The effects of paroxetine on the pharmacokinetics of paliperidone extended-release tablets.

INTRODUCTION: Co-morbid medical and psychiatric conditions are common in individuals with schizophrenia. As such, selecting antipsychotic medications with a low potential for drug-drug interactions (DDIs) is crucial, as many are extensively metabolized by hepatic cytochrome P450 (CYP) isozymes. METHODS: This randomized, crossover study examined the effects of paroxetine (a potent CYP2D6 inhibitor) on the pharmacokinetic parameters of a single dose of the novel antipsychotic agent, paliperidone extended-release tablets (paliperidone ER), in healthy subjects. RESULTS: The mean C (max) and AUC of paliperidone were slightly higher and paliperidone clearance was slightly lower following co-administration of paliperidone ER with paroxetine. There was a ratio of geometric treatment means of 116.48% for AUC (infinity) [90% CI: 104.49-129.84]. However, the increase in total exposure to paliperidone was not considered clinically relevant. The incidence of adverse events was lower when subjects received the combination of paliperidone ER and paroxetine compared with paroxetine alone. DISCUSSION: Results suggest that no clinically relevant pharmacokinetic interaction occurs when paroxetine and paliperidone ER are co-administered and, therefore, initiation or discontinuation of concomitant treatment with CYP2D6-inhibiting drugs does not appear to warrant an adjustment in paliperidone ER dosage.

The influence of hepatic impairment on the pharmacokinetics of paliperidone.

OBJECTIVES: This study assessed the impact of hepatic impairment on the pharmacokinetics (PK) of paliperidone and its enantiomers. METHODS: A single 1 mg dose of paliperidone immediate-release (IR) was administered to subjects with moderate hepatic impairment (n = 10) and demographically matched individuals with normal hepatic function (n = 10). RESULTS: Plasma protein binding was lower in hepatically impaired subjects resulting in a 27% higher unbound fraction of paliperidone compared with healthy individuals. After correcting for the difference in plasma protein binding, unbound exposures were comparable between groups. All other PK parameters were similar between the two groups. Paliperidone IR was equally well tolerated in both groups. CONCLUSIONS: The impact of moderate hepatic impairment on paliperidone PK is not considered clinically relevant as the PK profile of unbound paliperidone is similar for subjects with moderate hepatic impairment and those with normal hepatic function. Dosage adjustments of paliperidone are not required in subjects with mild or moderate hepatic impairment.

Adaptive changes in the pharmacodynamics of midazolam in different experimental models of epilepsy: kindling, cortical stimulation and genetic absence epilepsy.

1. The objective of this investigation was to determine quantitatively whether experimental epilepsy is associated with a change in the pharmacodynamics of benzodiazepines in vivo. For that purpose the pharmacodynamics of midazolam were quantified by an integrated pharmacokinetic-pharmacodynamic approach in three different models of experimental epilepsy: amygdala kindling, cortical stimulation and genetic absence epilepsy. 2. The time course of the EEG effect was determined in conjunction with the decline of drug concentrations after intravenous administration of 10 mg kg(-1) midazolam. The pharmacokinetics of midazolam were most adequately described by a bi-exponential equation. No influence of epilepsy on the pharmacokinetics of midazolam was observed. 3. The increase in beta activity (11.5-30 Hz) of the EEG as derived by Fast Fourier Transformation analysis was used as pharmacodynamic endpoint. For each individual rat the increase in beta activity was directly related to the concentration in blood on the basis of the sigmoidal Emax pharmacodynamic model. In all three models a significant reduction in the maximal effect was observed, in amygdala kindling 28%, in the cortical stimulation model 49% and in genetic absence epilepsy 37%. No differences in the other pharmacodynamic parameters, E0 EC50,u and Hill factor, were observed. 4. It is inferred that in three different models of epilepsy there is a similar change in GABAergic functioning which is associated with a significant reduction in the intrinsic activity of midazolam in vivo. These models provide therefore a useful basis for further studies on the mechanism of epilepsy-induced changes in pharmacodynamics of anti-epileptic drugs.

Effect of amygdala kindling on the central nervous system effects of tiagabine: EEG effects versus brain GABA levels.

