Pharmacokinetic/pharmacodynamic model for prednisolone inhibition of whole blood lymphocyte proliferation

AIMS: Mitogen-induced ex vivo whole blood lymphocyte proliferation (WBLP) is a widely used method to assess lymphocyte responsiveness to immunosuppressive therapy. A three-component complex model was developed to characterize effects of prednisolone on cell trafficking, transduction, and lymphocyte suppression. METHODS: An oral dose (0.27 mg kg-1) of prednisone was given to 32 subjects. The study consisted of baseline and prednisone phases each with 32 h of sampling. Measurements included plasma prednisolone concentrations, in vitro and ex vivo WBLP, and lymphocyte cell counts during baseline and prednisone phases. RESULTS: The final model consists of a precursor-dependent indirect response model with a first-order periodic influx rate for lymphocyte trafficking. This accounts for the rebound phenomenon and the circadian rhythm seen in all individual ex vivo WBLP effect-time profiles. Prednisolone was modelled as inhibiting lymphocyte influx from the precursor to the blood pools. The direct suppressive effect of prednisolone on WBLP was modelled with the simple Imax model. A transduction step with rate constant kt was introduced to the simple Imax model to account for the delay ( approximately 4 h) in reaching the maximum inhibition. The IC50 values obtained ex vivo were circa 10 times lower than in vitro values (3.76 vs 38.8 ng ml-1), suggesting additional in vivo factors may have enhanced lymphocyte response to the inhibitory effect of prednisolone. CONCLUSIONS: This integrated PK/PD model enables evaluation of multicomponent direct and indirect inhibition of ex vivo WBLP by steroids and other immunosuppressants in relation to sex and race.     

基于治疗药物监测的重症患者哌拉西林他唑巴坦PK/PD研究

目的：探索临床使用哌拉西林他唑巴坦的重症感染患者首次治疗药物监测（TDM）后的峰谷浓度及PK/PD参数达标情况。方法：采用高效液相色谱法测定患者哌拉西林血药浓度,以本研究组建立的简易数学模拟法为基础,分别计算fT_>MIC ≥ 50%及100%的比例,并分析不同MIC值下各PK/PD目标值的达标情况。结果：58例患者的首次谷浓度为（31.68±44.33）μg·mL^-1,峰浓度为（206.59±101.37）μg·mL^-1,有5例（8.6%）患者首次谷浓度超过5 MIC,患者个体间变异较大;fT_>MIC ≥ 50%及100%的达标率分别为62.07%和36.21%。58例患者中7例确认为哌拉西林他唑巴坦耐药病原菌感染（MIC ≥ 128 μg·mL^-1）,当按耐药菌的最低MIC值（128 μg·mL^-1）计算时,其fT_>MIC ≥ 50%及100%的达标率仅为28.57%和0。结论：有必要在重症感染患者中开展基于TDM的哌拉西林他唑巴坦个体化给药方案设计。     

Ambroxol and pulmonary toxicity induced by antineoplastic drugs

The authors describe the potential effects of ambroxol on the pulmonary disorders induced by antineoplastic agents (in particular, bleomycin and the nitrosureas). An experimental stage focussed attention on the early modifications occurring in the alveolar surfactant and in the afflux of inflammatory and immune-effector cells following bleomycin-induced lung fibrosis in the rat (by intratracheal instillation). The ambroxol-protected rats showed a slower drop of alveolar lecithins in the first few hours after bleomycin administration and a lower afflux of neutrophils, macrophages and lymphocytes. In the clinical stage, respiratory function was studied in two groups of cancer patients treated with nitrosureas or bleomycin. Preliminary findings indicate a rapid worsening of some functional parameters--maximal expiratory flow at 25% vital capacity, diffusing capacity for carbon monoxide and diffusing capacity/ventilation--in controls, while no such changes occurred in the ambroxol-protected subjects. The possible pathogenetic implications of these results and perspective for future investigations are discussed.     

