Pharmacokinetic profile of tamsulosin OCAS

The tamsulosin oral‐controlled absorption system (OCAS®) is a new tablet formulation of the α₁‐adrenoceptor (α₁‐AR) antagonist tamsulosin, which is used for treating lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). The tablet uses the OCAS technology, which was specifically designed to give a more continuous 24‐h release of tamsulosin, resulting in a more consistent and continuous 24‐h plasma concentration, a lower maximum plasma concentration (C_max) and an independence of pharmacokinetics (PKs) on food intake. It was expected that the improved PK profile would translate into a better control of day‐ and night‐time symptoms of BPH and a lower risk of adverse events. Phase I PK studies showed that tamsulosin OCAS indeed has a flattened PK profile with a lower C_max and a more stable and consistent 24‐h concentration of tamsulosin, independent of food intake, compared to conventional tamsulosin. A study combining γ‐scintigraphy and PK analysis of blood samples confirmed that the improved PK profile of tamsulosin OCAS is attributed to the tablet being consistently and continuously released throughout the entire gastrointestinal tract, including the colon.     

Pharmacokinetic characteristics and tolerability of a novel intravenous immunoglobulin preparation

In two independent trials 10 and 12 healthy volunteers received the novel intravenous immunoglobulin (IVIG) preparations BT 511 and BT 507, respectively. BT 511 contains 5 g human plasma proteins per 100 ml, more than 95% of which are immunoglobulins of the G class (IgG). BT 507 contains in addition 61 IU antibody against hepatitis B surface antigen (anti-HBs)·ml^–1. In trial I volunteers received 4.0 ml/kg (n+4) and 8.0 ml·kg^–1 (n+6) BT 511 to study the tolerability and the magnitude of the increase in immunoglobulins in plasma as well as their decline over 1 month. After administration of the lower dose, plasma IgG increased from 10.7 to 14.7 g·l^–1 directly after the infusion. Following the 8.0 ml·kg^–1 dose a more pronounced increase from 12.4 to 21.2 g·l^–1 was observed. No adverse events occurred. After 1 month IgG concentrations had almost reached baseline values at 12.2 g·l^–1 in the 4.0 ml·kg^–1 group, but were still significantly increased at 15.2 g·l^–1 after the high dose. There was a linear correlation between the maximal IgG plasma concentration and the subsequent decline of IgG during the 29-day observation period. After administration of BT 507 maximal anti-HBs concentrations of 1778 mU·ml^–1 occurred 1.4 h after termination of the infusion. The terminal elimination half-life was 22.4 days, and total clearance and volume of distribution were determined to be 0.122 ml·min^–1 and 5.41, respectively. The pharmacokinetic parameters calculated for anti-HBs as an indicator of IgG were in accordance with the pharmacokinetic behaviour of native IgG.     

Influence of trastuzumab on epirubicin pharmacokinetics in metastatic breast cancer patients.

BACKGROUND: Anthracycline cardiotoxicity is increased by the contemporaneous administration of trastuzumab. The mechanism by which it occurs is as yet unknown. The aim of this study was to evaluate whether trastuzumab modifies the pharmacokinetics of epirubicin and its metabolites. PATIENTS AND METHODS: Women with HER2-positive metastatic breast cancer were treated with epirubicin 75 mg/m(2) i.v. bolus followed by docetaxel 75 mg/m(2) in a 1-h infusion, every 3 weeks for six cycles, and trastuzumab (once at 4 mg/m(2), then 2 mg/m(2) weekly thereafter) in a 30-min infusion. Epirubicin pharmacokinetic data of seven patients were evaluated at the first cycle of therapy (baseline, with trastuzumab administered 24 h after epirubicin), and at the sixth cycle (i.e. 15 weeks after baseline, with trastuzumab administered immediately before epirubicin). RESULTS: No pharmacokinetic change in the parent compound epirubicin was detected. The area under the plasma concentration-time curve (AUC(0-24 h)) was 1230 +/- 318 [mean +/- standard deviation (SD)] at the first cycle and 1287 +/- 385 h. micro g/l at the sixth. The mean (+/-SD) maximum plasma concentration (C(max)) and the terminal elimination half-life at the first cycle (1303 +/- 490 micro g/l and 12.5 +/- 3.1 h, respectively) were similar to those obtained at the sixth cycle (1229 +/- 580 micro g/l and 11.5 +/- 2.9 h, respectively). Pharmacokinetic data of epirubicin metabolites evaluated at the first and sixth cycle of chemotherapy were superimposable without any statistical difference. CONCLUSION: Enhanced anthracycline cardiotoxicity related to trastuzumab administration was not linked to pharmacokinetic interferences with epirubicin and its metabolites.     

