BACKGROUND & AIMS: :Piroxantrone (PRX, NSC 349174) is one of the first of a new class of intercalating agents, the anthrapyrazoles, to undergo clinical evaluation. Additionally, it is the first drug trial to prospectively test a new pharmacology-based dose escalation schema proposed for Phase I trials of anticancer compounds. In this Phase I trial, PRX was administered as a 1-h infusion every 3 weeks to patients with advanced cancer. Forty-four evaluable patients received 116 courses at doses ranging from 7.5 to 190 mg/m2. The dose-limiting toxicity was myelosuppression with leukopenia predominating. Nonhematological toxicities were minimal and consisted of nausea and vomiting, alopecia, mucositis, and phlebitis. Based on this trial, the maximum tolerated and recommended Phase II doses for PRX administered on this schedule are 190 and 150 mg/m2, respectively. PRX plasma elimination was rapid and best fit by a two-compartment model for 17 of 24 patients receiving greater than or equal to 90 mg/m2. The plasma clearance rate was 1290 +/- 484 ml/min (720 +/- 210 ml/min/m2) and did not vary with dose. The t1/2 alpha was 2.9 +/- 5.3 (SD) min and the t1/2 beta was 18.7 +/- 36.5 min. Area under the concentration versus time curve (AUC) at the maximal tolerated dose (MTD) was 435 mumol.min/liter, 40% higher than the predicted AUC from preclinical testing. The percentage decrease in WBC and neutrophil count was correlated with the AUC. The potential advantage of pharmacology-based dose escalation was limited in this study by assay insensitivity, extremely rapid plasma elimination, and the proximity of the starting dose to the dose where the target AUC was achieved and standard dose escalations were to begin. Consequently, there was no reduction in the number of dose escalations required to define the maximum tolerated dose. However, the practical aspects of this approach have been established and its use is recommended for further trials where detailed preclinical pharmacological studies are available.

背景与目标： : 吡罗克蒽醌 (PRX，NSC 349174) 是首批接受临床评估的新型插层剂-蒽唑。此外，这是第一个前瞻性测试新的基于药理学的剂量递增方案的药物试验，该方案为抗癌化合物的I期试验提出。在此I期试验中，PRX每3周以1小时输注的方式向晚期癌症患者施用。44名可评估的患者接受了116疗程，剂量范围为7.5至190 mg/m2。剂量限制性毒性是骨髓抑制，白细胞减少为主。非血液学毒性很小，包括恶心和呕吐，脱发，粘膜炎和静脉炎。基于该试验，按本方案施用的PRX的最大耐受剂量和推荐的II期剂量分别为190和150 mg/m2。对于接受大于或等于90 mg/m2的24名患者中的17名，PRX血浆消除是快速且最适合的两室模型。血浆清除率为1290 +/-484毫升/min (720 +/-210毫升/min/m2)，且不随剂量变化。t1/2α 为2.9 +/- 5.3 (SD) 分钟，t1/2β 为18.7 +/- 36.5分钟。在最大耐受剂量 (MTD) 下的浓度与时间曲线 (AUC) 下的面积为435 mumol.min/l，40% 高于临床前测试的预测AUC。WBC和中性粒细胞计数下降的百分比与AUC相关。在这项研究中，基于药理学的剂量递增的潜在优势受到测定不敏感性，极其快速的血浆消除以及起始剂量与达到目标AUC并开始标准剂量升级的剂量的接近程度的限制。因此，定义最大耐受剂量所需的剂量升级数量没有减少。然而，这种方法的实际方面已经建立，并建议将其用于可获得详细的临床前药理学研究的进一步试验。

BACKGROUND & AIMS: :An increasing number of cancer patients are using herbs in combination with conventional chemotherapeutic treatment. It is therefore important to study the potential consequences of the interactions between herbs and anticancer drugs. The effects of extracts from Panax ginseng (PGS) and Salvia miltiorrhiza Bunge (SMB) on the pharmacokinetics of 5-fluorouracil (5-FU) were performed in vivo and detected by high performance liquid chromatography (HPLC), while, an ATP assay was used to study the pharmacodynamic interactions in vitro. The results of the pharmacokinetic experiments showed a significant increase in the elimination half-life (t1/2(k e )) of 5-FU in the PGS-pretreated group and in the area under the curve (AUC) in the SMB-pretreated group compared with the control group. However, after SMB pretreatment, weight loss was observed in rats. The results of pharmacodynamic experiments showed that neither PGS nor SMB, when used alone, directly inhibited cancer cell growth at 0.1-100 μg/ml. Moreover, PGS had a synergistic cytotoxic effect with 5-FU on human gastric cancer cells but not on normal gastric cells. The results imply that when combined with 5-FU, PGS may be a better candidate for further study. This study might provide insights for the selection of herbal-chemotherapy agent interactions.

