Time Course Of Receptor Occupancy Research Articles

Scale-up of a physiologically-based pharmacokinetic model to predict the disposition of monoclonal antibodies in monkeys.

Preclinical assessment of monoclonal antibody (mAb) disposition during drug development often includes investigations in non-human primate models. In many cases, mAb exhibit non-linear disposition that relates to mAb-target binding [i.e., target-mediated disposition (TMD)]. The goal of this work was to develop a physiologically-based pharmacokinetic (PBPK) model to predict non-linear mAb disposition in plasma and in tissues in monkeys. Physiological parameters for monkeys were collected from several sources, and plasma data for several mAbs associated with linear pharmacokinetics were digitized from prior literature reports. The digitized data displayed great variability; therefore, parameters describing inter-antibody variability in the rates of pinocytosis and convection were estimated. For prediction of the disposition of individual antibodies, we incorporated tissue concentrations of target proteins, where concentrations were estimated based on categorical immunohistochemistry scores, and with assumed localization of target within the interstitial space of each organ. Kinetics of target-mAb binding and target turnover, in the presence or absence of mAb, were implemented. The model was then employed to predict concentration versus time data, via Monte Carlo simulation, for two mAb that have been shown to exhibit TMD (2F8 and tocilizumab). Model predictions, performed a priori with no parameter fitting, were found to provide good prediction of dose-dependencies in plasma clearance, the areas under plasma concentration versu time curves, and the time-course of plasma concentration data. This PBPK model may find utility in predicting plasma and tissue concentration versus time data and, potentially, the time-course of receptor occupancy (i.e., mAb-target binding) to support the design and interpretation of preclinical pharmacokinetic-pharmacodynamic investigations in non-human primates.

Dopamine D2/3 occupancy of ziprasidone across a day: a within-subject PET study

Ziprasidone is an atypical antipsychotic recommended to be administered twice daily. The purpose of this study was to investigate whether occupancy of the dopamine D2/3 receptors by ziprasidone is maintained across a day employing a within subject design. Positron emission tomography (PET) scans with [(11)C]-raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60 mg twice daily. Each patient completed [(11)C]-raclopride PET scans at 5, 13 and 23 h after the last dose of ziprasidone. Dopamine D2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum. Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-h scans were 66, 39 and 2 % in the putamen; 62, 35 and -6 % in the caudate; and 68, 47 and 11 % in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 h. The serum level of ziprasidone associated with 50 % D2/3 receptors occupancy was estimated to be 204 nmol/L (84 ng/ml). Prolactin levels were highest at 5-h post-dose and none showed hyperprolactinemia at 23-h scans. The absence of ziprasidone striatal D2/3 receptor binding 23 h after taking 60 mg under steady-state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D2/3 receptor occupancy (i.e. 60 %). 24-Hour Time Course of Striatal Dopamine D2 Receptor Occupancy of Ziprasidone: A PET Study, www.clinicaltrials.gov/ct2/show/NCT00818298 , NCT00818298.

Clinical Pharmacokinetics of Atypical Antipsychotics

In the past, the information about the dose-clinical effectiveness of typical antipsychotics was not complete and this led to the risk of extrapyramidal adverse effects. This, together with the intention of improving patients' quality of life and therapeutic compliance, resulted in the development of atypical or second-generation antipsychotics (SGAs). This review will concentrate on the pharmacokinetics and metabolism of clozapine, risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole and sertindole, and will discuss the main aspects of their pharmacodynamics. In psychopharmacology, therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding adverse effects by keeping long-term exposure to the minimal effective blood concentration. The rationale for using therapeutic drug monitoring in relation to SGAs is still a matter of debate, but there is growing evidence that it can improve efficacy, especially when patients do not respond to therapeutic doses or when they develop adverse effects. Here, we review the literature concerning the relationships between plasma concentrations of SGAs and clinical responses by dividing the studies on the basis of the length of their observation periods. Studies with clozapine evidenced a positive relationship between plasma concentrations and clinical response, with a threshold of 350-420 ng/mL associated with good clinical response. The usefulness of therapeutic drug monitoring is well established because high plasma concentrations of clozapine can increase the risk of epileptic seizures. Plasma clozapine concentrations seem to be influenced by many factors such as altered cytochrome P450 1A4 activity, age, sex and smoking. The pharmacological effects of risperidone depend on the sum of the plasma concentrations of risperidone and its 9-hydroxyrisperidone metabolite, so monitoring the plasma concentrations of the parent compound alone can lead to erroneous interpretations. Despite a large variability in plasma drug concentrations, the lack of studies using fixed dosages, and discrepancies in the results, it seems that monitoring the plasma concentrations of the active moiety may be useful. However, no therapeutic plasma concentration range for risperidone has yet been clearly established. A plasma threshold concentration for parkinsonian side effects has been found to be 74 ng/mL. Moreover, therapeutic drug monitoring may be particularly useful in the switch between the oral and the long-acting injectable form. The reviewed studies on olanzapine strongly indicate a relationship between clinical outcomes and plasma concentrations. Olanzapine therapeutic drug monitoring can be considered very useful in assessing therapeutic efficacy and controlling adverse events. A therapeutic range of 20-50 ng/mL has been found. There is little evidence in favour of the existence of a relationship between plasma quetiapine concentrations and clinical responses, and an optimal therapeutic range has not been identified. Positron emission tomography studies of receptor blockade indicated a discrepancy between the time course of receptor occupancy and plasma quetiapine concentrations. The value of quetiapine plasma concentration monitoring in clinical practice is still controversial. Preliminary data suggested that a therapeutic plasma amisulpride concentration of 367 ng/mL was associated with clinical improvement. A therapeutic range of 100-400 ng/mL is proposed from non-systematic clinical experience. There is no direct evidence concerning optimal plasma concentration ranges of ziprasidone, aripiprazole or sertindole.

