Table of Content

Volume 12 Issue 10
26 October 2007

Invited review
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Invited review

Quantitative pharmacology in a translational research environment

Jeffrey S Barrett

2007, 12(10):  1081-1088. 

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Translational research is generally described as the application of basic science discoveries to the treatment or prevention of disease or injury.Its value is usually determined based on the likelihood that exploratory or developmental research can yield effective therapies.While the pharmaceutical industry has evolved into a highly specialized sector engaged in translational research, the academic medical research community has similarly embraced this paradigm largely through the motivation of the National Institute of Health (NIH) via its Roadmap initiative.The Clinical and Translational Science Award (CTSA) has created opportunities for institutions which can provide the multidisciplinary environment required to engage such research.A key component of the CTSA and an element of both the NIH Roadmap and the FDA Critical Path is the bridging of bench and bedside science via quantitative pharmacologic relationships.The infrastructure of the University of Pennsylvania (Penn) Children' s Hospital of Philadelphia CTSA is highlighted relative to both research and educational objectives reliant upon quantitative pharmacology.A case study, NIHsponsored research program exploring NK1r antagonism for the treatment NeuroAIDS is used to illustrate the application of quantitative pharmacology in a translational research paradigm.

Pharmacokinetic and pharmacodynamic evaluation of biologics:challenges and pitfalls

Bernd Meibohm

2007, 12(10):  1089-1098. 

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In recent years, biotechnologically-derived peptides and proteins have developed into mainstream therapeutic agents.Peptide and protein drugs now constitute a substantial portion of the compounds under preclinical and clinical development as well as in clinical practice.The understanding of the pharmacokinetics and pharmacodynamics, including the dose-concentration-effect relationship, is crucial to any drug-including peptides and proteins-as it lays the foundation for optimal dosing regimen design and rational clinical application.Compared to traditional small molecule-based therapeutics, pharmacokinetic and exposure/response evaluations for peptide and protein therapeutics are frequently complicated by their similarity to endogenous peptides and proteins as well as nutrients, by their intimate involvement in physiologic processes on the molecular level, by their macromolecule character and immunogenicity, and by analytical challenges to identify and quantify them in the presence of a myriad of similar molecules.Peptides and proteins, unlike conventional small molecule drugs, are generally not therapeutically active upon oral administration, and selection of the most appropriate route of administration requires comprehensive knowledge of their absorption characteristics beyond physicochemical properties, including chemical and metabolic stability at the absorption site, immunoreactivity, passage through biomembranes, and active uptake and exsorption processes.Various distribution properties dictate whether peptide and protein therapeutics can reach optimum target site exposure in order to exert the intended pharmacological response.Binding phenomena and receptor-mediated cellular uptake may further complicate this issue.Elimination processes-a critical determinant for the drug' s systemic exposure-may follow a combination of numerous pathways, including renal and hepatic metabolism routes as well as generalized proteolysis and receptor-mediated endocytosis. Pharmacokinetic/pharmacodynamic (PK/PD) correlations for peptide and protein-based drugs are frequently convoluted by their close interaction with endogenous substances and physiologic regulatory feedback mechanisms.
The manuscript highlights some of the major pharmacokinetic properties and processes relevant for the majority of biologics and will provide examples of well characterized pharmacodynamic relationships for peptide and protein therapeutics.Appreciation of the pharmacokinetic and pharmacodynamic differences between therapeutic biologics and traditional small molecule drugs will empower the drug development scientist as well as the healthcare provider to handle, evaluate and apply these compounds in an optimal fashion during the drug development process as well as in applied pharmacotherapy

Integretion of pharmacokinetics and pharmacodynamics in antibacterial drug development and pharmacotherap

SHI Jun

2007, 12(10):  1099-1113. 

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There is a pressing need for new antibacterial agents due to the development of drug-resistant pathogens.Unfortunately drug development is a difficult and complicated process.The traditional approach in searching for a right dose is quite empirical, both costly and time-consuming.To enhance the ability to predict the likelihood of success for lead compound selection, in vitro pharmacodynamic and in vivo animal infection models are now extensively used.The value of these pre-clinical experiments, combined with mathematical modeling, helps to identify a pharmacokinetic (PK) -pharmacodynamic (PD) exposure measure which best predicts the therapeutic efficacy, and to quantify the magnitude of this index required for in vivo efficacy.PK-PD target attainment analyses using Monte Carlo simulation to integrate interpatient variability in drug exposure (PK), drug potency (MIC), and in vivo exposure targets that are predictive of positive therapeutic outcomes are influencing antibacterial drug development for proof of concept, for dose and dosing interval selection, for determining susceptibility breakpoints, and for evaluating the clinical meaning of antibacterial resistance.In this article, the key concepts of antibacterial PK-PD and model based antibacterial drug development strategy and process are critically reviewed.