背景与目标： : 越来越多的癌症患者正在使用草药与常规化学治疗相结合。因此，研究草药与抗癌药物之间相互作用的潜在后果非常重要。研究了人参 (PGS) 和丹参 (SMB) 提取物对5-氟尿嘧啶 (5-FU) 药代动力学的影响，并通过高效液相色谱 (HPLC) 检测，同时使用ATP测定法研究了体外药效学相互作用。药代动力学实验的结果表明，在PGS预处理组中5-FU的消除半衰期 (t1/2(k e )) 显着增加，在SMB-预处理组中，曲线下面积 (AUC) 显着增加与对照组相比。然而，SMB预处理后，大鼠体重减轻。药效学实验结果表明，单独使用时，PGS和SMB都不能直接抑制0.1-100 μ g/ml的癌细胞生长。此外，PGS与5-FU对人胃癌细胞具有协同的细胞毒性作用，但对人胃癌细胞没有协同作用。结果表明，与5-FU联合使用时，PGS可能是进一步研究的更好候选者。这项研究可能为选择草药-化疗药物相互作用提供见解。

BACKGROUND & AIMS: BACKGROUND:To assess the pharmacokinetic profile and time-course of trough concentrations and hemoglobin levels associated with subcutaneous weekly administration of epoetin beta in lung cancer patients with chemotherapy-induced anemia. METHODS:Epoetin beta was subcutaneously administered to 15 anemic lung cancer patients once weekly for 8 weeks at doses of 9000, 18,000 and 36,000 IU. Pharmacokinetic parameters (C(max), AUC(inf) and T(1/2)) were determined after the first single dose administration on a model-independent basis, and the relationship between the dose and these parameters was examined for linearity. RESULTS:Weekly administration of epoetin beta at 9000, 18,000 and 36,000 IU produced C(max) values of 308 +/- 117 (mean +/- standard deviation), 678 +/- 86.7 and 1316 +/- 766 mIU/ml, and AUC(inf) values of 15,300 +/- 9524, 54,574 +/- 16,265 and 88,501 +/- 55,687 hr mIU/ml, respectively, showing dose-proportional increases. Trough concentrations tended to increase in the presence of severe bone marrow suppression induced by chemotherapy or other factors. Extremely high values were seen in three patients, but there was no apparent trend toward an increase with repeated doses. After 8 weeks' administration at 9000, 18,000 and 36,000 IU, hemoglobin levels were changed by -0.37 +/- 1.26, 2.15 +/- 1.36 and 2.82 +/- 2.17 g/dl, respectively. CONCLUSIONS:Epoetin beta exhibited linear pharmacokinetics when administered to anemic cancer patients at weekly doses of 9000-36,000 IU and did not cause drug accumulation. Hemoglobin levels increased with weekly doses of 18,000 or 36,000 IU.

背景与目标：

BACKGROUND & AIMS: We have investigated the dynamics for the removal of 5-hydroxytryptamine (5-HT) from the circulation using the isolated perfused rabbit lung. 5-HT was removed from the circulation at a constant rate and metabolized completely to 5-hydroxyindoleacetic acid which effluxed from the lung into the circulation. Two methods were developed to determine the constant rate of removal of 5-HT(1) the constant rate is equal to the difference between the 5-HT concentration flowing into the lung and the 5-HT concentration in the effluent times the flow rate and (2) extrapolation of the rate of appearance of radioactivity in the effluent to zero time. With these methods, we have confirmed the 5-HT is removed by the lung by a carrier-mediated Na+-dependent transport system. Studies of transport systems in perfused organs required an adequate supply of the chemical to the lung. Supply rates less than removal rate will result in erroneous measurements of the constant removal rate. The relationships between the rate of removal, perfusate concentration and perfusion rate were analyzed.

