquely produced by specific male accessory glands. To determine the original glandular concentrations of the surrogate markers, Lundquist solved a simultaneous series of linear equations. This method has several limitations. In particular, it does not yield a unique solution, it does not address measurement error, and it does not provide population-averaged estimates after taking into account inter-subject variability in the parameters. To cope with these limitations, we developed a mechanistic latent variable model based on the physiology of the male genital tract and surrogate markers. We employ a Bayesian approach and perform a sensitivity analysis on the distributional assumptions on the random effects and priors. The model and Bayesian approach are validated on experimental data where the concentration of a drug should be (biologically) differentially distributed between the two glands. In this example, the Bayesian model-based conclusions are found to be robust to model specification and this hierarchical approach leads to more scientifically valid conclusions than the original methodology. In particular, unlike existing methods, the proposed model-based approach was not affected by a common form of outliers.

The central nervous system (CNS) pharmacokinetics of the H(1) receptor antagonist diphenhydramine (DPHM) were studied in 100- and 120-day-old fetuses, 10- and 30-day-old newborn lambs, and adult sheep using in vivo microdialysis. DPHM was administered i.v. at five infusion rates, with each step lasting 7 h. In all ages, cerebrospinal fluid (CSF) and extracellular fluid (ECF) concentrations were very similar to each other, which suggests that DPHM between these two compartments is transferred by passive diffusion. In addition, the brain-to-plasma concentration ratios were >or=3 in all age groups, suggesting the existence of a transport process for DPHM into the brain. Both brain and plasma DPHM concentrations increased in a linear fashion over the dose range studied. However, the ECF/unbound plasma and CSF/unbound plasma DPHM concentration ratios were significantly higher in the fetus and lambs (approximately 5 to 6) than in the adult (approximately 3). The factors f(CSF) and f(ECF), the ratios of DPHM areas under the curves (AUCs) in CSF and ECF to the plasma DPHM AUC, respectively, decreased with age, indicating that DPHM is more efficiently removed from the brain with increasing age. The extent of plasma protein binding of the drug increased with age. This study provides evidence for a transporter-mediated mechanism for the influx of DPHM into the brain and also for an efflux transporter for the drug, whose activity increases with age. Moreover, the higher brain DPHM levels in the fetus and lamb compared with the adult may explain the greater CNS effects of the drug at these ages.

Positron emission tomography (PET) is a highly sensitive noninvasive functional imaging modality that can provide quantitative in vivo tissue data with high temporal resolution. Such information can be exploited to assess the behavior of a drug within the body (pharmacokinetics) and its effects on the biosystem (pharmacodynamics). Knowledge of in vivo drug pharmacology is especially invaluable in the assessment and development of anticancer agents and is likely to play a significant role in the development of novel targeted therapies. Specifically, PET pharmacokinetic studies can provide information on drug access, kinetics, and drug concentration in tumors and normal tissues, all of which have a bearing on drug activity, tissue toxicity, and drug scheduling. In addition, such studies can provide proof of principle of the in vivo mechanism of drug action and in vivo targeting of molecular therapeutic targets. In this review, basic principles of PET drug kinetic measurement techniques are discussed, followed by examples of PET kinetic studies performed at various stages of the drug developmental process and their utility and contribution to anticancer drug development are highlighted.

A common calculation of oral bioavailability is based on the comparison of the areas under the concentration-time curves after intravenous and oral drug administration. It does not take into account that after the oral dosing a drug enters the systemic circulation in different states, that is, as free fraction, protein bound and partitioned into blood cells, and plasma lipids, while after intravenous input it is introduced into the systemic circulation only as a free fraction. Consideration of this difference leads to a novel equation for the oral bioavailability. In general, the traditional calculation overestimates the oral bioavailability. For a widely applied model of a linear pharmacokinetic system with central (plasma) drug elimination it is shown that the traditional calculation of the oral bioavailability could substantially overestimate the true value. If the existence of an immediate equilibrium between different drug fractions in blood is assumed, the obtained equation becomes identical to the traditional one. Thus the deviation of oral bioavailability from the value given by a common calculation appears to be a kinetic phenomenon. The difference could be significant for the drugs with the rate constant of elimination from plasma of the same order of magnitude or greater than the dissociation rate constant of drug-protein complexes, or the off-rate constant of partitioning from the blood cells, if the blood concentration profiles were used to calculate the oral bioavailability.

