Quantitative structure-pharmacokinetic/pharmacodynamic relationships

Quantitative structure-activity relationships have long been considered a vital component of drug discovery and development, providing insight into the role of molecular properties in the biological activity of similar and unrelated compounds. Recognition that in vitro bioassay and/or pre-clinical activity are insufficient for anticipating which compounds are suitable leads for further development has shifted the focus toward integrated pharmacokinetic (PK) and pharmacodynamic (PD) processes. Over the last decade, considerable progress has been made in constructing empirical and mechanistic quantitative structure-PK relationships (QSPKR), as well as diverse mechanism-based pharmacodynamic models of drug effects. In this review, traditional and contemporary approaches to developing QSPKR models are discussed, along with selected examples of attempts to couple QSPKR and pharmacodynamic models to anticipate the intensity and time-course of the pharmacological effects of new or related compounds, or quantitative structure-pharmacodynamic relationships modeling. Such models are in accordance with the goals of systems biology and the ideal of designing drugs and delivery systems from first principles.     

喹诺酮类化合物的定量构动关系

目的应用量子化学和神经网络方法,研究喹诺酮类化合物的的定量构动关系。方法计算了21个喹诺酮类化合物的结构参数,建立了含两个隐含层的反传神经网络定量构动关系模型。输出层为试验获得的喹诺酮类化合物的3个药动学参数Cm ax、AUC和t1/2;输入层为筛选出的喹诺酮类化合物的6个结构参数。结果随机挑选20个化合物作为训练集并进行leave-one-out分析。剩下1个化合物作为预测集,预测结果能够很好地与试验数据相吻合。结论所建立的定量构动关系模型能够有效地分析喹诺酮类化合物的定量构动关系。     

药物生物利用度的定量构动关系研究

目的 确定药物分子结构与药物的生物利用度之间的关联关系，以得到一种能够对药物的生物利用度进行定量预测的模型，对药物的生物利用度进行预测。方法 计算药物分子的理化、量化参数，并用神经网络对药物分子的理化、量化参数与药物的生物利用度进行关联。结果 利用得到的关联关系预测了药物的生物利用度，预测结果令人满意。结论 根据所用的方法，利用药物分子的理化、量化参数可预测药物的生物利用度。     

抗生素药物血浆蛋白结合率的定量构动关系

目的 应用人工神经网络方法对61种抗生素进行药物分子结构和药物血浆蛋白结合率的定量结构—药物动力学关系的研究(QSPR)。方法 建立了含一个隐含层的反传神经网络，输出层为实验获得的药物血浆蛋白结合率；输入层为计算获得的药物分子的理化参数，量化参数和分子连接性指数等药物分子结构参数。为了验证网络训练结果，随机挑选51个药物为训练集，进行了1eave—one—out分析。结果 最后利用挑选剩下的10个药物进行预测，其血浆蛋白结合率的预测值能很好地与实验数据相吻合。结论所建立的神经网络模型能够有效地进行药物血浆蛋白结合率与药物分子结构的相关性分析。同时也证明了人工神经网络功能强大，将成为药物QSPR研究的一个有效工具。     

Comparison of the fluoroquinolones based on pharmacokinetic and pharmacodynamic parameters

Assessment of pharmacodynamic activity from standard in vitro minimum inhibitory concentrations (MICs) alone is insufficient to predict in vivo potency. Achievable serum and tissue concentrations as well as pharmacokinetic characteristics must be considered. When pharmacokinetic and pharmacodynamic values are combined, the area under the inhibitory curve (AUIC) and peak concentration:MIC ratio predict clinical cure for fluoroquinolones. Clinical data and animal models indicate that a peak:MIC of 10:1 and above and an AUIC of 125 and above are predictive of a clinical cure for this class of antimicrobials against gram-negative organisms. The values may be used to compare and contrast fluoroquinolones to determine which would be best for treating a specific microorganism. Pharmacodynamic data also can be used to design regimens that minimize the risk of suboptimal drug levels. Ensuring the optimal fluoroquinolone dosage based on pharmacodynamic principles would diminish the emergence of resistant organisms and prevent treatment failures.     

