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Beta-lactam antimicrobial dosing optimization in obese patients compared to non-obese patients using population pharmacokinetic/pharmacodynamic approach.

机译：使用群体药代动力学/药效学方法，与非肥胖患者相比，肥胖患者的β-内酰胺抗菌药物剂量优化。

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摘要

Obesity is a significant global health problem and has been associated with altered pharmacokinetics and pharmacodynamics of many drugs. However, little is known regarding the effect of obesity on the pharmacokinetics and pharmacodynamics of many broad-spectrum, beta-lactam antibiotics such as piperacillin/tazobactam, meropenem, and cefepime. The objective of this study is to evaluate the population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam, meropenem, and cefepime in hospitalized obese patients in order to determine dosing regimens that provide similar exposures between obese and non-obese patients.;For piperacillin/tazobactam, a retrospective analysis was conducted using prospectively collected serum concentration-time data from two previous studies (Study 1 and Study 2) published by our research group. Hospitalized, adult patients who required antimicrobial therapy for a suspected or documented bacterial infection were eligible to participate in both studies. In Study 2, only patients with total body weight (TBW) greater than 120 kg were eligible to be enrolled. Patients were classified as either obese [body mass index (BMI) ¡Y 30 kg/m2] or non-obese (BMI < 30 kg/m2). In Study 1, all patients received piperacillin/tazobactam 4.5 g every 8 hours (q8h), infused over 4 hours. In Study 2, patients received piperacillin/tazobactam either 4.5 g or 6.75 g q8h, infused over 4 hours. After 2 or more days of therapy, serial blood samples were collected from an indwelling IV catheter immediately prior to drug administration, and at 1, 2, 3, 4 (end of infusion), 5, 6, 7 and 8 hours after the start of infusion. Piperacillin and tazobactam serum concentrations were determined by the previously validated high performance liquid chromatography (HPLC) method. Population pharmacokinetic parameters were estimated using NONMEM, and the final pharmacokinetic model was built by evaluating the effects of covariates on the pharmacokinetic parameters of piperacillin and tazobactam using the stepwise forward inclusion followed by the backward elimination process. Tested covariates included: 1) age; 2) sex; 3) body size descriptor, including TBW, ideal body weight (IBW), lean body weight (LBW), and BMI; 4) creatinine clearance (CRCL); and 5) admission to an intensive care unit (ICU; ICU=1, general medical ward=0). In the stepwise forward inclusion process, covariates that reduced the model objective function value (OFV) > 3.84 (p < 0.05; ¦O2 distribution; 1 df) were considered significantly associated with the pharmacokinetic parameters in the model. In the backward elimination process, a covariate was removed if its elimination increased the model OFV by 0.025; ¦O2 distribution; 1 df). Using the final pharmacokinetic model, Monte Carlo simulations were performed for three 4-hour dosing regimens to calculate probability of target attainment (PTA) using ¡Y 50%fT>MIC.;Overall, a convenience sample of 27 patients (11 non-obese and 16 obese) were studied. TBW ranged from 60 kg to 211 kg, BMI from 19.7 kg/m2 to 72.9 kg/m2, and measured creatinine clearance (CRCL) from 23 mL/min to 260 mL/min. Patient demographics [median (range)] in non-obese vs. obese group are: age, 53 (27-76) vs. 48 (35-69) years; CRCL, 88 (23-148) vs. 111 (28-260) mL/min; height, 175 (163-190) vs. 175 (157-190) cm; TBW, 74 (60-100) vs. 151 (98-211) kg; LBW, 54 (39-72) vs. 78 (50-94) kg; IBW, 71 (55-84) vs. 71 (50-84) kg; BMI, 24.8 (19.7-29.4) vs. 50.1 (32.7-72.9) kg/m2. The number of male patients was seven in non-obese and ten in obese patient groups, and the number of patients admitted to an intensive care unit (ICU) was seven each in non-obese and obese patient groups. Compared to non-obese patients, obese patients had significantly larger TBW, LBW, and BMI (p < 0.05); other demographics were similar between non-obese and obese patients. Observed serum concentration-time