Application of Bayesian Methods for laboratory to clinical translation and for identifying hidden subpopulations

David Z. D’ Argenio, WANG Xiao-ning, ZHOU Ze-xun

2007, 12(10):  1114-1121. 

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Modeling methodologies developed for studying pharmacokinetic (PK)/pharmacodynamic (PD) processes confront many challenges related in part to the severe restrictions on the number and type of measurements that are available from laboratory experiments and clinical trials, as well as the variability in the experiments and the uncertainty associated with the processes themselves.Bayesian methods have provided a framework for PK/PD modeling and drug development that can address some of the above-mentioned challenges.This paper presents two illustrations of the application of Bayesian methods :the first involves a population modeling study of the cellular kinetics of the antiretroviral compound Lamivudine in the PBMCs of HIV-1 infected adolescents ;the second uses a population mixture modeling approach to identifying hidden subpopulations that can not be identified by available measured covariates.

Challenges in research and development of Traditional Chinese Medicines

LIU Chang-xiao, SI Duan-yun, XIE Hai-tang

2007, 12(10):  1122-1129. 

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In this review, the author analyzed the challenges in modern research and development of Traditional Chinese Medicine (TCM) products.Chinese traditional and herb drugs have gained interest from the international medical, biomedical and pharmaceutical institutions as potential source of valuable medicinal agents.For the researches and development of TCMs, the first challenge is to evaluate the efficacy, pharmacological properties, action mechanism and active chemical constituents. The second one is to summarize the issues for developing safety research methodologies, to improve the quality and enhance the value of research in TCM and to provide appropriate evaluation methods to facilitate the regulation and registration of TCM products, and the third is to study drug metabolism and pharmacokinetics, and the fourth is to apply new “-omics” techniques and tools in new revolution in drug discovery-development and to impact on modern research of TCM products.This interest is needed to apply modern research on the development and exploration of the promising medical potential resources of Chinese traditional and herbal drugs, especially from medicinal plants.

Full article

Effects ofβ₁-adrenergic receptor and CYP2D6 genetic polymorphism on metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy

LIU Jie, LIU Zhao-qian, LIU Ying-zi, TAN Zhi-rong, HU Dong-li, LI Zhi, WANG Dan, ZHANG Wei, ZHOU Hong-hao

2007, 12(10):  1130-1137. 

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BACKGROUND: Metoprolol is a selectiveβ₁-Blocker commonly used in essentiaL/hypertension. It is metabolized by CYP2D6.CYP2D6 *10, which was identified to decrease activity of CYP2D6, is the main variance in Chinese population.β1-adrenergic receptor, with Ser49Gly and Gly389Arg polymorphisms, is the target of metoprolol.It was still unknown that whether the CYP2D6 andβ₁-adrenergic receptor had a synergic effect on metoprolol antihypertension therapy. AIM: To clarify the genetic polymorphism associated with metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy. METHODS: 125 mild-to-med essentiaL/hypertension patients were enrolled in this study.Patients were mono-therapied with metoprolol for 12 weeks.Blood pressure was monitored every 4 weeks.PCR-RFLP method was use to identify CYP2D6 *10 andβ₁-adrenergic receptor Ser49Gly and Gly389Arg polymorphisms.Plasma metoprolol concentration was measured by HPLC- fluorescence detection. RESULTS: Trough blood level (C0)of metoprolol was associated with CYP2D6 *10 variance in a gene-dose-effect manner, whereas the extent of blood pressure decrease was not significant different in CYP2D6 *1 *1, *1 *10 and CYP2D6 *10 *10 patients. After 12 weeks metoprolol therapy, Gly49 carriers had stronger decrease in systolic and diastolic blood pressure than that of Ser49 homozygotes.Similarly, subjects homozygous for Arg389 had stronger decrease in blood pressure than that of Gly389 carriers.CONCLUSION: CYP2D6 *10 variance significantly change the pharmacokinetics of metoprolol, and the genetic polymorphisms of β₁-adrenergic receptorwere associated with the pharmacodynamics of metopolol in antihypertension therapy.

