BACKGROUND & AIMS: BACKGROUND:The UGT1A1*28 polymorphism, although closely linked with CPT-11-related adverse effects, cannot be used alone to guide individualized treatment decisions. However, CPT-11 dosage can be adjusted according to measured SN-38 pharmacokinetics. Our study is designed to investigate whether there is a relationship between SN-38 peak or valley concentrations and efficacy or adverse effects of CPT-11-based chemotherapy. We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)6/(TA)6 and (TA)6/(TA)7 genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai. METHODS:One hundred and sixty-four advanced colorectal cancer patients were enrolled. To understand differences in genotype expression, the frequency of UGT1A1*28 thymine-adenine (TA) repeats in TATA box arrangement was assessed by PCR with genomic DNA extracted from peripheral blood. For ninety-eight cases with the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes treated with CPT-11 as first-line chemotherapy, the plasma concentration of SN-38 was detected by HPLC 1.5 and 49 h after CPT-11 infusion. Efficacy and adverse effects were observed subsequently, and the relationship between SN-38 plasma concentration and efficacy or adverse effects within genotype groups, as well as differences in efficacy and adverse effects between (TA)6/(TA)6 and (TA)6/(TA)7 genotypes were analyzed statistically. RESULTS:One hundred and fourteen patients (69.51 %) were identified with the (TA)6/(TA)6 genotype, forty-eight patients (29.27 %) with the (TA)6/(TA)7 genotype, and two patients (1.22 %) with the (TA)7/(TA)7 genotype. The average peak and valley concentrations of SN-38 after CPT-11 infusion and plasma bilirubin average levels before and after CPT-11 treatment in the (TA)6/(TA)7 genotype group were all higher than those in (TA)6/(TA)6 group, and the difference was statistically significant (p = 0.00). Stepwise regression analysis showed that SN-38 peak and valley concentration was correlated with PFS in the (TA)6/(TA)6 genotype. In the (TA)6/(TA)7 group, SN-38 peak concentration was correlated with CPT-11 starting dose and OS, valley concentration correlated with plasma bilirubin levels before CPT-11 treatment, delayed diarrhea, and OS. For the (TA)6/(TA)6 genotype, mPFS of the SN-38 peak concentration >43.2 ng/ml subgroup was significantly longer than that of ≤43.2 ng/ml subgroup (8.0 ± 0.35 vs. 6.5 ± 0.79 months, χ (2) = 17.18, p = 0.00) with a relatively high incidence of Grade I/II° myelosuppression; for the (TA)6/(TA)7 genotype, there was no significant difference in mOS between the SN-38 valley concentration >16.83 ng/ml and ≤16.83 subgroups (17.3 ± 0.45 vs. 18.8 ± 0.50 months, χ (2) = 1.38, p = 0.24), but the former had a higher incidence of Grade III/IV° mucositis and delayed diarrhea. For 2 (TA)7/(TA)7 cases, although 25 % dose reduction of CPT-11, which is calculated according to body surface area, Grade IV° bone marrow suppression and Grade III° delayed diarrhea still occurred after CPT-11 treatment, though both adverse effects resolved and did not recur again after a 50 % dose reduction. CONCLUSION:The (TA)6/(TA)6 genotype and (TA)6/(TA)7 genotype accounted for the most, and (TA)7/(TA)7 genotype only account for a very small portion of advanced colorectal cancer patients in Shanghai. For the (TA)6/(TA)6 genotype, CPT-11 dosage can be increased gradually to improve efficacy for patients with SN-38 peak concentration ≤43.2 ng/ml after CPT-11 infusion; and for (TA)6/(TA)7 genotype patients, CPT-11 dosage may be lowered appropriately to reduce serious adverse effects such as bone marrow suppression and delayed diarrhea without affecting the efficacy for those with SN-38 valley concentration >16.83 ng/ml. For (TA)7/(TA)7 genotype patients, adverse effects should be closely observed after treatment even if CPT-11 dosage has been reduced.