The necessary parameters for estimating the time-course of receptor occupancy

The dissociation of the kinetics between plasma and the brain has been reported for antipsychotic drugs such as risperidone and olanzapine (Tauscher et al., 2002), and the kinetic profile of antipsychotics at receptor sites has been viewed as an important profile for antipsychotic actions and dosing schedule (Tauscher et al., 2002). Our recent report in this Journal (Takano et al., 2004) showed that the time-course of receptor occupancy could be estimated using plasma pharmacokinetics and drug-affinity parameters.

Estimation of time course of dopamine D 2 receptor occupancy from plasma pharmacokinetics of antipsychotics

Although the kinetic profile of antipsychotics at dopamine D 2 receptor sites has been suggested to be important for antipsychotic action and dosing schedule, the kinetic profiles of the respective antipsychotic drugs in the brain have not yet been clearly defined. We aimed to estimate the time course of dopamine D 2 receptor occupancy from plasma pharmacokinetics and the apparent in vivo affinity parameter (ED 50; concentration to induce 50% occupancy). Dopamine D 2 receptor occupancies and plasma concentrations of risperidone, one of the atypical antipsychotics, were measured in five patients with schizophrenia using positron emission tomography (PET) with [ 11C]FLB 457. Measured dopamine D 2 occupancies were compared with those estimated from plasma kinetics and in vivo ED 50. Mean half-life of dopamine D 2 receptor occupancy of risperidone was about 80 h, while that of the plasma concentration was about 18 h. Dopamine D 2 receptor occupancy estimated from plasma pharmacokinetics and in vivo ED 50 was within 1 S.D. of the mean measured occupancy. Using plasma pharmacokinetics and in vivo ED 50, the time course of receptor occupancy could be calculated. The investigation of drug kinetics at receptors using PET would provide useful information for the evaluation of antipsychotics.

Progesterone receptor regulation in T47D human breast cancer cells: analysis by density labeling of progesterone receptor synthesis and degradation and their modulation by progestin.

We have examined the effect of progestin on the regulation of cellular progesterone receptor (PR) levels and have used dense amino acid-density shift experiments to determine the mechanism by which progestin markedly decreases PR. We have utilized T47D human breast cancer cells which contain high levels of PR and are progestin responsive. When these cells are exposed to the progestin R5020, there is a time- and concentration-dependent decrease in PR levels. Experiments with different concentrations of R5020 reveal that the rate and extent of PR decrease reflect the time course of receptor occupancy and the fractional saturation of receptor. With a high concentration of ligand (20 nM) that labels all receptors rapidly, reductions in PR levels (processing) occur immediately and proceed rapidly to levels that are 15-20% of the initial; at lower concentrations (5 nM), where it takes several hours to achieve full saturation of receptors, there is a delay before the maximal rate of processing develops and then continues to achieve final receptor levels that are 15-20% of the initial; with a low concentration of ligand (0.5 nM), binding is even slower and never reaches full receptor saturation, with the consequence that processing is not only delayed but also less complete. Immunochemical detection of PR with a monoclonal antibody (B39) reveals a good correspondence between the loss of immunoreactive and hormone binding PR, and analysis of the A (Mr 85,000) and B (Mr 115,000) receptor forms on Western blots demonstrates that both A and B receptor forms are reduced after exposure to R5020. Density labeling of PR by biosynthetic incorporation of 2H, 13C, 15N (dense) amino acids reveals that PR turns over with a half-life of 21 h in control cells. In cells exposed to 20 nM R5020, PR levels decline and receptor half-life is reduced to 6 h. In addition, there is also a time-dependent decrease in the rate constant of PR synthesis, k8, which decreases to less than 10% of its initial value after 24 h of R5020 exposure. Thus, the R5020-evoked reduction in PR levels in this progestin-sensitive cell line is due both to a marked increase in the rate of receptor degradation as well as a dramatic decrease in the rate of receptor synthesis.

A QUANTITATIVE INVESTIGATION OF THE RELATIONSHIP BETWEEN RATE OF ACCESS OF A DRUG TO RECEPTOR AND THE RATE OF ONSET OR OFFSET OF ACTION.

Solutions of the differential interaction equations describing the behaviour of a drug with a receptor molecule have been obtained. The cases of the exponential rise in drug concentration and of the rise in drug concentration occuring during diffusion into a plane sheet were examined. The time course of receptor occupancy and of rate of combination of drug with receptor were calculated for onset and washout of the effect of the drug.