1. The objective of this investigation was to determine the influence of amygdala kindling on the pharmacodynamics of tiagabine in vivo, using quantitative EEG parameters and extracellular GABA concentrations as pharmacodynamic endpoints. In integrated pharmacokinetic/pharmacodynamic (PK/PD) studies the time course of these effects was determined in conjunction with plasma concentrations following intravenous administration of 10 mg kg(-1). An 'effect compartment' model was used to derive individual concentration - effect relationships. 2. ++Tiagabine produced an increase in the amplitude of the 11.5 - 30 Hz frequency band of the EEG. The relationship between concentration and EEG effect was non-linear and described by the Hill equation. 3. In kindled rats the EC(50) was reduced to 291 ng ml(-1) from the original value of 521 ng ml(-1) in controls. The values of all other parameters were unchanged. In kindled rats the baseline extracellular GABA concentration was increased to 1.58 microM from 0.74 microM in controls. The relationships between tiagabine concentration and extracellular GABA concentration were again non-linear and described by the Hill equation. No differences were observed between kindled rats and controls. In the synaptoneurosmal preparation in vitro no changes in the functioning of the GABA transporter were observed. 4. It is concluded that unlike the situation with midazolam, there is no resistance to the EEG effect of tiagabine in the kindling model of experimental epilepsy. The observed shift in the concentration - EEG effect relationship to lower concentrations can presumably be explained by the increase in the baseline GABA levels.

Rate of change of blood concentrations is a major determinant of the pharmacodynamics of midazolam in rats.

The objective of this investigation was to characterize quantitatively the influence of the rate of increase in blood concentrations on the pharmacodynamics of midazolam in rats. The pharmacodynamics of midazolam were quantified by an integrated pharmacokinetic-pharmacodynamic modelling approach. Using a computer controlled infusion technique, a linear increase in blood concentrations up to 80 ng ml(-1) was obtained over different time intervals of 16 h, resulting in rates of rise of the blood concentrations of respectively, 1.25, 1.00, 0.87, 0.46, 0.34 and 0.20 ng ml(-1) min(-1). In one group of rats the midazolam concentration was immediately brought to 80 ng ml(-1) and maintained at that level for 4 h. Immediately after the pretreatment an intravenous bolus dose was given to determine the time course of the EEG effect in conjunction with the decline of midazolam concentrations. The increase in beta activity (11.5-30 Hz) of the EEG was used as pharmacodynamic endpoint. For each individual animal the relationship between blood concentration and the EEG effect could be described by the sigmoidal Emax model. After placebo, the values of the pharmacodynamic parameter estimates were Emax = 82+/-5 microV, EC50,u = 6.4+/-0.8 ng ml(-1) and Hill factor = 1.4+/-0.1. A bell-shaped relationship between the rate of change of midazolam concentration and the value of EC50,u was observed with a maximum of 21+/-5.0 ng ml(-1) at a rate of change of 0.46 ng ml(-1) min(-1); lower values of EC50,u were observed at both higher and lower rates. The findings of this study show that the rate of change in plasma concentrations is an important determinant of the pharmacodynamics of midazolam in rats.

Pharmacokinetic modelling of the haemodynamic effects of the A2a adenosine receptor agonist CGS 21680C in conscious normotensive rats.

1. The aim of the present investigation was to determine the relationship between the blood concentration and haemodynamic effects of the adenosine A2a receptor agonist, CGS 21680C (the sodium salt of 2-p-(2-carboxyethyl)phenylethylamino-5'-N-ethylcarboxamidoadeno sin e) in conscious normotensive rats. 2. Chronically cannulated rats were randomly assigned to three groups which received 300, 1000 or 3000 micrograms kg-1 (0.56, 1.9 or 5.6 mumol kg-1) of CGS 21680C intravenously over 15 min. The mean arterial blood pressure (MAP) and heart rate (HR) were monitored continuously during the experiment and serial arterial blood samples were taken for analysis of drug concentration. The ratio MAP/HR was also calculated, which may reflect changes in total peripheral resistance on the assumption that no changes in stroke volume occur. 3. For each individual rat the reduction in mean arterial pressure was related to the blood concentration according to the sigmoidal Emax model. The concentration-effect relationships were consistent for the different treatment groups. The potency based on free drug concentrations (EC50,u) was 5.8 ng ml-1 (11 nM) (mean +/- s.e.; n = 19) and correlated well with the reported adenosine A2a receptor affinity (Ki 19 nM). In comparison with the reduction in blood pressure, CGS 21680C exhibited a greater potency for the reduction of the ratio MAP/HR. 4. It is concluded that estimates can be obtained for the potency and intrinsic activity of adenosine A2a receptor agonists in vivo by pharmacokinetic-pharmacodynamic analysis of mean arterial pressure data in a rat model. In future studies, total peripheral resistance may also be useful as a pharmacodynamic parameter for A24 activation, provided that possible changes of the stroke volume are also assessed.