背景与目标： 我们已经研究了使用分离的灌注兔肺从循环中去除5-羟色胺 (5-HT) 的动力学。将5-HT以恒定的速率从循环中除去，并完全代谢成5-羟基吲哚乙酸，该乙酸从肺排出到循环中。开发了两种方法来确定5-HT的恒定去除速率 (1) 恒定速率等于流入肺的5-HT浓度与流出物中的5-HT浓度之间的差乘以流速和 (2) 将流出物中放射性的出现速率外推至零时间。通过这些方法，我们已经确认5-HT通过载体介导的Na依赖性转运系统被肺去除。对灌注器官中运输系统的研究需要向肺提供足够的化学物质。小于去除率的供应速率将导致对恒定去除率的错误测量。分析了清除率，灌注液浓度和灌注率之间的关系。

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVES:The objective of this study was to assess the pharmacokinetics, sensory/motor effects, and safety of epidurally administered liposome bupivacaine versus bupivacaine HCl in healthy volunteers. METHODS:Thirty subjects were randomized to receive liposome bupivacaine 89, 155, or 266 mg, or bupivacaine HCl 50 mg in a double-blind fashion. Occurrence/duration of motor blockade, pinprick/cold sensitivity, and plasma bupivacaine levels were assessed for 96 hours after study drug administration. Tolerability parameters were also assessed. RESULTS:All doses of liposome bupivacaine resulted in greater area under the curve and a longer time to observed maximum plasma concentration and terminal elimination half-life than bupivacaine HCl 50 mg. Mean maximum plasma concentration with liposome bupivacaine 89 and 155 mg (but not 266 mg) was statistically significantly lower than with bupivacaine HCl 50 mg (P < 0.001). Median duration of motor blockade with liposome bupivacaine 266 mg was 1 hour versus 2.8 hours for bupivacaine HCl. Of subjects who received liposome bupivacaine 266 mg, 29% (2/7) were unable to ambulate at 4 hours postdose versus 67% (4/6) of those receiving bupivacaine HCl. Median durations of pinprick/cold sensitivity loss were 36 and 69 hours, respectively, in the liposome bupivacaine 266-mg group versus 12 hours for both pinprick and cold in the bupivacaine HCl group. Liposome bupivacaine was well tolerated; the most common adverse event in all treatment groups was injection site pain, which resolved within 30 days for most subjects. CONCLUSIONS:Epidurally administered liposome bupivacaine 266 mg resulted in a longer duration of sensory blockade than liposome bupivacaine 89 or 155 mg or bupivacaine HCl 50 mg. Duration of motor blockade was shorter with liposome bupivacaine 266 mg versus bupivacaine HCl.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:Omalizumab (Xolair), is a recombinant humanised monoclonal anti-immunoglobulin E (IgE) antibody, for the treatment of allergic asthma. This review describes how the correlation between clinical outcomes and a suitable surrogate marker (free serum IgE) led to the development of an individualised dosing strategy for omalizumab. It also demonstrates how subsequent studies using this dosing strategy were able to achieve low levels of IgE and clinical benefit. DATA SOURCES:Published articles and data on file (Novartis Pharma AG, Genentech). RESULTS:Studies in patients with IgE-mediated diseases of the airways have shown that clinical benefit with omalizumab is observed when free IgE levels in serum are reduced to 50 ng/ml (20.8 IU/ml) or less (target 25 ng/ml (10.4 IU/ml)). The ability of omalizumab to reduce free IgE levels to such levels is dependent on dose, the patient's weight and baseline IgE level. To simplify dosing, and ensure that free IgE reduction is achieved, an individualised tiered dosing table was developed from which patients with asthma, depending on weight and starting IgE level, receive omalizumab 150-375 mg by subcutaneous injection every 2 or 4 weeks. This dosing strategy has proved clinically efficacious for improving disease control in patients with allergic asthma, as shown by significantly lower exacerbation rates and decreased dependence on treatment with inhaled corticosteroids, along with improvements in symptoms, lung function and usage of rescue bronchodilators. CONCLUSIONS:The clinical efficacy of omalizumab has been optimised through the development of an individualised dosing table that emerged from an understanding of the pharmacodynamics of this agent.

背景与目标：

BACKGROUND & AIMS: :MKC253 is glucagon-like peptide 1 (GLP-1, 7-36 amide) adsorbed onto Technosphere microparticles for oral inhalation. The pharmacokinetics of inhaled GLP-1 and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between inhaled GLP-1 and insulin were analyzed in two trials, one in healthy normal volunteers and the other in patients with type 2 diabetes. Inhaled GLP-1 was absorbed quickly, with peak concentrations occurring within 5 min, and levels returned to baseline within 30 min. Inhaled GLP-1 appeared to produce plasma levels of GLP-1 comparable to those of parenteral administration and sufficient to induce insulin secretion resulting in attenuation of postmeal glucose excursions in subjects with type 2 diabetes. An E(max) (maximum effect) model described the relationship between GLP-1 concentration and insulin release. The variability in the E(max) may be due to differences in baseline glucose levels, differences resulting from genetic polymorphisms in GLP-1 receptors (GLP-1Rs), or the stage of diabetes of the patient.

