Journal of Pharmacokinetics and Biopharmaceutics最新文献

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.

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16-21% was predicted for FP 250 micrograms, FLU 500 micrograms, and TCA 1000 micrograms. For multiple dosing, a respective CCS of 28-33% was calculated for FLU 500 micrograms bid, FP 250 micrograms, bid, and TCA 1000 micrograms bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.

Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor alpha-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 microgram/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20 mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7-52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7-58.3 days.

In pharmacokinetic/pharmacodynamic (PK/PD) modeling the first blood sample is usually taken 1 to 2 min after drug administration (late sampling). Therefore, investigators have to extrapolate the plasma concentration to Time 0. Extrapolation, however, erroneously assumes instantaneous and complete mixing of drug in the central volume of distribution. We investigated whether plasma concentrations obtained from early arterial blood sampling would improve PK/PD modeling. In 14 pigs, one of five neuromuscular blocking agents (NMBAs) was administered into the right ventricle within 1 sec and arterial sampling was performed every 1.2 sec (1st min). The response of the tibialis muscle was measured mechanomyographically. The influence of inclusion of data from early arterial sampling on PK/PD modeling was determined. Furthermore, the concentrations in the effect compartment at 50% block (EC50) derived from modeling were compared to the measured concentration in plasma during a steady state 50% block. A very high peak in arterial plasma concentration was seen within 20 sec after administration of the NMBA. Extensive modeling revealed that plasma concentrations obtained from early arterial blood sampling improve PK/PD modeling. Independent of the type of modeling, the EC50 and KeO based on data sets that include early arterial blood sampling were, for all five NMBAs, significantly higher and lower respectively, than those based on data sets obtained from late sampling. Early arterial sampling shows that the mixing of the NMBA in the central volume of distribution is incomplete. A parametric PD (sigmoid Emax) model could not describe the time course of effect of the NMBAs adequately.

Sumatriptan is indicated for the treatment of migraine attack and cluster headache; it is currently marketed as a subcutaneous injection, nasal spray, and oral tablet. New formulations are under consideration. The knowledge of sumatriptan absorption, combined with PK/PD information would help the design of more efficient formulations. In this perspective, we attempted to model the absorption of sumatriptan by population PK analysis. Data following administration by the intravenous (i.v.), the subcutaneous (s.c.), and the oral (po) route in healthy subjects were analyzed. A large database with full kinetic profiles was constituted. Sumatriptan was administered to 215 healthy subjects (i.v., s.c., and po) and to 143 migraine sufferers (po). The mean age was 31 years (18-86 years) in healthy subject population and was 38 years (18-65 years) in migraine patients. The mean weights were 74 kg (54-104 kg) and 66 kg (38-136 kg) in healthy subjects and migraine patients, respectively, and the mean heights were 176 cm (157-193 cm) and 164 cm (152-183 cm) in healthy subjects and migraine patients, respectively. A NONMEN analysis was performed using a two-compartment disposition model. Oral absorption was modeled with a first-order input followed by a zero-order input. Less biased results were obtained using the FOCE method. The total clearance and the distribution volume at steady state were 71.2 L/hr and 94.5 L after i.v. dosing and 68.7 L/hr and 109 L after inclusion of the s.c. and po data. The absorption phase appeared to last for about 5 hr. The interindividual variability of the main PK parameters was low: It was around 20% for the total clearance and around 30% for the distribution volume at steady state. Although significant, the combination of age and height on clearance did not decrease considerably the interindividual variability of this parameter (decrease of 2.2%); nor was it possible to establish clearly if a migraine attack has an effect on drug absorption because of the sampling scheme during absorption. Simulations have shown that it would have been possible to estimate all the PK parameters with a data set reduced to one quarter of its actual number of samples.

Based on toxicokinetic studies of a destructive sampling design, this work was aimed at selecting the number of time points, their locations, and the number of replicates per time point in order to obtain the most accurate and precise noncompartmental estimate of the area under the concentration-time curve (AUC). From a prior population pharmacokinetic model, the design is selected to minimize the scaled mean squared error of AUC. Designs are found for various sample sizes, number of time points, and a distribution of animals across time points from being very unbalanced to balanced. Their efficiencies are compared both theoretically and based on simulations. An algorithm has been implemented for this purpose using the symbolic resolution and numerical minimization capabilities of Mathematica and an example of its use is provided. This method provides efficient tools for constructing, validating, and comparing optimal sampling designs for destructive sampled toxicokinetic studies.