背景与目标：

BACKGROUND & AIMS: :Allopurinol is the drug most widely used to lower the blood concentrations of urate and, therefore, to decrease the number of repeated attacks of gout. Allopurinol is rapidly and extensively metabolised to oxypurinol (oxipurinol), and the hypouricaemic efficacy of allopurinol is due very largely to this metabolite. The pharmacokinetic parameters of allopurinol after oral dosage include oral bioavailability of 79 +/- 20% (mean +/- SD), an elimination half-life (t((1/2))) of 1.2 +/- 0.3 hours, apparent oral clearance (CL/F) of 15.8 +/- 5.2 mL/min/kg and an apparent volume of distribution after oral administration (V(d)/F) of 1.31 +/- 0.41 L/kg. Assuming that 90 mg of oxypurinol is formed from every 100mg of allopurinol, the pharmacokinetic parameters of oxypurinol in subjects with normal renal function are a t((1/2)) of 23.3 +/- 6.0 hours, CL/F of 0.31 +/- 0.07 mL/min/kg, V(d)/F of 0.59 +/- 0.16 L/kg, and renal clearance (CL(R)) relative to creatinine clearance of 0.19 +/- 0.06. Oxypurinol is cleared almost entirely by urinary excretion and, for many years, it has been recommended that the dosage of allopurinol should be reduced in renal impairment. A reduced initial target dosage in renal impairment is still reasonable, but recent data on the toxicity of allopurinol indicate that the dosage may be increased above the present guidelines if the reduction in plasma urate concentrations is inadequate. Measurement of plasma concentrations of oxypurinol in selected patients, particularly those with renal impairment, may help to decrease the risk of toxicity and improve the hypouricaemic response. Monitoring of plasma concentrations of oxypurinol should also help to identify patients with poor adherence. Uricosuric drugs, such as probenecid, have potentially opposing effects on the hypouricaemic efficacy of allopurinol. Their uricosuric effect lowers the plasma concentrations of urate; however, they increase the CL(R) of oxypurinol, thus potentially decreasing the influence of allopurinol. The net effect is an increased degree of hypouricaemia, but the interaction is probably limited to patients with normal renal function or only moderate impairment.

背景与目标： : 别嘌醇是最广泛用于降低尿酸盐血药浓度的药物，因此，减少痛风反复发作的次数。别嘌醇迅速而广泛地代谢为氧嘌呤醇 (oxipurinol)，别嘌醇的低尿酸功效很大程度上归因于这种代谢物。口服后别嘌醇的药代动力学参数包括口服生物利用度79 +/- 20% (平均值 +/- SD)，消除半衰期 (t((1/2) 1.2 +/- 0.3小时，15.8 +/- 5.2 ml/min/kg的表观口服清除率 (CL/F) 和1.31 +/- 0.41 L/kg的口服施用后的表观分布体积 (V(d)/F)。假设每100毫克别嘌醇形成90毫克氧嘌呤醇，肾功能正常的受试者中氧嘌呤醇的药代动力学参数为23.3 +/- 6.0小时的t((1/2))，0.31 +/- 0.07毫升/分钟/千克的CL/F，V(d)/F为0.59 +/- 0.16 L/kg，肾清除率 (CL(R)) 相对于肌酐清除率为0.19 +/- 0.06。氧嘌呤醇几乎完全通过尿排泄清除，多年来，建议在肾功能损害时应减少别嘌醇的剂量。减少肾功能损害的初始目标剂量仍然是合理的，但是有关别嘌醇毒性的最新数据表明，如果血浆尿酸盐浓度的降低不足，则该剂量可能会增加到本指南以上。在选定的患者中，尤其是那些患有肾功能不全的患者中，测量氧尿醇的血浆浓度可能有助于降低毒性风险并改善低尿酸反应。监测氧脲醇的血浆浓度也应有助于识别依从性差的患者。尿尿药物，如丙磺舒，对别嘌醇的低尿酸疗效具有潜在的相反作用。它们的尿尿作用降低了尿酸盐的血浆浓度; 但是，它们会增加氧嘌呤醇的CL(R)，从而可能降低别嘌醇的影响。净效应是低尿酸血症的程度增加，但相互作用可能仅限于肾功能正常或仅中度受损的患者。