背景与目标： : MKC253是胰高血糖素样肽1 (GLP-1，7-36酰胺) 吸附在用于口服吸入的technsphere微粒上。在两项试验中分析了吸入GLP-1的药代动力学以及吸入GLP-1与胰岛素之间的药代动力学-药效学 (pk-pd) 关系，一项在健康正常志愿者中，另一项在2型糖尿病患者中。吸入的GLP-1被迅速吸收，峰值浓度在5分钟内出现，水平在30分钟内恢复到基线。吸入的GLP-1似乎产生的血浆GLP-1水平与肠胃外给药相当，足以诱导胰岛素分泌，导致2型糖尿病患者餐后葡萄糖漂移减弱。E(max) (最大效应) 模型描述了GLP-1浓度与胰岛素释放之间的关系。E(max) 的变异性可能是由于基线葡萄糖水平的差异，由GLP-1受体 (GLP-1Rs) 的遗传多态性引起的差异或患者的糖尿病阶段。

BACKGROUND & AIMS: Prednisolone pharmacokinetics (PK) and pharmacodynamics (PD) were investigated in relation to sex and race in white males, black males, white females, and black females (n = 8/group) after a single oral dose (0.27 mg/kg) of prednisone. The study consisted of baseline and prednisone phases with 32-hour sampling in each phase. Women were studied during the luteal phase of their menstrual cycle. Total and free plasma prednisolone concentrations were assayed by HPLC and ultrafiltration, and pharmacokinetic data were analyzed by compartmental fitting using WinNonlin. Plasma cortisol concentrations were assayed by HPLC; T-helper, T-suppressor lymphocyte, and neutrophil cell counts were determined by FACS and hemocytometry, and these pharmacodynamic data were evaluated by basic and extended indirect response models using ADAPT II. Total body weight-normalized free prednisolone oral clearance and apparent volume of distribution were higher in men compared with women, regardless of race (by 22% in whites and 40% in blacks for oral clearance, p < 0.01; by32% in whites and 38% in blacks for apparent volume of distribution, p < 0.01). The 50% inhibitory concentration (IC50) values for T-suppressor cell-trafficking inhibition were higher in whites than in blacks, regardless of sex (by 125% in men and 208% in women, p < 0.01). The IC50 or SC50 values for effects of prednisolone on cortisol secretion and T-helper lymphocyte or neutrophil trafficking were not statistically different between men and women, blacks and whites. The findings of this study suggest that there are some prednisolone PK/PD differences related to sex and race. However, these differences do not suggest the need for dosage adjustments, and additional experiments with repeat dosing are needed to fully evaluate the clinical implication of these findings.

背景与目标： 在单次口服 (0.27 mg/kg) 泼尼松后，研究了与白人男性，黑人男性，白人女性和黑人女性 (n = 8/组) 的性别和种族有关的泼尼松药代动力学 (PK) 和药效学 (PD)。该研究包括基线和泼尼松阶段，每个阶段均进行32小时采样。在月经周期的黄体期对妇女进行了研究。通过HPLC和超滤测定血浆中泼尼松龙的总浓度和游离浓度，并使用WinNonlin通过区室拟合分析药代动力学数据。通过HPLC测定血浆皮质醇浓度; 通过FACS和血液细胞测定法确定T辅助细胞，T抑制淋巴细胞和中性粒细胞计数，并使用ADAPT II通过基本和扩展间接反应模型评估这些药效学数据。无论种族如何，男性的总体重-标准化游离泼尼松龙口腔清除率和表观分布量均高于女性 (白人和黑人的口腔清除率为22%，黑人为40%，p <0.01; 白人和黑人为32%，黑人为38%。p <0.01)。不论性别，白人T抑制细胞运输抑制的50% 抑制浓度 (IC50) 高于黑人 (男性125%，女性208%，p <0.01)。泼尼松龙对皮质醇分泌和T辅助淋巴细胞或中性粒细胞贩运的影响的IC50或SC50值在男女，黑人和白人之间没有统计学差异。这项研究的结果表明，泼尼松龙PK/PD与性别和种族有关。但是，这些差异并不表明需要调整剂量，并且需要进行重复给药的其他实验来充分评估这些发现的临床意义。