Evaluation of survival and pharmacodynamic relationships for five fluoroquinolones in a neutropenic murine model of pneumococcal lung infection

STUDY OBJECTIVE: To compare the antistreptococcal activity of five fluoroquinolone antibiotics, using a neutropenic murine model of pneumococcal pulmonary infection. DESIGN: Animal experiment. SETTING: University-affiliated research center. ANIMALS: Neutropenic and control mice weighing 24-29 g. INTERVENTION: After induction of neutropenia, renal failure, and infection with Streptococcus pneumoniae, the mice received one of five fluoroquinolones twice/day for 72 hours beginning 12 hours after infection. Dosages were selected to approximate 0.1 x AUC0-24 (area under the concentration-time curve from 0-24 hours) and AUC0-24 achieved in humans. Control mice received normal saline. Survival was assessed at regular intervals for up to 10 days. At least 10 mice were included in each cohort (range 10-34). MEASUREMENTS AND MAIN RESULTS: Ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, and moxifloxacin were studied at subtherapeutic and therapeutic dosages against three quinolone-susceptible isolates of S. pneumoniae that lacked mutations in parC, parE, and gyrA. Pharmacokinetic profile of each agent and dosing regimen was determined. A composite survival curve for all fluoroquinolones and isolates was constructed. Relationships between survival rate at 72 hours and AUC:MIC (minimum inhibitory concentration), peak:MIC, time above the MIC (percentage of dosing interval) for total and free drug concentrations were fit by using a sigmoid maximal effect (Emax) model. Survival was significantly better in the higher dosage group than in the lower dosage group. Time above MIC did not display a correlation with outcome. The AUC:MIC showed a greater correlation with outcome (R2 = 0.56 total, 0.54 free) than did peak:MIC (R2 = 0.52 total, 0.51 free). With use of composite data, total AUC:MIC ratios associated with 50%, 90%, and 99% of Emax were 34:1, 56:1, and 95:1, respectively CONCLUSIONS: In this model, efficacy was achieved with the fluoroquinolone antibiotics at dosages yielding AUC0-24 comparable to those obtained in humans. One pharmacodynamic parameter (i.e., AUC:MIC) may be applied to various fluoroquinolones and isolates of S. pneumoniae. The AUC:MIC was more predictive of outcome than was time above the MIC or peak:MIC.     

Pharmacokinetic/pharmacodynamic relationship of eptazocine, a narcotic-antagonist analgesic, in rats

The relationship between the pharmacokinetics and the pharmacodynamics of eptazocine, a narcotic-antagonist analgesic, was investigated in rats. The analgesic effect of eptazocine (2.5, 5 and 10 mg/kg) following intravenous (i.v) administration was evaluated by both the Randall-Selitto method and the D'Amour-Smith method. The analgesic effects were determined before and at designed intervals for a period of 120 min after eptazocine administration, and are expressed as area under the effect-time curve (AUC(E)). The plasma concentration of eptazocine was determined by fluorescence HPLC and was analyzed with a two compartment open model using the nonlinear least-squares method. Eptazocine produced a dose-dependent analgesic effect. It was demonstrated that eptazocine has a linear relationship between AUC(E) and the area under the plasma concentration-time curve (AUC) following i.v. administration for three different doses ranging from 2.5 to 10 mg/kg.     

Methodology for pharmacokinetic/pharmacodynamic data analysis

This review will highlight the role of exploratory data analysis and nonlinear regression software in pharmacokinetic–pharmacodynamic (PK/PD) data analysis. Kinetic and dynamic modelling situations typical to the pharmacokineticist in the drug industry will be addressed, and two case studies, including single-dose intravenous bolus plasma data and multiple-dose response-time data will be analysed. Approaches to assessing the suitability of model fit to the observed data will be discussed, and a summary of the key features of available commercial PK software will be given. Specific emphasis will be placed on the application of WinNonlin.     