Atypical antipsychotics are a relatively new group of medications for the management of psychosis. Currently approved medications of this category include clozapine, risperidone, quetiapine, and olanzapine. Olanzapine was first marketed in 1996 in the United States as an atypical antipsychotic medication similar to clozapine for schizophrenia. By 2002, olanzapine was widely used and in the top 20 drugs by sales (1). Olanzapine belongs to the thienobenzodiazepine drug class and is known to have a high affinity for dopamine D2, D3, and D4 receptors, all five serotonin HT2 receptor subtypes, the 5-HT6 receptor, acetylcholine muscarinic receptors, and α1-adrenergic and histamine H1 receptors (2). The drug is well absorbed from the gut and reaches maximum plasma concentration about 6 hours after an oral dose (3). In plasma, 93% of the drug is bound to serum proteins, especially albumin (3). The drug is extensively eliminated by first-pass metabolism in the liver and has a mean elimination half-life of 30 hours, with a range of 21–54 hours (3). Olanzapine is considered to have a good overall safety profile at therapeutic doses (4). Adverse effects of olanzapine that affect the nervous system include mental status deterioration and extrapyramidal signs and, rarely, delirium, mutism, confusion, aggression, and lethargy that can progress to coma. Seizures, status epilepticus, and hypersalivation occasionally develop (5, 6). Extrapyramidal signs may include dystonia, parkinsonism, akathisia, choreoathetosis, and neuroleptic malignant syndrome (7– 9). Serious systemic complications include diabetes mellitus, tachycardia and supraventricular tachycardia, arrhythmias, and cardiopulmonary arrest (10, 11). Overdoses can lead to deaths. The American Association of Poison Control Centers Toxic Exposure Surveillance System reported the number of deaths associated with olanzapine to be six in 2000 (12), 10 in 2001 (13), and 10 in 2002 (14). Before some of these deaths, concomitant agents were ingested. The majority of deaths occurred within 12 hours of overdose, and the results of autopsies, when available, were often unremarkable (15–17). We report here a patient who survived the early phase of an overdose. He then developed coma with persistent choreoathetosis and hypersalivation, and neuroimaging and autopsy findings suggested damage to the basal ganglia.

Administration of peginterferon alfa-2b plus ribavirin results in an early hepatitis C virus (HCV) RNA decay followed by an increase as the drug concentration declines between doses. Upon administration of the next dose 1 week later, the same pattern is observed. We have incorporated pharmacokinetic/pharmacodynamic analysis into a model of viral dynamics to describe the effect that changes in drug concentration and effectiveness can have on viral levels. To illustrate the relationship between pharmacokinetics and viral dynamics, we fit the model to data from four HCV/human immunodeficiency virus co-infected patients, and obtained good agreement with the measured serum HCV RNA levels. We were able to account for the observed increases in HCV RNA, and estimate virion and drug half-lives that are in agreement with previous reports. Models incorporating pharmacokinetics are needed to correctly interpret viral load changes and estimate drug effectiveness in treatment protocols using peginterferon alfa-2b.

Administration of peginterferon alfa-2b plus ribavirin results in an early hepatitis C virus (HCV) RNA decay followed by an increase as the drug concentration declines between doses. Upon administration of the next dose 1 week later, the same pattern is observed. We have incorporated pharmacokinetic/pharmacodynamic analysis into a model of viral dynamics to describe the effect that changes in drug concentration and effectiveness can have on viral levels. To illustrate the relationship between pharmacokinetics and viral dynamics, we fit the model to data from four HCV/human immunodeficiency virus co-infected patients, and obtained good agreement with the measured serum HCV RNA levels. We were able to account for the observed increases in HCV RNA, and estimate virion and drug half-lives that are in agreement with previous reports. Models incorporating pharmacokinetics are needed to correctly interpret viral load changes and estimate drug effectiveness in treatment protocols using peginterferon alfa-2b.

To use the drug kinetics in dermis to predict the in vivo blood concentration after topical administration.A two-step pharmacokinetic model was established. The first step was to calculate the drug input rate or flux from the skin to the systemic circulation using the drug kinetic parameters in dermis. These parameters include (a) distance over which the drug concentration declines by 50%, (b) drug concentration at the epidermal-dermal junction, and (c) minimal plateauing drug concentration in the muscle layer. These parameters were experimentally determined from the drug concentration-tissue depth profiles in the dermis, after the application of a topical dose of ddI (200 mg/kg) to rats. The second step was to use the drug input rate together with the systemic disposition pharmacokinetics of ddI in rats to predict the plasma concentration-time profiles. The model-predicted plasma concentration-time profiles were compared with the observed profiles, to determine the validity of the proposed pharmacokinetic model.The observed steady state concentration (CSS) in individual animals (n = 6) deviated from the predicted values by 3 to 55% with 3 of 6 rats showing a15% deviation. The mean observed CSS of all animals deviated from the mean predicted values by less than 15%.The close agreement between the observed and the model-predicted drug concentrations indicates that the systemic drug input can be calculated from the drug kinetics in the dermis.

To solve the problems of side effects and medicinal lowering, studies on the magnetic drug delivery system (MDDS) have been applied. MDDS is a technique to accumulate drugs by using magnetic force as the physical driving force. It is necessary to apply a strong external magnetic field and high magnetic gradient to accumulate the ferromagnetic drugs to a deep diseased part noninvasively. However, by applying a static magnetic field from one direction, the drug accumulates only at the body surface near the magnet. In this study, we proposed a new method of MDDS in which a high-temperature superconducting (HTS) bulk magnet rotates around a target part. First, the particle trajectory simulation was conducted to examine the drug kinetics in a capillary blood vessel under the condition of rotating a magnet. Based on the results, the accumulation experiments of ferromagnetic particles with model blood vessels were conducted. As a result, the accumulation possibility of the ferromagnetic particles in the deep targeted part of the body was confirmed.

Nonlinear models of drug kinetics are considered at enzymatic elimination. New method of mathematical description of the concentration variations of drug/free, bound and total/in the course of time are proposed. Examples of verification of this method are reported. Evidence is given that the conventional method of simulation of concentration variations can be improved. Subject area: Pharmacokinetics

A compartmental model with a structure that describes drug kinetics by incorporating the ideas of diffusion and gamma distributed clearance times is proposed. The equations describing this model may be solved by elementary numerical techniques, and the model is shown to fit a data set describing renal gentamicin concentrations, better than a simple power-function model.