BACKGROUND & AIMS: Quantitative analysis of electroencephalography (EEG) is used increasingly to evaluate the pharmacodynamics of benzodiazepines. The present study aimed to apply the EEG method as well as more traditional approaches to an interaction study of bromazepam and fluconazole. Twelve healthy male volunteers participated in a randomized, double-blind, four-way crossover study. The subjects received single oral or rectal doses of bromazepam (3 mg) after 4-day pretreatment of oral fluconazole (100 mg daily) or its placebo. Plasma bromazepam concentrations were measured before and 0.5, 1, 2, 3, 4, 6, 12, 22, 46, and 70 hours after bromazepam administration. Pharmacodynamic effects of bromazepam were assessed using self-rated drowsiness, continuous number addition test, and EEG. Fluconazole caused no significant changes in pharmacokinetics and pharmacodynamics of oral or rectal bromazepam. Rectal administration significantly increased AUC (1.7-fold, p < 0.0001) and Cmax (1.6-fold, p < 0.0001) of bromazepam. These changes following rectal dose may be due to avoidance of degradation occurring in the gastrointestinal tract. Rectal bromazepam also increased the area under the effect curves assessed by EEG (p < 0.05) and subjective drowsiness (p < 0.05). EEG effects were closely correlated with mean plasma bromazepam concentrations (r = 0.92, p < 0.001 for placebo; r = 0.89, p < 0.0001 for fluconazole). Thus, the EEG method provided pharmacodynamic data that clearly reflected the pharmacokinetics of bromazepam.

背景与目标： 脑电图 (EEG) 的定量分析越来越多地用于评估苯二氮卓类药物的药效学。本研究旨在将EEG方法以及更传统的方法应用于溴西epa和氟康唑的相互作用研究。12名健康男性志愿者参加了一项随机，双盲，四向交叉研究。受试者在口服氟康唑 (每天100毫克) 或其安慰剂4天预处理后接受单次口服或直肠剂量的溴西epa (3毫克)。在给予溴西epa之前和0.5、1、2、3、4、6、12、22、46和70小时后测量血浆溴西epa浓度。使用自测嗜睡，连续加数试验和EEG评估溴马西泮的药效学作用。氟康唑对口服或直肠溴西epa的药代动力学和药效学没有显着变化。直肠给药显着增加了bromazepam的AUC (1.7倍，p <0.0001) 和Cmax (1.6倍，p <0.0001)。直肠剂量后的这些变化可能是由于避免了胃肠道中的降解。直肠溴西epa还增加了通过EEG评估的效应曲线下的面积 (p < 0.05) 和主观嗜睡 (p <0.05)。EEG效应与平均血浆溴西泮浓度密切相关 (r = 0.92，安慰剂p <0.001; r = 0.89，氟康唑p <0.0001)。因此，EEG方法提供的药效学数据清楚地反映了溴西epa的药代动力学。

BACKGROUND & AIMS: :17 beta-Estradiol (E2) exerts negative feedback effects at the hypothalamo-pituitary level on serum FSH. This study investigated the effects of repeated daily administration of intranasal E2 (S21400) on the pharmacokinetics (PK) of E2 and estrone (E1) and the pharmacodynamics (PD) of FSH and assessed the PK/PD relationship between E2 and FSH using population model-dependent analysis. Postmenopausal volunteers (n = 24) received according to a balanced cross-over design, two 28-d treatments separated by a 2-month wash-out period: 300 microg E2, either alone or combined with oral dydrogesterone (20 mg/d) during the last 14 d of one of the treatments. Absorption of E2 was rapid, with maximal plasma concentrations at 10-30 min, returning to postmenopausal levels within 12 h. Over the 24-h period, FSH levels showed a U curve, with a minimum around 8 h after E2 administration. Moreover, over the treatment period, FSH basal values decreased by 17% between d 1 and 14 and an additional 5% between d 14 and 28. A PK/PD model described these short- and mid-term effects, possibly reflecting separate regulation mechanisms by E2 on FSH release and biosynthesis, respectively. The administration of progestin had no influence on E1, E2, and FSH model parameters. This study suggests that daily transient tissue exposure to E2 after pulsed estrogen therapy elicits short- and mid-term effects on the gonadotropin axis.

背景与目标： : 17β-雌二醇 (E2) 在下丘脑-垂体水平对血清FSH产生负反馈作用。本研究调查了重复每天鼻内给药E2 (S21400) 对E2和雌酮 (E1) 的药代动力学 (PK) 和FSH的药效学 (PD) 的影响，并使用人群模型依赖性分析评估了E2和FSH之间的PK/PD关系。绝经后志愿者 (n = 24) 根据平衡交叉设计接受了两次28天的治疗，间隔了2个月的冲洗期: 300 microg E2，在其中一种治疗的最后14天内，单独或与口服地屈孕酮 (20 mg/d) 联合使用。E2的吸收迅速，在10-30分钟时血浆浓度最高，在12小时内恢复到绝经后水平。在24小时内，FSH水平呈U曲线，在E2给药后8小时左右最低。此外，在治疗期间，FSH基础值在d 1和14之间下降了17%，在d 14和28之间下降了额外的5%。PK/PD模型描述了这些短期和中期影响，可能分别反映了E2对FSH释放和生物合成的单独调节机制。孕激素的给药对E1，E2和FSH模型参数没有影响。这项研究表明，脉冲雌激素治疗后每天短暂的组织暴露于E2会引起促性腺激素轴的短期和中期影响。