BACKGROUND & AIMS: AIM:To investigate the pharmacokinetics and clinical efficacy of intravenous (i.v.) and intramuscular (i.m.) lorazepam (LZP) in children with severe malaria and convulsions. METHODS:Twenty-six children with severe malaria and convulsions lasting > or =5 min were studied. Fifteen children were given a single dose (0.1 mg kg(-1)) of i.v. LZP and 11 received a similar i.m. dose. Blood samples were collected over 72 h for determination of plasma LZP concentrations. Plasma LZP concentration-time data were fitted using compartmental models. RESULTS:Median [95% confidence interval (CI)] LZP concentrations of 65.1 ng ml(-1) (50.2, 107.0) and 41.4 ng ml(-1) (22.0, 103.0) were attained within median (95% CI) times of 30 min (10, 40) and 25 min (20, 60) following i.v. and i.m. administration, respectively. Concentrations were maintained above the reported therapeutic concentration (30 ng ml(-1)) for at least 8 h after dosing via either route. The relative bioavailability of i.m. LZP was 89%. A single dose of LZP was effective for rapid termination of convulsions in all children and prevention of seizure recurrence for >72 h in 11 of 15 children (73%, i.v.) and 10 of 11 children (91%, i.m), without any clinically apparent respiratory depression or hypotension. Three children (12%) died. CONCLUSION:Administration of LZP (0.1 mg kg(-1)) resulted in rapid achievement of plasma LZP concentrations within the reported effective therapeutic range without significant cardiorespiratory effects. I.m administration of LZP may be more practical in rural healthcare facilities in Africa, where venous access may not be feasible.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Immunoglobulin products are widely used across multiple therapeutic areas such as immunodeficiency syndromes, infection and autoimmune diseases. The pharmacokinetics (PK) of immunoglobulins are well characterized in adults, but very little is known about the PK of immunoglobulins in neonates and infants (<2 years of age). OBJECTIVE:The objectives of the present study were: (1) characterize the PK of immunoglobulin intravenous preparation using model-independent (non-compartmental analysis), and (2) develop and evaluate a population PK model with extensive blood samples (8 blood samples) and sparse blood samples (2-3 blood samples). METHOD:Immunoglobulin G (IgG) concentration versus time data from very low birth weight neonates (n = 20) following intravenous administration were analyzed using nonlinear mixed effect modeling and non-compartmental approaches. Population pharmacokinetic models were developed from extensive and sparse sampling schemes. Models were evaluated based on the difference in objective function, goodness-of-fit plots and simulation based visual predictive check analysis. RESULTS:A non-compartmental analysis of IgG from neonates (bodyweight range 0.78-1.38 kg) indicated an average clearance of 3.0 ± 2.1 mL/day and volume of distribution at steady state 68 ± 25 mL. The population pharmacokinetic model from extensive sampling adequately described concentration- time data with mean clearance (2.7 mL/day), volume of central compartment (8.7 mL) and peripheral compartment (60 mL). The clearance and volume of distribution estimates using sparse sampling model (1 pre-and 2 post-dose blood samples) were comparable with extensive sampling. CONCLUSION:Our study provides important bridging data in scaling PK and dosing of immunoglobulins across a wide age range.

背景与目标：

BACKGROUND & AIMS: :The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3-a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38alpha, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.v.) administration, 1 exhibited low volumes of distribution at steady state (Vd(ss)) ranging from 0.4-1.3 l/kg (2.4-26 l/m(2)) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m(2)) and Sprague-Dawley rats (7.65+/-1.08 ml/min/kg, 45.9+/-6.48 ml/min/m(2) in male rats and 3.15+/-0.27 ml/min/kg, 18.9+/-1.62 ml/min/m(2) in female rats) and moderate in beagle dogs (12.3+/-5.1 ml/min/kg, 246+/-102 ml/min/m(2)) resulting in plasma half-lives ranging from 1 to 5 h in preclinical species. Moderate to high bioavailability of 1 was observed in rats (30-65%), dogs (87%) and monkeys (40%) after oral (p.o.) dosing consistent with the in vitro absorption profile of 1 in the Caco-2 permeability assay. In rats, the oral pharmacokinetics were dose dependent over the dose range studied (5, 50 and 100 mg/kg). The principal route of clearance of 1 in rat, dog, monkey and human liver microsomes and in vivo in preclinical species involved oxidative metabolism mediated by cytochrome P450 enzymes. The major metabolic fate of 1 in preclinical species and humans involved hydroxylation on the isopropyl group to yield the tertiary alcohol metabolite 2. In human liver microsomes, this transformation was catalysed by CYP3A4 as judged from reaction phenotyping analysis using isozyme-specific inhibitors and recombinant CYP enzymes. Metabolite 2 was also shown to possess inhibitory potency against p38alpha in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (f(u) approximately 0.1-0.33) in rat, mouse, dog, monkey and human. 1 as well as the active metabolite 2 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC(50)>50 microM). Overall, these results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of 1 is relatively consistent across preclinical species and predict potentially favorable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans as an anti-inflammatory agent.