喹诺酮类药物与老年抗生素相关性精神异常的关系

目的:观察喹诺酮类药物与老年抗生素相关性精神异常的关系。方法:选择2015年—2016年收治的使用喹诺酮类药物的感染患者643例,分析两年间喹诺酮类药物引起的不同程度的精神异常,并观察2016年通过采取改善措施后精神异常发生情况。结果:2016年喹诺酮类抗生素引起的精神异常较2015年明显减少(P<0.05)。结论:老年患者需谨慎使用喹诺酮类药物,从而减少其相关精神异常的发生。     

New findings on the structure-phototoxicity relationship and photostability of fluoroquinolones

The present study examined the phototoxicities of a series of 7-(3-aminopyrrolidinyl) quinolones containing various substituents at position 1 by use of a mouse model. For the 7-(3-aminopyrrolidinyl) quinolones with a halogen atom at position 8, well-known substituent groups such as a cyclopropyl, an ethyl, or a difluorophenyl at position 1 were found to be responsible for severe phototoxicity. However, when an aminodifluorophenyl or an isoxazolyl group was placed at position 1, even 8-halogeno quinolones were found to be mildly phototoxic. This is the first report of 8-halogeno quinolones that are not severely phototoxic. Two structurally similar 8-chloro quinolones (the 1-aminodifluorophenyl 8-chloro quinolone and the 1-difluorophenyl 8-chloro quinolone) were investigated further. The former was mildly phototoxic; the latter was severely phototoxic. We demonstrate that these two 8-chloro quinolones have practically the same areas under the concentration-time curves from 0 to 4 h in auricular tissue, suggesting that the mild phototoxicity is not due to pharmacokinetic instability. The rates of UV photodegradation of these compounds were also measured. We found that these two quinolones photodegrade at similar rates, suggesting that the mild phototoxicity is not attained through increased photostability. In conclusion, the phototoxic potentials of fluoroquinolones are influenced not only by the substituent at position 8 but also by that at position 1. We also discovered a mildly phototoxic 8-chloro quinolone which did not have increased photostability.     

Quantitative analysis of fluoroquinolones by 1H- and 19F-NMR spectroscopy

¹H- and ¹⁹F-NMR assay of pefloxacin (I), norfloxacin (II) and ofloxacin (III) in some pharmaceutical forms has been developed. The method, based on the integration of appropriate signals of both analytes and internal standards, is simple, rapid, precise, and accurate, and can be used for quality control of these drugs.     

In vitro activities of mutant prevention concentration-targeted concentrations of fluoroquinolones against Staphylococcus aureus in a pharmacodynamic model

To test the validity of the mutant selection window, we simulated mutant prevention concentration-targeted fluoroquinolone concentrations using an in vitro model with infected fibrin clots. Therapeutic ciprofloxacin (peak 5 microg/mL; t(1/2) 4 h), gatifloxacin (3.5 microg/mL; 8h), gemifloxacin (1.25 microg/mL; 8 h), levofloxacin (6 microg/mL; 6 h) and moxifloxacin (4.5 microg/mL; 12 h) were tested against methicillin-susceptible and -resistant Staphylococcus aureus, as were mutant prevention concentration (MPC)-targeted regimens achieving a trough of 1/4x or 2x MPC. MIC/MPC for MSSA K553 were 0.125/2, 0.03/0.125, 0.03/0.063, 0.125/1 and 0.015/0.25 microg/mL for ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin, respectively. Corresponding values for MRSA 494 were 0.125/1, 0.063/0.125, 0.03/0.063, 0.125/0.5 and 0.063/0.125 microg/mL. All regimens produced efflux mutants of MSSA K553. For MRSA 494, therapeutic and 1/4x MPC levofloxacin regimens produced resistance, whereas only 1/4x MPC regimens of gatifloxacin, gemifloxacin, and moxifloxacin produced resistance. All ciprofloxacin regimens produced resistance. Ciprofloxacin 1/4x MPC and therapeutic levofloxacin caused outgrowth of GrlA mutants (S80Y amino acid substitution); efflux mutants were isolated in all other cases. Overall, gatifloxacin, gemifloxacin, and moxifloxacin displayed a lesser propensity to select resistant isolates of S. aureus than ciprofloxacin and levofloxacin. The mutant selection window premise appeared valid for MRSA only. Additional studies are necessary to define the applicability of the MPC.     