BACKGROUND & AIMS: WHAT IS KNOWN AND OBJECTIVE:The pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin were investigated following administration of levofloxacin injection in healthy Chinese volunteers for optimizing dosing regimen. METHODS:The PK study included single-dose (750 mg/150 mL) and multiple-dose (750 mg/150 mL once daily for 7 days) phases. The concentration of levofloxacin in blood and urine was determined using HPLC method. Both non-compartmental and compartmental analyses were performed to estimate PK parameters. Taking fC(max) /MIC ≥5 and fAUC(24 h) /MIC ≥30 as a target, the cumulative fraction of response (CFR) of levofloxacin 750 mg for treatment of community-acquired pneumonia (CAP) was calculated using Monte Carlo simulation. The probability of target attainment (PTA) of levofloxacin at various minimal inhibitory concentrations (MICs) was also evaluated. RESULTS AND DISCUSSION:The results of PK study showed that the C(max) and AUC(0-∞) of levofloxacin were 14·94 μg/mL and 80·14 μg h/mL following single-dose infusion of levofloxacin. The half-life and average cumulative urine excretion ratio within 72 h post-dosing were 7·75 h and 86·95%, respectively. The mean C(ss,max), C(ss,min) and AUC(0-τ) of levofloxacin at steady state following multiple doses were 13·31 μg/mL, 0·031 μg/mL and 103·7 μg h/mL, respectively. The accumulation coefficient was 1·22. PK/PD analysis revealed that the CFR value of levofloxacin 750-mg regimen against Streptococcus pneumoniae was 96·2% and 95·4%, respectively, in terms of fC(max) /MIC and fAUC/MIC targets. WHAT IS NEW AND CONCLUSION:The regimen of 750-mg levofloxacin once daily provides a satisfactory PK/PD profile against the main pathogenic bacteria of CAP, which implies promising clinical and bacteriological efficacy for patients with CAP. A large-scale clinical study is warranted to confirm these results.

背景与目标：

BACKGROUND & AIMS: :In recent years the use of the opioid oxycodone has increased markedly and replacing morphine as the first-line choice of opioid in several countries. There are formulations for oral immediate, oral extended release and intravenous use. The bioavailability is higher than for morphine and less variable. Oxycodone is primarily metabolized in the liver by the cytochrome P450 (CYP) enzymes with CYP3A as the major metabolic pathway and CYP2D6 as the minor metabolic pathway to noroxycodone, oxymorphone and noroxymorphone. Oxycodone exerts its analgesic effect via the µ-opioid receptor. The metabolism of CYP2D6 substrates varies to a large degree between individuals as a result of allele functionality. Poor metabolizers (PM) have two non-functional alleles, extensive metabolizers (EM) are homozygous with two functional alleles or heterozygous with one functional allele and ultrarapid metabolizers (UM) have more than two functional alleles. There are pronounced interethnic differences in the allele distribution. On the basis of studies performed thus far, oxycodone concentrations in comparison with EM are similar in PM and reduced in UM. The pharmacokinetics in UM are insufficiently investigated. Simultaneous inhibition of both CYP3A and CYP2D6 results in increased oxycodone concentrations and such a combination should be avoided. A similar effect is to be expected with use of a CYP3A inhibitor in CYP2D6 PM. Concomitant use of enzyme inducers such as rifampicin, St John's wort and carbamazepine should be avoided because of the risk of subtherapeutic concentrations of oxycodone. When the dosage of morphine may result in unpredictable bioavailability, like in patients with severe hepatic cirrhosis, oxycodone might be beneficial because it has higher and less variability in bioavailability between patients than morphine.