profiles of both piperacillin and tazobactam were best described by a one-compartment model with zero-order input and first-order, linear elimination. The final model for piperacillin was: clearance (CL; L/h) = 11.3 + [0.0646*(CRCL-105)] + [0.0579*(BMI-35)]; and volume of distribution (V; L) = 31.3 + [0.132*(TBW-120)]. The final model for tazobactam was: CL (L/h) = 10.1 + [0.0272*(CRCL-105)]; and V (L) = 34.3. For both piperacillin and tazobactam, obese patients had significantly increased CL and V compared to non-obese patients. The pharmacokinetic parameters [median (range)] in non-obese vs. obese patients were: piperacillin CL, 9.0 (4.8-14.2) vs. 13.1 (6.8-20.0) L/h (p=0.026); piperacillin V, 24.6 (17.1-37.8) vs. 32.5 (19.8-69.8) L (p=0.014); tazobactam CL, 6.8 (4.4-15.5) vs. 13.1 (5.6-26.4) L/h (p=0.005); and tazobactam V, 17.1 (9.4-70.3) vs. 45.5 (10.5-116.6) L (p=0.019). Based on the pharmacodynamic analysis using Monte Carlo simulation, at the piperacillin MICs ¡U 16 mg/L in the presence of tazobactam, which is the susceptibility breakpoint for Enterobacteriaceae and Pseudomonas aeruginosa, PTA was > 90% for 4-hour infusion dosing regimens ¡Y 3.375 g q8h in non-obese patients and ¡Y 4.5 g q8h in obese patients, respectively.;For meropenem, a retrospective analysis was conducted using prospectively collected serum concentration-time data from three previous studies (Study 3, Study 4, and Study 5) published by our research group. Hospitalized, adult patients who required antimicrobial therapy for a suspected or documented bacterial infection were eligible to participate in all three studies. Although patients with CRCL less than 50 mL/min were eligible to participate in Study 3, they were excluded in Study 4 and 5 due to different study objectives. In Study 3, only patients with BMI ¡Y 40 kg/m2 were enrolled, and in Study 4, only patients with BMI ¡Y 40 kg/m2 or TBW ¡Y 100 pounds over their IBW were enrolled. Patients were classified as either obese (BMI ¡Y 30 kg/m2) or non-obese (BMI < 30 kg/m2). In Study 3, patients received the following meropenem dosing regimens: 500 mg q6h if CRCL > 60 mL/min; 500 mg q8h if CRCL was 40 to 60 mL/min; and 500 mg q12h if CRCL was 10 to 39 mL/min. In Study 4, all patients received either 500 mg or 1000 mg q6h. In Study 5, all patients received 1000 mg q8h. In all studies, all dosing regimens were infused over 30 minutes. After 2 or more days of therapy, serial blood samples were collected from an indwelling IV catheter as scheduled in each study: immediately prior to drug administration, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8 (if receiving q8h or q12h dosing regimens), and 12 hours (if receiving q12h dosing regimens) after the start of infusion in Study 3; prior to drug administration, 0.5 (end of infusion), 1, 2, 3, 4, and 6 hours after the start of infusion in Study 4; and prior to drug administration, 0.5 (end of infusion), 1, 1.5, 2, 3, 4, 5, 6, and 8 hours after the start of infusion in Study 5. Serum meropenem concentrations were determined by previously described analytical methods: HPLC in Study 3 and Study 4; and ultraperformance liquid chromatography in Study 5. Population pharmacokinetic parameters were estimated using NONMEM, and the final pharmacokinetic model was built by evaluating the effects of covariates on the meropenem pharmacokinetic parameters using the stepwise forward inclusion followed by the backward elimination process. Tested covariates included: 1) age; 2) sex; 3) body size descriptor, including TBW, IBW, LBW, and BMI; 4) CRCL; and 5) admission to an ICU (ICU=1, general medical ward=0). In the stepwise forward inclusion process, covariates that reduced the model OFV > 3.84 (p < 0.05; ¦O2 distribution; 1 df) were considered significantly associated with the pharmacokinetic parameters in the model. In the backward elimination process, a covariate was removed if its elimination increased the model OFV by 0.025; ¦O2 distribution; 1 df). Using the final pharmacokinetic model, Monte Carlo simulations were performed for five different meropenem dosing regimens to calculate PTA using ¡Y 40%fT>MIC. Each dosing regimen was simulated as 30-minute infusion, 