Pharmacokinetic/pharmacodynamic analysis of tacrolimus-induced QT prolongation in guinea pigs

Recently, several reports of clinical cases of QT prolongation and torsades de pointes, associated with the use of tacrolimus (FK506), have come to light. We have previously demonstrated FK506-induced QT prolongation in guinea pigs [Minematsu T., et al., Life Sci., 65, PL197-PL202 (1999)]. We now examined the relationship between QTc prolongation and the pharmacokinetics of FK506 in guinea pigs, in order to evaluate the arrhythmogenicity of FK506 when compared with that of quinidine sulfate (QND). Thus, dose-response relationships for FK506 (0.01 or 0.1 mg/h/kg) or QND (30 mg/h/kg) were investigated during and after intravenous infusion and also following intravenous bolus administration of FK506 (0.2 mg/kg). The dose-response relationship between plasma drug concentration and QTc prolongation for FK506 and QND were subsequently analyzed using an effect compartment model. The pharmacodynamic parameters thus obtained were as follows: kE0 2.72 x 10(-4) (min-1), Emax 27.1 (ms), EC50 0.376 (ng/ml) for FK506; and kE0 0.148 (min-1), K 8.41 (ms.ml/microgram) for QND. The anti-clockwise hysteresis observed for FK506-induced QT prolongation was successfully analyzed by the present pharmacokinetic/pharmacodynamic model, which may provide a rational basis for developing a clinical dosing regimen to avoid possible QT prolongation induced by FK506.     

Pharmacokinetic/pharmacodynamic profile of voriconazole

Voriconazole is the first available second-generation triazole with potent activity against a broad spectrum of clinically significant fungal pathogens, including Aspergillus,Candida, Cryptococcus neoformans, and some less common moulds. Voriconazole is rapidly absorbed within 2 hours after oral administration and the oral bioavailability is over 90%, thus allowing switching between oral and intravenous formulations when clinically appropriate. Voriconazole shows nonlinear pharmacokinetics due to its capacity-limited elimination, and its pharmacokinetics are therefore dependent upon the administered dose. With increasing dose, voriconazole shows a superproportional increase in area under the plasma concentration-time curve (AUC). In doses used in children (age < 12 years) voriconazole pharmacokinetics appear to be linear. Steady-state plasma concentrations are reached approximately 5 days after both intravenous and oral administration; however, steady state is reached within 24 hours with voriconazole administered as an intravenous loading dose. The volume of distribution of voriconazole is 2-4.6 L/kg, suggesting extensive distribution into extracellular and intracellular compartments. Voriconazole was measured in tissue samples of brain, liver, kidney, heart, lung as well as cerebrospinal fluid. The plasma protein binding is about 60% and independent of dose or plasma concentrations. Clearance is hepatic via N-oxidation by the hepatic cytochrome P450 (CYP) isoenzymes, CYP2C19, CYP2C9 and CYP3A4. The elimination half-life of voriconazole is approximately 6 hours, and approximately 80% of the total dose is recovered in the urine, almost completely as metabolites. As with other azole drugs, the potential for drug interactions is considerable.Voriconazole shows time-dependent fungistatic activity against Candida species and time-dependent slow fungicidal activity against Aspergillus species. A short post-antifungal effect of voriconazole is evident only for Aspergillus species. The predictive pharmacokinetic/pharmacodynamic parameter for voriconazole treatment efficacy in Candida infections is the free drug AUC from 0 to 24 hour : minimum inhibitory concentration ratio.     

Pharmacokinetic/pharmacodynamic evaluation of inhalation drugs: application to targeted pulmonary delivery systems

Inhaled therapy with either glucocorticoids and/or beta(2)-adrenergic drugs remains the mainstay of asthma treatment. In the last few years, a number of new products have been introduced into the market with the goal of improving efficacy and safety. This review article summarises the pharmacokinetic and pharmacodynamic properties of inhaled drugs for topical delivery necessary to achieve this goal. Pharmacokinetic properties include a high pulmonary deposition, low oral bioavailability, optimised pulmonary residence time and a very high systemic clearance. Optimisation of pharmacodynamic properties, such as receptor selectivity, may also yield drugs with improved pulmonary selectivity. As existing drugs also provide high efficacy and safety profiles, future developments will represent only slight improvements and quantum leap improvements are unlikely to occur.     

Pharmacokinetic/pharmacodynamic evaluation of inhalation drugs: application to targeted pulmonary delivery systems

Inhaled therapy with either glucocorticoids and/or β₂-adrenergic drugs remains the mainstay of asthma treatment. In the last few years, a number of new products have been introduced into the market with the goal of improving efficacy and safety. This review article summarises the pharmacokinetic and pharmacodynamic properties of inhaled drugs for topical delivery necessary to achieve this goal. Pharmacokinetic properties include a high pulmonary deposition, low oral bioavailability, optimised pulmonary residence time and a very high systemic clearance. Optimisation of pharmacodynamic properties, such as receptor selectivity, may also yield drugs with improved pulmonary selectivity. As existing drugs also provide high efficacy and safety profiles, future developments will represent only slight improvements and quantum leap improvements are unlikely to occur.     