背景与目标： : 6-(4-(2,5-二氟苯基) oxazol-5-yl)-3-异丙基-[1,2，4]-三唑并 [4,3-a] 吡啶 (1) 的处置，这是一种有效且选择性的丝裂原活化蛋白 (MAP) 激酶p38alpha抑制剂，在几种动物物种中被描述为支持其临床前安全性研究和潜在临床开发的选择。1在所有被检查的物种中表现出普遍有利的药代动力学特性。静脉注射 (静脉注射) 给药后，1在大鼠，狗和猴子中表现出0.4-1.3 l/kg (2.4-26 l/m(2)) 的稳态下低分布量 (Vd(ss))。食蟹猴的全身血浆清除率低 (6.00毫升/min/kg，72.0毫升/min/m(2)) 和Sprague-Dawley大鼠 (7.65 +/-1.08毫升/min/kg，45.9 +/-6.48毫升/min/m(2) 在雄性大鼠和3.15 +/-0.27毫升/min/kg，18.9 +/-1.62毫升/min/m (雌性大鼠2) 和比格犬中等 (12.3 +/-5.1毫升/min/kg，246 +/-102毫升/min/m(2)) 导致临床前物种的血浆半衰期为1至5 h。在大鼠 (30-65%) 中观察到中度至高生物利用度1，狗 (87%) 和猴子 (40%) 口服 (p.o.) 给药后与Caco-2通透性测定中1的体外吸收曲线一致。在大鼠中，口服药代动力学在研究的剂量范围内是剂量依赖性的 (5，50和100 mg/kg)。1在大鼠，狗，猴子和人类肝微粒体以及临床前物种的体内涉及细胞色素P450酶介导的氧化代谢。1在临床前物种和人类中的主要代谢命运涉及异丙基上的羟基化以产生三级醇代谢物2。在人类肝微粒体中，根据使用同工酶特异性抑制剂和重组CYP酶的反应表型分析判断，这种转化是由CYP3A4催化的。在各种体外测定中，代谢物2也显示出对p38alpha的抑制能力。1以及活性代谢物2与血浆蛋白中度至高度结合 (f(u) 大约0.1-0.33) 在大鼠中，小鼠，狗，猴子和人。1以及活性代谢物2没有表现出对五种主要细胞色素P450酶的竞争性抑制，即CYP1A2，2C9，2C19，2D6和3A4 (IC(50)>50微米)。总的来说，这些结果表明吸收，分布，1的代谢和排泄 (ADME) 概况在临床前物种中相对一致，并预测了人类潜在的有利药代动力学特性，支持其选择毒性/安全性评估研究以及在人类中作为抗炎剂的可能研究。

BACKGROUND & AIMS: :This study included 24 healthy volunteers who received a single 37.5 mg oral dose of tramadol. We analyzed 18 polymorphisms within CYP2D6, CYP2B6, CYP3A, COMT, ABCB1, SLC22A1 and OPRM1 genes by quantitative PCR, to study whether these polymorphisms affect its pharmacokinetics, pharmacodynamics and safety. CYP2D6 intermediate metabolizers (n = 6) showed higher tramadol plasma concentrations and lower clearance compared with normal and ultrarapid metabolizers. CYP2B6 G516T T/T (n = 2) genotype was also associated to higher tramadol plasma levels. No other polymorphism affected tramadol pharmacokinetics. Three volunteers experienced a prolonged QTc not associated with the genetic variants studied or altered phamacokinetic parameters. The correlation of CYP2B6 genotype with higher tramadol concentrations is remarkable since its influence on its elimination is also relevant and has been less studied to date. However, given our small sample size, it is important to interpret our results with caution.

背景与目标： : 这项研究包括24名健康志愿者，他们接受了单次37.5毫克的曲马多口服剂量。我们通过定量PCR分析了CYP2D6，CYP2B6，CYP3A，COMT，ABCB1，SLC22A1和OPRM1基因内的18个多态性，以研究这些多态性是否影响其药代动力学，药效学和安全性。CYP2D6中间代谢者 (n = 6) 显示出较高的曲马多血浆浓度和较低的清除率与正常和超类代谢者相比。CYP2B6 G516T T/T (n = 2) 基因型也与较高的曲马多血浆水平相关。没有其他多态性影响曲马多的药代动力学。三名志愿者经历了长时间的QTc，与所研究的遗传变异或遗传动力学参数的改变无关。CYP2B6基因型与较高曲马多浓度的相关性是显着的，因为它对其消除的影响也是相关的，迄今为止研究较少。但是，鉴于我们的样本量较小，因此谨慎解释我们的结果很重要。