背景与目标： : 近年来，在一些国家，阿片类羟考酮的使用显着增加，并取代吗啡成为阿片类药物的一线选择。有口服立即，口服缓释和静脉内使用的制剂。生物利用度高于吗啡，且变化较小。羟考酮主要由细胞色素P450 (CYP) 酶在肝脏中代谢，其中CYP3A是主要代谢途径，CYP2D6是去甲氧可酮，羟吗啡酮和去甲氧吗啡酮的次要代谢途径。羟考酮通过 µ-阿片受体发挥镇痛作用。由于等位基因功能，CYP2D6底物的代谢在个体之间有很大程度的变化。不良代谢因子 (PM) 具有两个非功能性等位基因，广泛代谢因子 (EM) 具有两个功能性等位基因的纯合或具有一个功能性等位基因的杂合，而超类代谢因子 (UM) 具有两个以上的功能性等位基因。等位基因分布存在明显的种族间差异。根据迄今为止进行的研究，与EM相比，羟考酮的浓度在PM中相似，在UM中降低。对UM的药代动力学研究不足。同时抑制CYP3A和CYP2D6会导致羟考酮浓度增加，应避免这种组合。在CYP2D6 PM中使用CYP3A抑制剂可以预期类似的效果。应避免同时使用酶诱导剂，例如利福平，圣约翰草和卡马西平，因为存在亚治疗浓度的羟考酮的风险。当吗啡的剂量可能导致不可预测的生物利用度时，例如在严重肝硬化患者中，羟考酮可能是有益的，因为与吗啡相比，羟考酮在患者之间的生物利用度具有更高且更小的变异性。

BACKGROUND & AIMS: :Imrecoxib is a registered treatment for osteoarthritis pain symptoms in China. This study aims to assess the effect of imrecoxib on the pharmacodynamics and pharmacokinetics of warfarin. 12 healthy male volunteers with CYP2C9*3 AA and VKORC1 AA genotypes took a 5 mg dose of warfarin both alone and concomitantly with steady-state imrecoxib. Both warfarin alone and concomitantly with imrecoxib have safey and good tolerance across the trial. Following warfarin and imrecoxib co-administration, neither Cmax, AUC0-t and t1/2 of warfarin enantiomers nor AUC of international normalized ratio (INR) were markedly different from those of warfarin alone. The geometric mean ratios (GMRs) (warfarin + imrecoxib: warfarin alone) of INR(AUC) was 1 (0.99, 1.01). The GMRs of warfarin AUC0-∞ (90% confidence interval, CIs) for warfarin + imrecoxib: warfarin alone were 1.12 (1.08, 1.16) for R-warfarin and 1.13 (1.07, 1.18) for S- warfarin. The 90% CIs of the GMRs of AUC0-∞, Cmax and INR (AUC) were all within a 0.8-1.25 interval. The combination of warfarin and imrecoxib did not impact the pharmacodynamics and pharmacokinetics of single-dose warfarin; therefore, when treating a patient with imrecoxib and warfarin, it is not required to adjust the dosage of warfarin.

背景与目标： : Imrecoxib是中国骨关节炎疼痛症状的注册治疗方法。本研究旨在评估伊瑞昔布对华法林药效学和药代动力学的影响。12名具有CYP2C9 * 3 AA和VKORC1 AA基因型的健康男性志愿者单独服用5  mg剂量的华法林，同时服用稳态imrecoxib。在整个试验中，单独使用华法林和同时使用imrecoxib都具有安全性和良好的耐受性。华法林和imrecoxib共同给药后，华法林对映体的Cmax，AUC0-t和t1/2或国际标准化比率 (INR) 的AUC与单独的华法林均无显着差异。INR(AUC) 的几何平均比率 (GMRs) (华法林   + imimrecoxib: 单独使用华法林) 为1 (0.99，1.01)。华法林   + imimrecoxib的华法林AUC0-∞ (90% 置信区间，CIs) 的GMRs: R-华法林单独1.12 (1.08，1.16)，S-华法林1.13 (1.07，1.18)。AUC0-∞ 、Cmax和INR (AUC) 的GMRs的90% CIs均在0.8-1.25区间内。华法林和伊瑞昔布的组合不会影响单剂量华法林的药效学和药代动力学; 因此，在用伊瑞昔布和华法林治疗患者时，不需要调整华法林的剂量。