Pharmacokinetic/pharmacodynamic profile of reslizumab in asthma

Introduction: Allergic asthma is a Th2-driven inflammatory process characterized by the infiltration of eosinophils into the airways. IL-5 is a key trigger for eosinophil expansion and release from the bone marrow and plays a crucial role in the entire life span of eosinophils from differentiation to maturation and survival. IL-5 can be considered among the most obvious targets to selectively inhibit eosinophilic airway inflammation.

Areas covered: The preclinical and clinical development of reslizumab, a humanized mAb against IL-5 that has been developed to block IL-5 bioactivity and reduce biologically available IL-5, are described with a particular focus on its pharmacodynamics (PK)/pharmacokinetic (PD) profile.

Expert opinion: Although pivotal trials have documented that reslizumab can be recommended as add-on therapy for the treatment of patients with severe eosinophilic asthma, there is still important information that is lacking and some PK and PD properties of reslizumab are still not fully understood.     

Pharmacokinetic/pharmacodynamic modelling in oncological drug development

For many oncological agents, myelosuppression is the dose-limiting toxicity and the quantitative characterisation of the relationship between drug dose, plasma concentration and haematological toxicity is of importance in the drug development. Mechanism-based population pharmacokinetic-pharmacodynamic models have been developed for this purpose and the applications of these in candidate selection, first-in-man studies, prodrug and formulation development, dose finding, schedule optimisation, assessing influence of modifying agents, drug combination studies, subgroup identification and feedback individualisation are reviewed.     

Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs

Therapeutic drug monitoring (TDM) is widely accepted as a method to improve the effectiveness and safety of the first generation antiepileptic drugs (AEDs) and to identify an individual's optimum concentration. Like the older AEDs, the new AEDs also have significant pharmacokinetic variability. A similar relationship between concentration and effect for the new and old AEDs in experimental seizure models suggests that it is reasonable to use TDM for the new AEDs. With the addition of generic formulations of the new AEDs, TDM can play an important role to validate bioequivalence in patients. There is a history of problems with generics of the older AEDs, primarily carbamazepine and phenytoin. The Biopharmaceutics Classification System, which correlates the solubility and permeability of a drug with oral drug absorption, predicts that there should be no significant problems with the majority of the new AEDs. Because of the controversy over the risk-benefit of generic substitution of AEDs, the use of TDM will provide a way to ensure patient safety while establishing that generics of AEDs proven to be bioequivalent in population studies are also bioequivalent in individuals. The goal of personalized medicine is to use genetic testing to target therapy and identify those individuals unlikely to respond to a drug or likely to respond adversely to the same drug. Of all the AEDs, only phenytoin undergoes significant metabolism by cytochrome P450 isozymes with significant genetic polymorphisms (CYP2C9, CYP2C19). Studies are still needed to identify genetic and biomarkers to identify patients at risk for serious idiosyncratic reactions. There have been significant advances in the understanding of the role of genetics in idiopathic as well as acquired epilepsies. Identification of experimental and clinical evidence linking functional changes associated with gene mutations to epilepsy syndromes will help provide new molecular targets for future AEDs.     

Quantification of the EEG effect of midazolam by aperiodic analysis in volunteers. Pharmacokinetic/pharmacodynamic modelling

The effects of midazolam on the EEG were related to plasma midazolam concentrations in 8 healthy male volunteers in order to develop a pharmacokinetic-pharmacodynamic model. The EEG parameters were derived by aperiodic analysis. The EEG was recorded between Fp1-M1 and Fp2-M2. Following a 15-minute baseline EEG registration, midazolam 15 mg was given intravenously over 5 minutes. Venous blood samples were taken until 8 hours after the start of the infusion. Within 2 to 4 minutes of starting the infusion all subjects became asleep, with loss of eyelid reflex. The most obvious EEG changes, in the beta frequency range (12 to 30 Hz), were observed within 2 minutes of the start of drug administration. Seven subjects awoke 60 to 70 minutes after the start of the infusion and 1 awoke after 45 minutes. The EEG parameter that best characterised the effect of midazolam was the total number of waves per second in the frequency range 12 to 30 Hz (TNW12-30). This was used as the effect parameter in the pharmacokinetic-pharmacodynamic modelling. The plasma concentration-time data were characterised by a triexponential function for all subjects. To allow for a possible delay between plasma midazolam concentration and EEG effect, a hypothetical effect compartment was included in the pharmacokinetic-pharmacodynamic model. A sigmoid maximum effect (Emax) model was used to characterise the effect compartment midazolam concentration-TNW12-30 data. The plasma drug concentration corresponding to half the maximum increase in TNW12-30 (EC50) was 290 +/- 98 micrograms/L.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic/pharmacodynamic modeling of pegfilgrastim in healthy subjects