BACKGROUND & AIMS: OBJECTIVE:To study the effect of continuous veno-venous hemofiltration (CVVHF) on the pharmacokinetics of levofloxacin in critically ill patients with acute renal failure. DESIGN:Open-label study. SETTING:Anesthesiology ICU, University Hospital of Regensburg. PATIENTS:Six critically ill patients treated with CVVHF because of acute renal failure needing antimicrobial therapy. INTERVENTIONS:Levofloxacin i.v. 250 mg qd with a starting dose of 500 mg. CVVHF with the following characteristics: hemofilter AN69 hollow fibers of 0.90 m2 area, blood flow 150 ml/min, ultrafiltrate flow 1.3 l/h, filtrate substitution in post-dilution mode. MEASUREMENTS AND RESULTS:The plasma pharmacokinetics and clearance of levofloxacin by hemofiltration were established on day 1 and day 4-6 of treatment. Levofloxacin was determined by high-performance liquid chromatography (HPLC). Mean (range) peak plasma concentrations after levofloxacin 500 mg single dose (s.d.) and 250 mg multiple dose (m.d.) were 6.4 (2.7-9.4) and 8.2 (4.7-10.3) mg/l, trough levels 2.7 (1.4-5.0) and 2.9 (1.7-3.9) mg/l, half-life 28 (19-38) and 22 (17-31) h, volume of distribution 1.2 (0.72-1.6) l/kg and 0.91 (0.52-2.0) l/kg, respectively. The mean sieving coefficient was 0.96 (0.79-1.09), mean total clearance 47 (20-89) ml/min, and mean clearance by hemofiltration 21 (13-27) ml/min, respectively. CONCLUSIONS:A dosage schedule of levofloxacin 250 mg qd with a 500 mg loading dose seems appropriate for anuric patients during CVVHF. Sufficiently high steady-state concentrations of levofloxacin were achieved after the first dose. Undesired accumulation of levofloxacin was not observed.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:To testify that the asialoorosomucoid (ASOR) prepared by us has liver-targeting specificity and to investigate its pharmacokinetic characteristics. METHODS:The distribution of 125I-ASOR in vivo was determined by single photon emission computed tomography (SPECT) and immunohistochemical technique after 125I-ASOR was injected into Sprague-Dawley (S-D) rats through their caudal veins. In vitro, different doses of pEGFP-N1 plasmid were transfected into both HepG2 cells and HT1080 cells with the use of ASOR-poly-L-lysine. At 24 and 48 h after transfection, the expression of green fluorescent protein (GFP) was determined under fluorescent microscope. Pharmacokinetic parameters were calculated according to two-compartment open system model with first-order kinetics. RESULTS:SPECT images showed that 125I-ASOR was located only in liver/stomach and root of caudal vein/bladder at 10 min after injection. The 125I-ASOR radioactivities of organs taken out from S-D rats were different at different times, and about 63% of 125I-ASOR was located in the liver at 10 min after injection. At 30 min after injection a peak of radioactivity was seen in stomach. The times of these two radioactivity peaks were different. Immunohistochemical study of liver frozen sections showed that ASOR was combined mainly with hepatocyte membrane, especially in areas with rich blood flow. In vitro study showed that ASOR targeted specifically cells with asialoglycoprotein receptor (ASGr). GFP expression was detected in HepG2 cells but not in HT1080 cells. Furthermore, the more quantity of pEGFP-N1 transfected and the longer expression time, the higher GFP expression level was in HepG2 cells. The 125I-ASOR pharmacokinetics equation for liver was Ct=662216e-3.362t+8896e-2343t. 125I-ASOR was excreted from liver slowly after an initial rapid decrease. The pharmacokinetic equation for stomach was Ct=-114815e-1.7t+1148153e-15t and the half-life of 125I-ASOR in stomach was 4.62 h. CONCLUSIONS:ASOR prepared by us could be an efficient gene transfer vector, ASOR was distributed mainly in the liver and stomach and had high targeting specificity to hepatocytes or hepatic originating cells.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:This study was undertaken to study the pharmacokinetics of intravenously administered amoxicillin in pregnant women with preterm premature rupture of the membranes (PPROM). STUDY DESIGN:Healthy women with PPROM were recruited and treated with amoxicillin (2 g initially and 1 g subsequently). Blood samples were obtained from the opposite arm and concentrations determined with the use of high-pressure liquid chromatography. Nonlinear mixed-effects modeling was performed in nonlinear mixed effect (population) modeling. RESULTS:The pharmacokinetics of 17 patients was described by a 3-compartment model. Clearance and volume of distribution at steady state were 22.8 L/h and 21.4 L/h, respectively, similar to values in nonpregnant individuals. There was little variability between patients. No relationship was observed between values of individual pharmacokinetic parameters and various covariates. CONCLUSION:The pharmacokinetics of amoxicillin in pregnant patients with PPROM similar to nonpregnant individuals. Given the small interindividual variability in pharmacokinetics, no dose adjustments are required to account for differences between subjects under normal circumstances.