Stereoselective central nervous system effects of the R- and S-isomers of the GABA uptake blocker N-(4, 4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid in the rat.

1. The 'effect compartment' model was applied to characterize the pharmacodynamics of the R- and S-isomers of tiagabine in conscious rats in vivo using increase in the beta activity of the EEG as a pharmacodynamic endpoint. 2. No pharmacokinetic differences in plasma were observed between R- and S-tiagabine. The values for clearance and volume of distribution at steady-state were 103+/-10 versus 90+/-6 ml min(-1) kg(-1) and 1.8+/-0.2 versus 1.6+/-0.2 l kg(-1) for the R- and S-isomer, respectively. In contrast, plasma protein binding showed a statistically significant difference with values of the free fraction of 5.7+/-0.5 and 11.4+/-0.6%. In addition the rate constant for transport to the effect compartment was also different with values of 0.027 versus 0.067 min(-1). 3. For both isomers the relationship between concentration and EEG effect was non-linear and successfully characterized on basis of the Hill equation. A statistically significant difference in the value of EC(50) of 328+/-11 versus 604+/-18 ng ml(-1) was observed for R- and S-tiagabine respectively. The values of the other pharmacodynamic parameters were identical. 4. It is concluded that the differences in in vivo pharmacodynamics of R- and S-tiagabine can be explained by stereoselective differences in both the affinity to the GABA-uptake transporter and the degree of non-specific protein binding in plasma and at the effect site.

Pharmacokinetic-pharmacodynamic modelling of tiagabine CNS effects upon chronic treatment in rats: lack of change in concentration-EEG effect relationship.

The pharmacodynamics of the gamma-aminobutyric acid (GABA) uptake inhibitor (R)-N-(4,4-di-(methylthien-2-yl)but-3-enyl) nipecotic acid (tiagabine) was quantified in rats following chronic (14 days) administration by an integrated pharmacokinetic-pharmacodynamic (PK/PD) modelling approach. The increase in beta activity (11.5-30 Hz) of the EEG as derived by fast Fourier transformation analysis was used as pharmacodynamic endpoint. Two groups of male Wistar rats were treated for 14 days with either tiagabine at a steady-state concentration of 198+/-10 ng ml(-1) or placebo. Chronic treatment with tiagabine resulted in an increase of the EEG effect parameter by 38+/-2 microV. In the PK/PD experiment the time course of the EEG effect was determined in conjunction with the decline of drug concentrations after an i.v. bolus administration of 10 mg kg(-1). The pharmacokinetics of tiagabine was most adequately described by a bi-exponential function. No influence of chronic treatment on the pharmacokinetics was observed. Hysteresis between plasma concentration and EEG effect was accounted for by incorporation of an 'effect-compartment' in the model. The observed relationship between tiagabine concentrations and EEG effect was non-linear and described on the basis of the Hill equation. Between the treatment groups no differences in the pharmacodynamic parameters were observed. The population means for the different pharmacodynamic parameters were: maximum EEG effect 82 microV, EC(50) 486 ng ml(-1), Hill factor 2.0 and k(e0) 0.060 min(-1). In the in vitro [(3)H]GABA uptake assay no changes in affinity or functionality for the GABA uptake transporter were observed, consistent with the absence of adaptation. It is concluded that chronic treatment with tiagabine in an effective dose range for 14 days does not produce functional adaptation to tiagabine-induced GABA-ergic inhibition in vivo.

A nonlinear mixed effects IVIVC model for multi-release drug delivery systems.

The purpose of this analysis was the development of an IVIVC model, which involves a convolution step as described by O'Hara et al. and to describe a dual-release system: a controlled release formulation, which contains an initial immediate release element. Four formulations of Galantamine were used to test this modelling technique and a level A IVIVC, which meets the FDA criteria for internal and external validation, was successfully developed.

Mechanism-based modeling of adaptive changes in the pharmacodynamics of midazolam in the kindling model of epilepsy.