This analysis was conducted to characterize the pharmacokinetics and pharmacodynamics of pegfilgrastim and to develop a pharmacokinetic-pharmacodynamic model to describe the granulopoietic effects of pegfilgrastim and the homeostatic regulation of pegfilgrastim clearance in healthy subjects. Pegfilgrastim serum concentration data and differential white cell counts were obtained from an open-label, single-dose, dose escalation study. Healthy subjects (8 subjects/dose group) received a single subcutaneous dose of 30, 60, 100, or 300 microg/kg pegfilgrastim. Pegfilgrastim exhibited nonlinear pharmacokinetics; clearance decreased with increasing dose. A dose-dependent increase in absolute neutrophil count with an increase in the percentage of band cells was observed. A pharmacokinetic-pharmacodynamic model was developed that adequately described the nonlinear pharmacokinetics of pegfilgrastim, feedback regulation of pegfilgrastim clearance by neutrophils, and the differential effects of pegfilgrastim on neutrophil populations in blood.     

Pharmacokinetic/pharmacodynamic studies in drug product development.

In the quest of ways for rationalizing and accelerating drug product development, integrated pharmacokinetic/pharmacodynamic (PK/PD) concepts provide a highly promising tool. PK/PD modeling concepts can be applied in all stages of preclinical and clinical drug development, and their benefits are multifold. At the preclinical stage, potential applications might comprise the evaluation of in vivo potency and intrinsic activity, the identification of bio-/surrogate markers, as well as dosage form and regimen selection and optimization. At the clinical stage, analytical PK/PD applications include characterization of the dose-concentration-effect/toxicity relationship, evaluation of food, age and gender effects, drug/drug and drug/disease interactions, tolerance development, and inter- and intraindividual variability in response. Predictive PK/PD applications can also involve extrapolation from preclinical data, simulation of drug responses, as well as clinical trial forecasting. Rigorous implementation of the PK/PD concepts in drug product development provides a rationale, scientifically based framework for efficient decision making regarding the selection of potential drug candidates, for maximum information gain from the performed experiments and studies, and for conducting fewer, more focused clinical trials with improved efficiency and cost effectiveness. Thus, PK/PD concepts are believed to play a pivotal role in streamlining the drug development process of the future.     

Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats

Aim:

To quantitatively evaluate the blood glucose-lowering effect of exenatide in diabetic rats.

Methods:

Male Harlan-Sprague-Dawley rats were treated with high-fat diet/streptozotocin to induce type 2 diabetes. After subcutaneous administration of a single dose of exenatide (4.2, 42, or 210 μg/kg), serum exenatide, insulin concentration and blood glucose were measured. The pharmacokinetics of exenatide was characterized by a two-compartment model with first-order absorption. Insulin turnover was characterized by an effect compartment and indirect response combined model. Glucose turnover was described using an indirect response model with insulin (in effect compartment) stimulating glucose disposition and insulin (in insulin compartment) inhibiting glucose production simultaneously. The model parameters were estimated using nonlinear mixed-effects model program. Visual predictive check and model evaluation were used to make assessments.

Results:

Exenatide exhibited rapid absorption with k_a=4.45 h^-1, and the two-compartment model well described its pharmacokinetic profile. For the pharmacodynamic model, exenatide increased insulin release with the estimated S_m1 of 0.822 and SC₅₀ of 4.02 μg/L. It was demonstrated that insulin stimulated glucose dissipation (S_m2=0.0513) and inhibited the production of glucose (I_m=0.0381). Visual predictive check and model evaluation study indicated that a credible model was developed.

Conclusion:

The glucose-lowering effect of exenatide in diabetic rats is reliably described and predicted by the combined effect compartment/indirect response model.     