背景与目标：

BACKGROUND & AIMS: :Vilaprisan is a novel selective progesterone receptor modulator for the long-term treatment of uterine fibroids and endometriosis. This study investigated the pharmacokinetics, safety, and tolerability of vilaprisan in healthy Chinese postmenopausal women. Twelve participants received multiple doses of vilaprisan once daily over 14 days as a 2-mg tablet. Plasma vilaprisan concentrations were determined using liquid chromatography-tandem mass spectrometry. The main pharmacokinetic parameters of vilaprisan were assessed with noncompartmental analysis, including maximum observed concentration (Cmax ), systemic exposure (area under the plasma concentration-time curve), time to reach Cmax and terminal half-life. Safety assessments include the documentation of adverse events, measurement of clinical/anthropometric parameters and vital signs, electrocardiogram, and physical and gynecologic examination. The participants had a mean age of 53.3 (± 4.2) years and a body mass index of 23.8 ± 2.8 kg/m2 . Median time to reach Cmax was 1.5 hours after both single and multiple vilaprisan administration. Mean Cmax values obtained after multiple dosing (23.3 μg/L [standard deviation (SD) = 6.73]) were 1.92-fold (SD = 0.554) higher compared to single dosing (12.5 μg/L [SD = 3.04]). Mean area under the plasma concentration-time curve in the dosing interval increased with an accumulation factor of 2.98 (SD = 0.767) between single (91.3 μg · h/L [SD = 20.4]) and multiple dosing (276 μg · h/L [SD = 109]). The mean terminal half-life of vilaprisan was 44.5 hours (SD = 10.3) after multiple dosing. Mild to moderate adverse events were observed similar to previous studies. Overall, daily oral administration of the therapeutic dose of 2 mg of vilaprisan over 14 days was safe and well tolerated by all participants.

背景与目标： : vilaprison是一种新型的选择性孕激素受体调节剂，可长期治疗子宫肌瘤和子宫内膜异位症。这项研究调查了vilaprison在健康的中国绝经后妇女中的药代动力学，安全性和耐受性。12名参与者在14天内每天接受一次多次剂量的vilaprisan，为2 mg片剂。使用液相色谱-串联质谱法测定血浆vilaprison浓度。通过非房室分析评估vilaprison的主要药代动力学参数，包括最大观察浓度 (Cmax)，全身暴露 (血浆浓度-时间曲线下的面积)，达到Cmax的时间和终末半衰期。安全性评估包括不良事件的记录，临床/人体测量参数和生命体征的测量，心电图以及体格和妇科检查。参与者的平均年龄为53.3 (± 4.2) 岁，体重指数为23.8 ± 2.8千克/m2。达到Cmax的中位时间为单次和多次维拉普瑞沙给药后1.5小时。与单次给药 (23.3 μ g/L [SD = 6.73]) 相比，多次给药 (12.5 μ g/L [SD = 3.04]) 后获得的平均Cmax值高1.92倍 (SD = 0.554)。在单次给药 (91.3 μ g · h/L [SD = 20.4]) 和多次给药 (276 μ g · h/L [SD = 109]) 之间，给药间隔内血浆浓度-时间曲线下的平均面积随累积因子2.98 (SD = 0.767) 而增加。在多次给药后，vilaprison的平均终末半衰期为44.5小时 (SD = 10.3)。观察到轻度至中度不良事件与先前的研究相似。总体而言，所有参与者在14天内每天口服2 mg vilaprissan的治疗剂量是安全的，并且耐受性良好。

BACKGROUND & AIMS: :TV-1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long-acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV-1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV-1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian populations. TV-1106 demonstrated relatively slow absorption (median tmax , 10-30 hours) and a mean elimination half-life of 26-36 hours. Apparent clearance and volume of distribution decreased with increasing TV-1106 doses in both populations and appeared to increase more than dose proportionality across the tested doses. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) increased in a dose-related manner, with maximum responses observed at 33-96 and 42-109 hours, respectively. IGF-1 and IGFBP-3 returned to baseline values at 168 hours following 7.5 and 15 mg of TV-1106, and 336 hours following 50 and 100 mg of TV-1106. TV-1106 appeared safe in both populations. There was no evidence of differences in pharmacokinetics, pharmacodynamics, or safety of TV-1106 between Japanese and caucasian populations. The data also demonstrate long-acting growth hormone properties of TV-1106 and support its potential for once-weekly dosing.