BACKGROUND & AIMS: :Bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir are members of the latest class of antiretrovirals available to treat human immunodeficiency virus (HIV) infection, the integrase strand transfer inhibitors. Integrase strand transfer inhibitors are potent inhibitors of the HIV integrase enzyme with IC90/95 values in the low nanogram per milliliter range and they retain antiviral activity against strains of HIV with acquired resistance to other classes of antiretrovirals. Each of the integrase strand transfer inhibitors have unique pharmacokinetic/pharmacodynamic properties, influencing their role in clinical use in specific subsets of patients. Cabotegravir, approved for use in Canada but not yet by the US Food and Drug Administration, is formulated in both oral and intramuscular formulations; the latter of which has shown efficacy as a long-acting extended-release formulation. Cabotegravir, raltegravir, and dolutegravir have minimal drug-drug interaction profiles, as their metabolism has minimal cytochrome P450 involvement. Conversely, elvitegravir metabolism occurs primarily via cytochrome P450 3A4 and requires pharmacokinetic boosting to achieve systemic exposures amenable to once-daily dosing. Bictegravir metabolism has similar contributions from both cytochrome P450 3A4 and uridine 5'-diphospho-glucuronosyltransferase 1A1. Bictegravir, dolutegravir, and raltegravir are recommended components of initial regimens for most people with HIV in the US adult and adolescent HIV treatment guidelines. This review summarizes and compares the pharmacokinetics and pharmacodynamics of the integrase strand transfer inhibitor agents, and describes specific pharmacokinetic considerations for persons with hepatic impairment, renal dysfunction, pregnancy, and co-infections.

背景与目标： : Bictegravir，cabotegravir，dolutegravir，elvitegravir和raltegravir是可用于治疗人类免疫缺陷病毒 (HIV) 感染 (整合酶链转移抑制剂) 的最新一类抗逆转录病毒药物的成员。整合酶链转移抑制剂是HIV整合酶的有效抑制剂，其IC90/95值在每毫升低纳克范围内，并且它们保留了对HIV菌株的抗病毒活性，对其他类型的抗逆转录病毒药物具有获得性抗性。每种整合酶链转移抑制剂具有独特的药代动力学/药效学特性，影响其在特定患者亚群中的临床应用作用。Cabotegravir已在加拿大批准使用，但尚未获得美国食品和药物管理局的批准，它以口服和肌内制剂配制; 后者已显示出长效缓释制剂的功效。Cabotegravir，raltegravir和dolutegravir具有最小的药物-药物相互作用，因为它们的代谢具有最小的细胞色素P450参与。相反，elviteggravir代谢主要通过细胞色素P450 3A4发生，并且需要药代动力学增强以实现适合每日一次给药的全身暴露。Bictegravir代谢对细胞色素P450 3A4和尿苷5 '-二磷酸葡萄糖醛酸基转移酶1A1的贡献相似。在美国成人和青少年HIV治疗指南中，大多数HIV患者推荐使用Bictegravir，dolutegravir和raltegravir。这篇综述总结并比较了整合酶链转移抑制剂的药代动力学和药效学，并描述了肝功能不全，肾功能不全，妊娠和合并感染患者的特定药代动力学考虑。

BACKGROUND & AIMS: :1. The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine based upon measurements of total and unbound serum concentrations were determined after a single dose (400 mg) and at steady state (200 mg every 6 h). 2. The oral clearance (7.6 +/- 1.9 vs 4.8 +/- 2.0 ml min-1 kg-1; P less than 0.05) and renal clearance (1.2 +/- 0.3 vs 0.63 +/- 0.25 ml min-1 kg-1; P less than 0.005) or quinidine were lower during steady state than after the single dose. 3. The area under the serum concentration vs time curve (AUC) of 3-hydroxyquinidine was greater at steady state than after the single dose (2.0 +/- 0.7 vs 3.0 +/- 0.6 mg l-1 h; P less than 0.05) and its renal clearance was less (3.0 +/- 1.1 vs 1.54 +/- 0.38 ml min-1 kg-1; P less than 0.05). 4. The slope of the relationship between quinidine concentration and change in QTc interval was greater at steady state (40.1 +/- 21.7 vs 72.2 +/- 41.7 ms/(mg l-1); P less than 0.05).

背景与目标： : 1。在单次剂量 (400 mg) 和稳态 (每6小时200 mg) 后，测定基于总血清浓度和未结合血清浓度的测量的奎尼丁和3-羟基奎尼丁的药代动力学和药效学。2.口服清除率 (7.6 +/- 1.9 vs 4.8 +/-2.0毫升min-1 kg-1; P小于0.05) 和肾脏清除率 (1.2 +/- 0.3 vs 0.63 +/-0.25毫升min-1 kg-1; P小于0.005) 或奎尼丁在稳态期间低于单剂量后。3.3-羟基奎尼丁的血清浓度与时间曲线 (AUC) 下面积在稳态时大于单剂量后 (2.0 +/- 0.7 vs 3.0 +/- 0.6 mg l-1 h; P小于0.05)，其肾脏清除率较小 (3.0 +/- 1.1 vs 1.54 +/-0.38毫升min-1 kg-1; P小于0.05)。4.奎尼丁浓度与QTc间期变化关系的斜率在稳态下较大 (40.1 +/- 21.7 vs 72.2 +/- 41.7 ms/(mg l-1); P小于0.05)。