Population pharmacokinetics of Guanxin Ⅱ prescription

CHEN Wen-qian, HU Yu-hui, ZHANG Yan-qing, ZHANG Guan-min, LI Liang, ANG Wei-ning, LU Wei

2007, 12(10):  1138-1143. 

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AIM: To evaluate the effect of components in Guanxin Ⅱ prescription on the pharmacokinetic profiles of paeoniflorin and ferulic acid. METHODS: Drug concentrations of rat plasmas after intravenous injection of paronia pall (PPE) or ferulic acid (FA) extract solution, as well as oral administration of PPE and FA solution, and different kinds of decoctions based on Guanxin Ⅱ prescription were determined by an HPLC system. NONMEM (nonlinear mixed-effect modeling) method was used to analyze the population pharmacokinetics of PF and FA. RESULTS: A two-compartment model with first order degradation in absorption phase, and an ordinary twocompartment model were adequately describe PF and FA pharmacokinetic profiles, respectively.The mean of PF population parameters, CL₁, V₁, CL₂, V₂, K_a0, and K_a1, were 0.509 L/h, 0.104 L, 0.113 L/h, 0.123 L, 0.135 h, and 0.0135 h, respectively, while the typical values of CL₁, V₁, CL₂, V₂, K_a1, and F in FA model were 0.295 L/h, 0.025 L, 0.0331 L/h, 0.0518 L, 0.110 h, and 0.40, respectively.Inter-individual variabilities were estimated and dose formulation (DF) was identified as a significant covariate in the model. CONCLUSION: The results indicate that the pharmacokinetic behaviors of index components in Guanxin Ⅱ prescription can be influenced by different dose formulations administrated in rats.

Metabolomics approach to the biochemical differentiation of Traditional Chinese Medicine syndrome types of hypertension

LU Yi-hong, HAO Hai-ping, WANG Guang-ji, CHEN Hu-xiao,ZHU Xuan-xuan, XIANG Bing-ren, HUANG Qing, A Ji-Y

2007, 12(10):  1144-1150. 

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AIM: Traditional Chinese Medicine (TCM) has been practiced in China for thousands of years, providing a unique theoretical and practical approach to the treatment of diseases.In TCM theory, the notions of the “whole” and the use of “ system” rather than isolation are important concepts, which well fit to systems biology theory.In the present study, we try to discover whether GC/MS-based metabolomics approaches contribute to differentiate the TCM syndrome types of hypertension. METHODS: The three phenotypes of constitution in patients with essential hypertension, the hyperactivity of liver yang type, tan shi yong sheng type and yin xu yang kang type, were classified by TCM approach. Serum metabolomic profiles for healthy persons and hypertension patients were acquired using GC/MS global analysis. Principal components analysis (PCA), partial least squares-discriminant analysis (PLS-DA), and Mahlanobis distance (MD) were applied to facilitate the metabolomics data differentiation and prediction. RESULTS: Using PCA and PLS-DA, it was capable of distinguishing normal blood pressure serum samples from those of the TCM syndrome types, while failed to discriminate the three TCM syndrome types of hypertension from each other. Further MD analysis contributed not only to a fine differentiation, but also to a clear exhibition of the progression, of the three syndrome types. CONCLUSION: This pilot study suggests that the metabolomics approach might be a powerful tool for exploring the scientific essence of the TCM theory.

Pharmacokinetic/pharmacodynamic studies in anestheticdrug-drug interactions-a response surface model with remifentanil and sevoflurane for Chinese adult patients

YANG Lu, YANG Ba-xian, ZHANG Li-ping, BI Shan-shan, LU Wei

2007, 12(10):  1151-1156. 

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AIM: To determine the interactions with response -surface modeling methodologies when sevoflurane (Sevo) and remifentanil (Remi) were administered simultaneously. METHODS: (1) Patients, Study design and drug delivery :Based on parallel slices design, sixtyfive patients were randomly assigned to inhale a specific end-tidal concentration of sevoflurane (0.3 % to 3.4 %), with different level of remifentanil (0 -10 ng mL).The responses to laryngoscopy were observed for each given concentration pair.(2) Pharmacokinetic/pharmacodynamic analysis with response surface mode :The probability of no response (P) was assessed in the modeling process as below. $P=\frac{(Us+Ur)^{r}}{[U_{50}/I(Q)]^{r}+(Us+Ur)^{r}}$ RESULTS AND DISCUSSION:NONMEM estimated average values (RSE %) of the model parameters for laryngoscopy of C_50,Sevo, _C50,remi, U₅₀, r, I_max and Q_max are 1.71 % (12.9), 12.4 ng/mL (19.0), 6.62 (10.6), 1.53 (8.76), 2.31 (8.23), 0.706 (2.46), respectively.The inter-individual variability (CV %) in parameter I_max and inter-occasion variability (S.D.) in this model are 12.7 and 0.0316, respectively.It is concluded that the response-surface modeling approach provided a novel method to study drug-drug interactions.