背景与目标： : TV-1106是一种与重组人生长激素基因融合的人血清白蛋白，旨在为GH缺乏症患者提供日常生长激素 (GH) 注射的长效替代品。这项研究调查了日本 (n = 44) 和白种人 (n = 44) 健康受试者单次皮下剂量的TV-1106 (7.5、15、50和100 mg) 的药代动力学，药效学和安全性。TV-1106药代动力学和药效学在日本和高加索人群中具有可比性。TV-1106显示相对缓慢的吸收 (中值tmax，10-30小时) 和26-36小时的平均消除半衰期。在两个群体中，表观清除率和分布体积随着TV-1106剂量的增加而降低，并且似乎在整个测试剂量中增加的剂量比例超过剂量比例。胰岛素样生长因子-1 (IGF-1) 和IGF结合蛋白-3 (IGFBP-3) 以剂量相关的方式增加，分别在33-96和42-109小时观察到最大反应。IGF-1和IGFBP-3在7.5和15 mg TV-1106后168小时以及50mg和100 mg TV-1106后336小时恢复到基线值。在这两个人群中，TV-1106似乎都是安全的。没有证据表明日本人和白种人之间的药代动力学，药效学或TV-1106安全性存在差异。数据还证明了TV-1106的长效生长激素特性，并支持其每周一次给药的潜力。

BACKGROUND & AIMS: :The pharmacokinetics and tissue distribution profiles of a novel series of traditional Chinese medicine-platinum (TCM-Pt) compounds [Pt(C(8)H(8)O(5))(NH(2)R)(2)]: 1 (where R=H), 3 (R=CH(3)) and 5 (R=C(6)H(10)), were studied in Sprague-Dawley rats following a single bolus intravenous (i.v.) injection. Platinum concentrations in total plasma, plasma ultrafiltrate, urine and tissues were measured by flameless atomic absorption spectroscopy. Pharmacokinetic studies showed that plasma concentrations of total and free platinum for the novel TCM-Pt compounds as well as cisplatin and carboplatin declined in a biexponential manner with a short distribution half-life (t(1/2alpha): 0.12-0.34h). Compared with cisplatin, the novel TCM-Pt compounds had a longer elimination half-life (t(1/2beta)), larger dose normalized area under the curve (AUC/D), larger volume of distribution at steady-state (V(ss)), slower clearance (CL) of free platinum and higher percentage of cumulative urinary excretion (CUE), which can be attributed to their lower chemical reactivities. In tissues, the highest Pt concentrations were found in the kidney, followed by the liver and the lowest in the heart; no Pt was detected in the brain. Twenty-four hours after drug administration, platinum concentrations in tissues were significantly lower for the novel TCM-Pt compounds. These findings suggest that the novel compounds might afford higher clinical efficacy and reduced systemic side effects, when compared with cisplatin.

背景与目标： : 一系列新型中药铂 (TCM-Pt) 化合物 [Pt(C(8)H(8)O(5))(NH(2)R)(2)]: 1 (其中R = H)，单次推注静脉 (i.v.) 后，在Sprague-Dawley大鼠中研究了3 (R = CH(3)) 和5 (R = C(6)H(10))。通过无火焰原子吸收光谱法测量总血浆，血浆超滤液，尿液和组织中的铂浓度。药代动力学研究表明，新型TCM-Pt化合物以及顺铂和卡铂的血浆总铂和游离铂浓度以双指数方式下降，半衰期短 (t(1/2α): 0.12-0.34h)。与顺铂相比，新型TCM-Pt化合物具有更长的消除半衰期 (t(1/2β))，更大的剂量标准化曲线下面积 (AUC/D)，更大的稳态分布体积 (V(ss))，游离铂的清除率 (CL) 较慢，累积尿排泄 (CUE) 的百分比较高，这可以归因于它们较低的化学反应性。在组织中，肾脏中的Pt浓度最高，其次是肝脏，心脏中的Pt浓度最低; 在大脑中未检测到Pt。给药24小时后，新型TCM-Pt化合物组织中的铂浓度显着降低。这些发现表明，与顺铂相比，新化合物可能具有更高的临床疗效和减少的全身副作用。