533例抗肿瘤药物不良反应报告分析

目的 分析我院抗肿瘤药物不良反应（ADR）报告,以期为临床安全、合理使用抗肿瘤药物提供参考。方法 收集2013年—2020年我院上报的533例抗肿瘤药物ADR报告,分别从患者年龄、性别、药品种类、累及系统、临床表现及给药途径等方面进行统计和分析。结果 533例抗肿瘤药物ADR中,男性256例,女性277例;发生ADR的患者年龄主要集中在61～70岁（28.5%）和51～60岁（25.7%）。ADR涉及的抗肿瘤药物种类占比最高的依次为抗肿瘤植物药（23.3%）、新型抗肿瘤药物（23.3%）和抗代谢类药物（22.0%）。ADR临床表现例次排名前3位的抗肿瘤药物分别为紫杉醇、多西他赛和奥沙利铂;排名前3位的新型抗肿瘤药物分别为利妥昔单抗、贝伐珠单抗和西妥昔单抗。ADR主要累及血液系统损害（30.6%）、胃肠系统损害（19.4%）、全身性损害（15.5%）和皮肤及其附件损害（14.4%）。静脉给药引起的ADR最多（81.2%）;给药后1 d内更易发生ADR,15 d内发生的ADR约占86.8%。严重的ADR有102例,主要涉及多西他赛、表柔比星和紫杉醇;新型抗肿瘤药物引起的严重ADR共13例,...     

Different initial steps of apoptosis induced by two types of antineoplastic drugs

O6-Methylguanine and O6-chloroethylguanine are primary DNA lesions produced by two types of antineoplastic drugs, 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide, TMZ) and 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), respectively. They can be repaired by O6-methylguanine-DNA methyltransferase, coded by the Mgmt gene. Otherwise, these two types of lesions induce apoptosis in different ways. O6-Chloroethylguanine blocks DNA replication thereby inducing apoptosis. On the other hand, O6-methylguanine does not block DNA replication and the resulting O6-methylguanine-thymine mispair is recognized by mismatch repair-related proteins, including MLH1, thereby inducing apoptosis. Reflecting this, mouse cells lacking both MGMT and MLH1 are resistant to TMZ, but not to ACNU. The translocation of phosphatidylserine in cell membrane as well as a change of mitochondrial transmembrane potentials occurred in an MLH1-dependent manner after treatment with TMZ, but no such MLH1 dependency was observed in the case of ACNU treatment. By using cell lines defective in both APAF-1 and MGMT, it was revealed that the APAF-1 function is required for execution of apoptosis induced by either TMZ or ACNU. There is almost 12h delay in occurrence of apoptosis-related mitochondrial depolarization in TMZ-treated cells in comparison to those of ACNU-treated cells, reflecting the fact that at least one cycle of DNA replication is required to trigger apoptosis in the former case, but not in the latter.     

Pharmacokinetic/pharmacodynamic modeling of corticosterone suppression and lymphocytopenia by methylprednisolone in rats

Adrenal suppression and lymphocytopenia are commonly monitored pharmacological responses during systemic exposure to exogenously administered corticosteroids. The pharmacodynamics of plasma corticosterone (CS) and blood lymphocytes were investigated in 60 normal rats which received either 50 mg/kg methylprednisolone (MPL) or vehicle intramuscularly. Blood samples were collected between 0.5 and 96 h following treatment. Plasma CS displayed a transient suppression with re-establishment of a normal circadian rhythm 24 h following drug treatment. An indirect response model with suppression of production well captured plasma CS profiles. An early stress-induced rise in CS was also factored into the model. Blood lymphocyte numbers exhibited a sharp decline and then returned to a new circadian rhythm which was half of the original baseline level. An integrated pharmacodynamic (PD) model with inhibition of lymphocyte trafficking from tissue to blood by both MPL and CS and induction of cell apoptosis by MPL reasonably captured this lymphocytopenia. Rats and humans differ in lymphocyte responses with humans showing full recovery of baselines. Modeling provides a valuable tool in quantitative assessment of dual, complex drug responses.     

肾移植术后泼尼松/泼尼松龙的临床药动学/药效学研究进展

目的:综述近年来肾移植术后糖皮质激素泼尼松/泼尼松龙临床药动学(PK)和药效学(PD)研究现状,为进一步优化其免疫抑制治疗方案提供参考。方法:检索国内外相关文献,总结泼尼松/泼尼松龙在肾移植术后药动学/药效学相关研究情况及未来发展方向。结果:糖皮质激素已应用多年,但其临床给药方案通常凭医生经验制定,缺乏临床药动学/药效学研究指导,因而在进行冲击治疗和长期给药时往往出现多种毒副作用。目前泼尼松/泼尼松龙肾移植术后的临床药动学和药效学研究局限:大部分药动学数据采用非房室分析方法以及两步统计法计算,大多数研究中测定血药浓度为总药物浓度而非实际起效的游离药物浓度,药效学研究多限于药物暴露与毒副作用之间的相关性研究。结论:泼尼松/泼尼松龙肾移植术后的临床药动学、药效学研究具有一定基础但尚不全面,有待考察其系统的定量关系用于指导个体化用药方案的制定。