Differential effects of PPARγligand rosiglitazone and selective antagonist GW9662 on adipocytokine gene expression in 3T3-L1 adipocytes

LIU Ying-zi, Vural Ozdemir, OUYANG Dong-sheng, LIU Zhao-qian, LIU ie, LI Zhi,WANG Dan, ZENG Fei-yue, TAN Zhi-rong, HU Dong-li, ZHOU Hong-hao

2007, 12(10):  1157-1162. 

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BACKGROUND: There is a growing recognition that the adipose tissue is an endocrine organ that secretes signaling molecules such as adiponectin and resistin.The peroxisome proliferator activated receptor γ (PPARγ)is expressed in high levels in the adipose tissue.Thiazolidinediones are selective PPARγagonists with insulin-sensitizing properties.It has been postulated that thiazolidinediones such as rosiglitazone exert their pharmacodynamic effects in part through modulation of resistin (implicated in insulin resistance)and adiponectin (an insulin- sensitizing molecule)expression subsequent to activation of PPARγ.There are conflicting data, however, on the biological direction in which resistin expression is modulated by PPARγagonists and whether an increase in adiponectin expression can occur in the face of an upregulation of resistin. METHODS: Using the murine 3T3-L1 adipocytes as a model, we evaluated the changes in resistin and adiponectin gene expression after vehicle, rosiglitazone (10 μmol/L, a PPARγagonist), GW9662 (5 μmol/L, a selective PPARγantagonist)or GW662 and rosiglitazone co-treatment. RESULTS: In comparison to vehicle treatment, rosiglitazone increased the average adiponectin and resistin mRNA expression by 1.66- and 1.55-fold, respectively (P<0.05).Importantly, GW9662 also upregulated adiponectin expression (by 1.57-fold, P<0.05)but did not influence resistin expression (P> 0.05).Co-treatment with rosiglitazone and GW9662 maintained the adiponectin upregulation (1.87-fold increase from vehicle, P<0.05)while attenuating resistin upregulation (1.31-fold increase from vehicle, P<0.05)induced by rosiglitazone alone (1.55-fold increase from vehicle, P<0.05). CONCLUSION: This study presents new evidence that adiponectin transcript is upregulated with both a PPARγagonist (rosiglitazone)and antagonist (GW9662), while GW9662 co-treatment does not block rosiglitazone-induced adiponectin upregulation.These data collectively suggest that biological mechanisms independent from PPARγmay underlie thiazolidinedione pharmacodynamics on adiponectin expression.Moreover, increased adiponectin expression by GW9662, in the absence of an upregulation of resistin expression, lends further support on the emerging clinical potential of PPARγ antagonists in treatment of insulin resistance.Decreased resistin expression may not be crucial for the insulin-sensitizing effect of rosiglitazone.These findings may serve as a foundation for future dose-ranging and time-course studies of thiazolidinedione pharmacodynamics on adipocytokine expression in human adipocytes.

Stereoselective bile excretion of ibuprofen glucuronide and the transport mechanism in the biliary efflux

CHEN Xi-jing, Masahiro Iwaki

2007, 12(10):  1163-1167. 

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AIM: To illustrate the effects of drug transporters on the bile efflux of ibuprofen glucuronide (IBG), the difference of bile excretion and plasma concentration of ibuprofen(IB)and its glucuronides was studied in EHBR and normal SD rat(SDR).METHODS: After 20 mg/kg of IB enantiomers administrated intravenously, the bile and blood were collected from the rats and the concentration of IB and their glucuronide were measured by HPLC methods.RESULTS: The bile excretion of IBG was obviously (but no totally)suppressed in EHBR (1.7 %±1.0 %, 0.6 %±0.9 % of the dose respectively for S-IBG and R-IBG)compared with that in SDR (18.4 %±4.0 %and 3.0 %±2.4 % of the dose respectively for S-IBG and R-IBG), for both kinds of rats, there are more S-IBG excreted than that of R-IBG.As the result of reduction of IBG excreted in bile, the concentration of IBG was higher in blood in EHBRs.CONCLUSION: The results suggest that Mrp2 is the most important transporter for IBG, and other transporter(s)may participate in the process.