Evaluation of pharmacokinetic and pharmacodynamic relationship for oral sustained-release atenolol pellets in rats

This study was designed to evaluate the in vitro release, pharmacokinetics (PK), pharmacodynamics (PD) and PK-PD relationships of atenolol sustained-release pellets (AT-SRPs), compared with those of atenolol immediate-release pellets (AT-IRPs). Blood sampling for AT plasma concentration was performed in normal rats and blood pressure-lowering effects were recorded continuously in hypertensive rats (HRs) before and at 1, 4, 8, 12, 16 and 24 h after drug administration. The parameters were calculated using DAS1.0 program and WinNonlin software. The release profile of SRPs was steadier and more sustained than that of IRPs. The mean Cmax and area under concentration-time curve from 0 to 24 h after administration (AUC0-24 h) of SRPs were significantly lower than that of IRPs (p<0.05), while area under concentration-time curve from 0 to infinity (AUC0-∞) was almost equivalent between the two formulations. The mean half life time (t1/2) of AT-SRPs was almost 2 times longer compared to that of AT-IRPs. The SRPs approximately achieved half of peak drug effect (Emax) of IRPs, while there were no significant differences in the area under effect-time curve from 0 to 24 h after administration (AUEC0-24 h) and the area under effect-time curve from 0 to infinity (AUEC0-∞). The value of the rate constant of equilibration between plasma and the effect-site (ke0) for SRPs was about 4 times higher than IRPs. The effect-concentration-time course for AT-SRPs was represented by the clockwise hysteresis loop, while the counter-clockwise hysteresis loop well showed that for AT-IRPs. The more favorable characteristics of SRPs would make it more appropriate as a potential dosage form for the treatment of hypertension.     

Ocular pharmacokinetic/pharmacodynamic modeling for multiple anti-glaucoma drugs

We have constructed a new ocular pharmacokinetic pharmacodynamic (PK/PD) model for anti-glaucoma drugs to describe ocular hypotensive effects on intraocular pressure (IOP) after instillation of a combination of an alpha(1)-adrenergic antagonist, bunazosin, and a beta-adrenergic antagonist, timolol, into rabbits. This model was constructed by the combination of two ocular PK/PD models for bunazosin and timolol by including aqueous humor dynamics based on both action mechanisms. We also verified the reliability of this model by confirming the drug concentrations in aqueous humor and ocular hypotensive effects after instillation of the drug combination. The aqueous humor concentrations of timolol and bunazosin were determined by an HPLC, and ocular hypotensive effect-time profiles were measured using a telemetry system, which was able to record automatically detailed effects. The combined model could simulate the aqueous humor concentrations of both drugs and the additive IOP-lowering effect after instillation of the combination using the MULTI (RUNGE) program and PK/PD parameters which were obtained from ocular hypotensive effects after instillation of bunazosin alone or timolol alone. The theoretical concentration curves of both drugs in the aqueous humor and the theoretical ocular hypotensive effect curves almost agreed with both the observed concentrations and ocular hypotensive effects after instillation of the drug combination. These results indicate the reliability and usefulness of PK/PD modeling considering aqueous humor dynamics to predict IOP in multidrug therapy. This is the first study to develop a PK/PD model for multidrug therapy for the eye.