附子理中丸方药的药物动力学研究

附子理中丸是中医治疗脾胃虚寒、脘腹冷痛、呕吐泄泻、手足不温的常用成药。本文通过小白鼠急性死亡实验,测得ip LD_(50)=42.4870g/kg;运用药物累积法对该复方方药进行了药物动力学研究。结果表明:附子理中丸在小鼠体内按一级动力学消除,呈二房室开放式模型分布。测得其t_(1/2)α=0.1922h,t_(1/2)β=11.2888h等动力学参数。阐明了该药的体内动态过程,为评价该药的内在质量及临床安全合理应用提供了参考依据。     

Comparing non-hierarchical models: Application to non-linear mixed effects modeling

There is no method available to compare the fit of two non-hierarchical non-linear mixed effects models, although the common practice is to select the model with the lower objective function. Bootstrapping the log-likelihood differences (LLDs) of non-hierarchical models and constructing a bootstrap confidence interval on the LLDs is proposed for comparing the goodness-of-fit of such models. This is illustrated with different parameterizations of clearance models for an anti-infective agent in a longitudinal pharmacokinetic study which are compared. Additive and exponential models of creatinine clearance as a predictor of clearance are used as examples.     

局麻药药代动力学研究进展

药物对映体结构特异性对局麻药药代动力学的各个过程都有着很大影响,包括药物的吸收、蛋白结合率、代谢等。近年研究较多的罗哌卡因和左旋布比卡因作为单一的左旋对映异构体,因其良好的局麻效应和较小的全身毒性正引起广泛的关注。     

Ocular pharmacokinetic models of clonidine-3H hydrochloride

A single topical instillation of clonidine-³H HCl solution (0.2%) was administered to the rabbit eye (30 μl) in order to study the drug's ocular pharmacokinetics. Seven different tissues and plasma were excised and assayed for drug over 180min. By 45–60 min pseudoequilibrium is reached for the cornea, iris/ciliary body, and aqueous humor. Thereafter, drug levels in these tissues decline in parallel. The data are fit separately to a physiological model and a classical diffusion model for which seven ocular tissue compartments and a plasma reservoir are constructed for each model. Clearance terms and distribution equilibrium coefficients are determined from the tissue level data and used as parameters in fitting the mass balance differential equations representing the physiological model. The model parameters can also be fit to a 0.4% single dose. In a separate experiment, a topical infusion technique was designed to provide a constant rate input to the cornea until an apparent steady state was reached in aqueous humor at 55 min. Aqueous humor levels were assayed for clonidine over the infusion and postinfusion periods. The physiological model parameters are fit to the topical infusion data and show good agreement between the predicted and experimental data. The classical model is too complex to fit the data to integrated exponential equations primarily because the method of residuals is inadequate in determining a sufficient set of initial estimates. This is overcome by dividing the eight-compartment model into seven fragmental models, each representing one to five compartments. A stepwise procedure is developed in which initial estimates are obtained for each separate fragmental model and refined. The refined parameter values can then be used as initial estimates for the complex model. Differential equations for the complex model are fit simultaneously to tissue levels representing each compartment. By observation, the classical model fit the data more closely than the physiological model. Statistical moment theory is also applied to the topical infusion data to determine ocular pharmacokinetic parameters for clonidine. The calculated values are: corneal absorption rate constantk _a , 0.00139 min^?1; aqueous humor elimination rate constantk ₁₀ , 0.0658min^?1; mean residence timeMRT _d , 35.6 min; apparent steadystate volume of distributionV _ss, 0.530 ml; and ocular clearanceQ _e , 14.9 =μl/min. The fraction absorbed from the single instillation is estimated as 0.0163.     

三种估算药动学—药效学参数方法的比较及应用

根据三种估算药动学和药效学结合模型参数的方法编制了软件。参数法包括十个药动学模型和三种药效学模型,可以同时求算药动学和药效学参数;非参数药效模型法不必预先假设药效学模型就可估算出反映药物效应的消除速率常数(K_(eo));非参数药效模型法中,药动学模型也用非参数方法描述,只要输入药动—药效数据就可求出K_(ro)。对6例吸入大麻的健康志愿者的药动—药效数据,用以上方法进行验算,结果表明三种方法各有优点,应比较使用。