BACKGROUND & AIMS: BACKGROUND:Natalizumab, an anti-α4 integrin monoclonal antibody, has demonstrated efficacy in phase 2 and 3 studies of predominantly Caucasian patients with relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE:To evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of natalizumab in Japanese RRMS patients. METHODS:This multicenter, phase 2 study included an open-label PK/PD study in 12 patients (part A) and a double-blind, placebo-controlled, randomized (computer-generated sequence) study in 94 patients (part B). For part B, patients received intravenous natalizumab 300mg (n=47) or placebo (n=47) every 4 weeks. The primary efficacy endpoint was the rate of development of new active lesions (gadolinium-enhancing or new/enlarging T2 lesions) over 24 weeks. Clinical relapses and safety were also assessed. RESULTS:New active lesions developed at a significantly lower mean rate in natalizumab-treated patients (0.06 lesions/24 weeks) than in placebo-treated patients (0.35 lesions/24 weeks) (p<0.001). The annualized relapse rate was 0.53 for natalizumab and 1.73 for placebo (p<0.001). Twice as many natalizumab-treated patients (79%) as placebo-treated patients (38%) were relapse-free (p<0.001). The safety, PK, and PD profiles of natalizumab in this study were consistent with data in Caucasian RRMS patients. CONCLUSIONS:In Japanese RRMS patients, natalizumab treatment every 4 weeks for 24 weeks was well tolerated and reduced the development of new brain lesions and relapses (Funded by Biogen; ClinicalTrials.gov identifier: NCT01440101).

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Timosaponin A-III is one of the most promising active saponins from Anemarrhena asphodeloides Bge. As an oral chemotherapeutic agent, there is an urgent need to clarify its biopharmaceutics and pharmacokinetics to improve its development potential. OBJECTIVE:This research explores the bioavailability of timosaponin A-III and clarifies its absorption and metabolism mechanisms by a sensitive and specific HPLC-MS/MS method. METHODS:Pharmacokinetics and bioavailability studies of timosaponin A-III were performed in Sprague-Dawley rats by oral (20 g/kg) and intravenous administration (2 mg/kg). Control group was given the same volume of normal saline. The absorption of timosaponin A-III was investigated in a rat intestinal perfusion model in situ and a Caco-2 cell transport model in vitro. The metabolic rate of timosaponin A-III was determined in a rat liver microsome incubation system. RESULTS:After the oral administration, timosaponin A-III reached Cmax of 120.90 ± 24.97 ng/mL at 8 h, and the t1/2 was 9.94 h. The absolute oral bioavailability of timosaponin A-III is 9.18%. The permeability coefficients of timosaponin A-III in four intestinal segments ranged from 4.98 to 5.42 cm/s, indicating a difficult absorption. A strikingly high transport of timosaponin A-III was found, PappBA 3.27 ± 0.64 × 10-6 cm/s, which was abolished by a P-gp inhibitor. Rat liver microsome incubation studies showed that timosaponin A-III could hardly be metabolized, with a t1/2 of over 12 h. In addition, the solubility test showed a low solubility in PBS solution, 30.58 μg/mL. CONCLUSION:Timosaponin A-III exhibited low oral bioavailability by oral and intravenous admiConclusion: nistration, which was probably caused by its low permeability and solubility. This study may provide a reference for the rational clinical use and further study on the pharmacology or toxicology of timosaponin A-III.

背景与目标：

BACKGROUND & AIMS: :Methotrexate (MTX) steady state concentrations were evaluated in 42 children who had received high-dose infusions (6-8 g/m2) for acute lymphocytic leukemia. Concentrations in serum and cerebrospinal fluid (CSF) measured by immunoassay were found to be highly variable. Reanalysis by a reference high-pressure liquid chromatography method ruled out analytical factors as a source of this variability. The correlation coefficient between the analytical methods was 0.77 for the serum data and 0.88 for the CSF data. The variability of serum and CSF concentrations was higher in younger patients (serum; P = 0.05 and CSF; P = 0.18), and the CSF concentration decreased with decreasing age and in later courses. Body surface area, body mass index, weight, and gender were not significantly related to MTX variability. We conclude that the pronounced pharmacokinetic variability seen during MTX infusions remains largely unexplained.

背景与目标： : 在42名接受高剂量输注 (6-8g/m2) 治疗急性淋巴细胞白血病的儿童中评估了甲氨蝶呤 (MTX) 的稳态浓度。通过免疫测定法测量的血清和脑脊液 (CSF) 中的浓度变化很大。通过参考高压液相色谱法进行的重新分析排除了分析因素作为这种变异性的来源。对血清数据0.77分析方法之间的相关系数，对CSF数据0.88。在年轻患者中，血清和CSF浓度的变异性更高 (血清; P = 0.05和CSF; P = 0.18)，并且CSF浓度随着年龄的降低和病程的后期而降低。体表面积，体重指数，体重和性别与MTX变异性没有显着相关。我们得出的结论是，在MTX输注期间看到的明显的药代动力学变异性在很大程度上仍未得到解释。