3-hour infusion for q6h regimens, and 4-hour infusion for q8h and q12h regimens. Overall, a convenience sample of 40 patients (11 non-obese and 29 obese) were studied. TBW ranged from 57 kg to 305 kg, BMI from 19.2 kg/m2 to 88.8 kg/m2, and CRCL from 15 mL/min to 186 mL/min. Patient demographics [median (range)] in non-obese vs. obese group are: age, 59 (20-79) vs. 57 (26-76) years; CRCL, 58 (15-182) vs. 87 (20-186) mL/min; height, 170 (165-183) vs. 170 (150-193) cm; TBW, 72 (57-88) vs. 149 (73-305) kg; LBW, 49 (40-66) vs. 66 (38-114) kg; IBW, 64 (57-78) vs. 64 (34-87) kg; BMI, 25.0 (19.2-28.6) vs. 53.7 (30.6-88.8) kg/m2. The number of male patients was seven in non-obese and 13 in obese patient groups, and the number of patients admitted to an intensive care unit (ICU) was seven in non-obese and 18 in obese patient groups. Compared to non-obese patients, obese patients had significantly larger TBW, LBW, and BMI (p < 0.05); other demographics were similar between non-obese and obese patients. Observed serum concentration-time profiles of meropenem were best described by a two-compartment model with zero-order input and first-order, linear elimination from the central compartment. The final meropenem model was: CL (L/h) = 8.62*(CRCL/85)0.533; volume of distribution in the central compartment (V1; L) = 13.6; inter-compartmental distribution clearance (Q; L/h) = 11.8; and volume of distribution in the peripheral compartment (V2; L) = 14.5. There was no significant difference in CL, V1, Q, and V2 between non-obese and obese patient groups. The meropenem pharmacokinetic parameters [median (range)] in non-obese vs. obese patients were: CL, 5.5 (3.3-17.7) vs. 8.2 (3.0-18.1) L/h; V1, 14.3 (10.1-20.7) vs. 12.3 (5.6-47.4) L; Q, 10.8 (5.0-25.9) vs. 14.6 (0.6-66.4) L/h; and V2, 12.6 (9.7-20.1) vs. 14.5 (5.6-27.1) L. Based on the pharmacodynamic analysis using Monte Carlo simulation, at MICs ¡U 2 mg/L, which is the susceptibility breakpoint for Pseudomonas aeruginosa, PTA was > 90% for dosing regimens ¡Y 500 mg q8h in both non-obese and obese patient groups.;For cefepime, a retrospective analysis was conducted using prospectively collected serum concentration-time data from three previous studies (Study 6, Study 7, and Study 8) published by our research group. Hospitalized, adult patients who required antimicrobial therapy for a suspected or documented bacterial infection were eligible to participate in all three studies. In Study 8, only patients with BMI ¡Y 40 kg/m2 were enrolled while in Study 6 and Study 7, there was no weight restriction in the inclusion and exclusion criteria. Patients were classified as either obese (BMI ¡Y 30 kg/m2) or non-obese (BMI < 30 kg/m2). In Study 6, patients received cefepime 1 g q6h if CRCL was ¡Y 60 mL/min and 1 g q8h or q12h if CRCL was < 60 mL/min. Patients received 1 g q8h in Study 7 and 2 g q8h in Study 8, respectively. All doses were infused over 30 minutes in Study 6 and over 4 hours in Study 7 and Study 8. After 2 or more days of therapy, serial blood samples were collected from an indwelling IV catheter as scheduled in each study: immediately prior to drug administration, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4, 6, 8 (if receiving q8h dosing regimens), and 12 hours (if receiving q12h dosing regimens) after the start of infusion in Study 6; and prior to drug administration, 1, 2, 3, 4 (end of infusion), 5, 6, 7, and 8 hours after the start of infusion in Study 7 and 8. Serum cefepime concentrations were determined by previously described HPLC method. Population pharmacokinetic parameters were estimated using NONMEM, and the final pharmacokinetic model was built by evaluating the effects of covariates on the cefepime pharmacokinetic parameters using the stepwise forward inclusion followed by the backward elimination process. Tested covariates included: 1) age; 2) sex; 3) body size descriptor, including TBW, IBW, LBW, and BMI; 4) CRCL; and 5) admission to an ICU (ICU=1, general medical ward=0). In the stepwise forward inclusion process, covariates that reduced the model OFV > 3.84 (p < 0.05; ¦O2 distribution; 1 df) were considered significantly associated with the pharmacokinetic parameters in