PURPOSE: A mechanism-based model is proposed for the analysis of adaptive changes in the pharmacodynamics of benzodiazepines in vivo. METHODS: The pharmacodynamics of midazolam was studied in the kindling model of experimental epilepsy. Concentration-EEG effect data from kindled rats and their controls were fitted to the operational model of agonism. A stepwise procedure was used, allowing changes in the parameters efficacy (tau) and tissue maximum (Em) either separately or in combination. The results were compared to data obtained in vitro in a brain synaptoneurosomal preparation. RESULTS: The relationship between midazolam concentration and EEG effect was non-linear. In kindled rats the maximum EEG effect was reduced by 27+/-8.3 microV from the original value of 94+/-4.4 microV. Analysis on the basis of the operational model of agonism showed that this decrease could be explained by a difference in the parameter system maximum (Em) rather than efficacy (tau). In the in vitro receptor binding assay no changes in density, affinity or functionality of the benzodiazepine receptor were observed, consistent with the lack of a change in efficacy (tau). CONCLUSIONS: The operational model of agonism provides a mechanistic basis to characterise adaptive changes in the pharmacodynamics of midazolam.

Application of a combined "effect compartment/indirect response model" to the central nervous system effects of tiagabine in the rat.

Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic-pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5-30 Hz frequency band (beta), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg-1 of tiagabine or vehicle over 10 min. The EEG was continuously recorded in conjunction with frequent arterial blood sampling. The pharmacokinetics of tiagabine could be described by a biexponential equation. The pharmacokinetics of tiagabine were not dose dependent, and the pooled values for clearance, volume of distribution at steady state and terminal half-life were (mean +/- SE, n 23) 96 +/- 9 ml min-1 kg-1, 1.5 +/- 0.1 L kg-1 and 20 +/- 0.2 min. A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were keo = 0.030 min-1 and kout = 81 min-1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates (mean +/- SE) were E0 = 155 +/- 6 microV, Emax = 100 +/- 5 microV, EC50 = 287 +/- 7 ng ml-1, Hill factor = 1.8 +/- 0.2 and keo = 0.030 +/- 0.002 min-1. The results of this analysis show that for tiagabine the combined "effect compartment-indirect response" model can be simplified to the classical "effect compartment" model.

Mechanism-based modeling of functional adaptation upon chronic treatment with midazolam.

PURPOSE: A mechanism-based model is applied to analyse adaptive changes in the pharmacodynamics of benzodiazepines upon chronic treatment in rats. METHODS: The pharmacodynamics of midazolam was studied in rats which received a constant rate infusion of the drug for 14 days, resulting in a steady-state concentration of 102 +/- 8 ng x ml(-1). Vehicle treated rats were used as controls. Concentration-EEG effect data were analysed on basis of the operational model of agonism. The results were compared to data obtained in vitro in a brain synaptoneurosomal preparation. RESULTS: The relationship between midazolam concentration and EEG effect was non-linear. In midazolam pre-treated rats the maximum EEG effect was reduced by 51 +/- 23 microV from the original value of 109 +/-15 microV in vehicle treated group. Analysis of this change on basis of the operational model of agonism showed that it can be explained by a change in the parameter tissue maximum (Em) rather than efficacy (tau). In the in vitro studies no changes in density, affinity or functionality of the benzodiazepine receptor were observed. CONCLUSIONS: It is concluded that the observed changes in the concentration-EEG effect relationship of midazolam upon chronic treatment are unrelated to changes in benzodiazepine receptor function.

Liquid chromatographic determination of the adenosine receptor agonist CGS 21680 in blood using on-line solid-phase extraction on a phenylboronic acid support and fluorescence detection.

An analytical method is described for the selective determination of A1 or A2 adenosine receptor agonists in blood. By implementing solid-phase extraction using immobilized-phenylboronic acid (PBA) in sample pretreatment, all adenosine derivatives are retained via their intact cis-diol group. On-line desorption of the analytes from the PBA support to the C18 analytical column is performed by injection of a small plug of perchloric acid. Fluorescence and UV detection are employed for the different adenosine derivatives. The method is applied to the determination of 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N- ethylcarboxyamidoadenosine (CGS 21680, I) in blood using fluorescence detection. The only off-line sample handling step is the extraction of blood with ethyl acetate and subsequent evaporation of the extraction solvent. The detection limit of the method was 0.25 ng (signal-to-noise ratio 3:1) and the determination limit for I in blood (pretreatment of 100 microliters) was 5 ng/ml. The method was validated and used to study the pharmacokinetics of I in rats.