Characteristics of the methods for estimating individual pharmacokinetic parameters are compared both theoretically and numerically. The methods examined represent the range of most of modern methods and include the ordinary least squares, iteratively reweighted least squares, extended least squares, generalized least squares, maximum quasi-likelihood and its extended scheme, and minimum relative entropy methods. When the function representing the mean itself is used as a variance function, which may be then related to a Poisson distribution, the iteratively reweighted least squares estimator and maximum quasi-likelihood estimator are both identical to that of the minimum relative entropy method. These methods work by minimizing a kind of relative entropy between observed data and corresponding theoretical values. Furthermore, these methods guarantee agreement between the sum of the observed values and the estimate of the sum. This relation does not hold in general for the other estimators. The sum can, in a sense, be viewed as an approximation of the area under the curve. In addition, it is shown by numerical study that these methods are robust against the misspecification of the variance model and work as effectively as such sophisticated methods as the extended least squares, generalized least squares, and maximum extended quasi-likelihood methods. These sophisticated methods require complicated numerical optimization techniques and should be used only in cases where the estimation of the variance function is demanded. In the other cases, the method of minimum relative entropy or its equivalent is sufficient or even preferable for estimating individual pharmacokinetic parameters.

Sampling times for Bayesian estimation of the pharmacokinetic parameters of an antidepressant drug, nortriptyline, during its therapeutic drug monitoring were optimized. Our attention was focused on designs including a limited number of measurements: one, two, and three sample designs in which sampling times had to be chosen between 0 and 24 hr after the last intake of a test-dose study. The optimization was conducted in four groups of patients defined by their gender and the administration or not of concomitant drugs inhibiting the metabolism of nortriptyline. The Bayesian design criterion was defined as the expected information provided by an experiment. A stochastic approximation algorithm, the Kiefer-Wolfowitz algorithm, was used for the criterion maximization under experimental constraints. Results showed that optimal Bayesian sampling times differ between patients in monotherapy and polytherapy. For one-sample designs the measurements have to be performed either at the lower (0 hr) or at the upper (24 hr) bound of the admissible interval. Replications were often found for 2- and 3-point designs. Other sampling designs can lead to criterion close to the optimum and can therefore be performed without great loss of information. In contrast, we found that several designs lead to low values of the information criterion, which justifies the approach.

Prednisolone (Pred) and sirolimus (SIR) are immunosuppressive compounds acting through different mechanisms with moderate synergism found in vitro. Both drugs are metabolized partly by CYP3A enzymes. After i.v. administration of placebo, Pred (5 mg/kg), SIR (1 mg/kg), or Pred with SIR (5 and 1 mg/kg doses) to adrenalectomized male rats, Pred plasma and SIR whole blood concentrations were followed for 48 hr along with circulating T-helper and T-cytotoxic cell counts. Ex vivo whole blood lymphocyte proliferation marked host responsiveness. An extended indirect PK/PD model was used to describe responses to these drugs, alone or combined. An interactive two-stage population analysis showed no modification in drug PK. Mean Pred plasma clearance was 0.655 L/hr (interrat++ variability: 11%) and significantly increased with weight. Mean SIR whole blood volume of distribution and clearance were 5.6 L (62%) and 0.28 L/hr (32%), and animal scaling showed weight-power proportionality. In vitro metabolism studies showed no significant inhibition of Pred or prednisone CYP3A metabolism by SIR (50 microM), but this pathway accounted for less than 5% of Pred metabolism. Pred decreased numbers of T-helper lymphocytes with a mean IC50 of 37.8 nM (21%) alone or 12.3 nM (130%) with SIR. Results for T-cytotoxic lymphocytes were similar. SIR increased lymphocyte numbers with a mean IC50 of 52.2 nM (24%) for T-helper and 28.8 nM (51%) for T-cytotoxic cells. Taking into account drug effects on lymphocyte trafficking, Pred directly inhibited ex vivo lymphocyte proliferation with a mean IC50 of 1.08 nM (38%). SIR, after a transduction step, inhibited proliferation with a mean IC50 of 1.00 nM (26%). Responses measured after drug coadministration were reasonably quantitated by addition of single drug effects. Since, at pharmacologic concentrations in rats, Pred and SIR did not interact in their PK but synergistically or additively interact in their dynamics, their joint therapeutic use is promising. The adrenalectomized rat may be a suitable animal model to characterize drug effects on lymphocyte trafficking and reactivity.

Different mixed-effects models were compared to evaluate the population dose-response and relative potency of two albuterol inhalers. Bronchodilator response was measured after ascending doses of each inhaler in 37 asthmatic patients. A linear mixed-effects model was developed based on the approach proposed by Finney for the evaluation of bioassay data. A nonlinear mixed-effects (Emax) model with interindividual and interoccasion variability (IOV) in the different pharmacodynamic parameters was also fit to the data. Both methods produced a similar estimate of relative potency. However, the estimate of relative potency was 22% lower with the nonlinear mixed-effects model if IOV was not taken into account. Monte Carlo simulations based on a similar study design demonstrated that more biased and variable estimates of ED50 and relative potency were obtained when the nonlinear mixed-effects model ignored the presence of IOV in the data. Furthermore, the linear mixed-effects model that did not account for IOV produced confidence intervals for relative potency that were too narrow and thus could lead to erroneous conclusions. These problems were avoided when the estimation model could account for IOV. Results of the simulations were consistent with those of the experimental data. Although the linear or the nonlinear mixed-effects model may be used to evaluate population dose-response and relative potency, there are important differences in the assumptions made by each method.