the model. In the backward elimination process, a covariate was removed if its elimination increased the model OFV by 0.025; ¦O2 distribution; 1 df). Using the final pharmacokinetic model, Monte Carlo simulations were performed for five different cefepime dosing regimens to calculate PTA using ¡Y 60%fT>MIC. Each dosing regimen was simulated as 30-minute infusion, 3-hour infusion for q6h regimens, and 4-hour infusion for q8h and q12h regimens.;Overall, a convenience sample of 30 patients (10 non-obese and 20 obese) were studied. TBW ranged from 54 kg to 276 kg, BMI from 18.5 kg/m2 to 92.5 kg/m2, and CRCL from 20 mL/min to 205 mL/min. Patient demographics [median (range)] in non-obese vs. obese group are: age, 44 (21-70) vs. 59 (32-81) years; CRCL, 101 (56-180) vs. 92 (20-205) mL/min; height, 178 (147-190) vs. 171 (147-183) cm; TBW, 74 (54-97) vs. 110 (81-276) kg; LBW, 60 (36-71) vs. 64 (42-96) kg; IBW, 73 (41-84) vs. 64 (41-78) kg; BMI, 22.5 (18.5-29.8) vs. 39.2 (30.9-92.5) kg/m2. The number of male patients was eight in non-obese and 13 in obese patient groups, and the number of patients admitted to an intensive care unit (ICU) was four in non-obese and 12 in obese patient groups. Compared to non-obese patients, obese patients were significantly older and had significantly larger TBW and BMI (p < 0.05); other demographics were similar between non-obese and obese patients. Observed serum concentration-time profiles of cefepime were best described by a one-compartment model with zero-order input and first-order, linear elimination. The final cefepime model was: CL (L/h) = 8.06 + [0.0598*(CRCL-90)]; and V (L) = 39.2 + [0.323*(TBW-95)]. Obese patients had significantly increased V compared to non-obese patients (p < 0.05), but CL was similar between non-obese and obese patients. The cefepime pharmacokinetic parameters [median (range)] in non-obese vs. obese patients were: CL, 8.0 (5.0-12.6) vs. 7.5 (3.6-27.9) L/h; and V, 27.6 (22.1-48.8) vs. 50.0 (19.3-94.5) L. Based on the pharmacodynamic analysis using Monte Carlo simulation, at MICs ¡U 2 mg/L, which is the susceptibility breakpoint for Enterobacteriaceae, PTA was > 90% for dosing regimens ¡Y 1 g q12h in both non-obese and obese patient groups. At an MIC of 4 mg/L, PTA was > 90% for dosing regimens ¡Y 1 g q8h in non- obese patients and ¡Y 1 g q12h in obese patients. At an MIC of 8 mg/L, which is the susceptibility breakpoint for Pseudomonas aeruginosa, PTA was > 90% for 30-minute infusions of 1 g q6h and 2 g q8h in non- obese patients and dosing regimens ¡Y 1 g q8h in obese patients. When prolonging the infusion times to 3 to 4 hours, dosing regimens ¡Y 1 g q12h achieved the PTA > 90% at MICs ¡U 4 mg/L in both non-obese and obese patient groups. The PTA at an MIC of 8 mg/L was > 90% for prolonged-infusion dosing regimens ¡Y 1 g q8h in both non-obese and obese patient groups.;In conclusion, piperacillin and tazobactam pharmacokinetics are altered in obesity, and larger doses (¡Y 4.5 g q8h), infused over 4 hours, may be needed to provide similar exposures in obese patients compared with non-obese patients receiving ¡Y 3.375 g q8h doses, infused over 4 hours. In contrast, meropenem pharmacokinetics are similar between obese and non-obese patients, so same dosages provide comparable pharmacodynamic exposures for susceptible organisms between obese and non-obese patients. Although cefepime pharmacokinetics are altered in obesity, same dosing regimens achieve similar pharmacodynamic exposures for susceptible organisms between obese and non-obese patients.
机译：肥胖是一个严重的全球性健康问题，与许多药物的药代动力学和药效学改变有关。然而，关于肥胖对许多广谱β-内酰胺抗生素（例如哌拉西林/他唑巴坦，美罗培南和头孢吡肟）的药代动力学和药效学影响的了解甚少。这项研究的目的是评估住院肥胖患者中哌拉西林/他唑巴坦，美罗培南和头孢吡肟的总体药代动力学和药效学，以确定在肥胖和非肥胖患者中提供相似暴露的给药方案;对于哌拉西林/他唑巴坦，使用前瞻性收集的来自我们研究小组的两项先前研究（研究1和研究2）的血清浓度-时间数据进行了回顾性分析。住院的成年患者，如果需要对疑似或已证明的细菌感染进行抗菌治疗，则有资格参加两项研究。在研究2中，只有体重（TBW）大于120千克的患者才有资格参加研究。患者分为肥胖[体重指数（BMI）≤30 kg / m2]或非肥胖（BMI <30 kg / m2）。在研究1中，所有患者每8小时（q8h）接受4.5 g哌拉西林/他唑巴坦输注，历时4小时。在研究2中，患者每8小时接受4.5 g或6.75 g哌拉西林/他唑巴坦输注，历时4小时。治疗2天或更多天后，在给药前以及刚开始后的1、2、3、4（输注结束），开始5、6、7和8小时后，从留置IV导管中采集系列血样。输液。哌拉西林和他唑巴坦的血清浓度通过先前验证的高效液相色谱（HPLC）方法确定。使用NONMEM估计群体药代动力学参数，并通过逐步向前包容和后向消除过程评估协变量对哌拉西林和他唑巴坦的药代动力学参数的影响，建立最终的药代动力学模型。测试的协变量包括：1）年龄； 2）性别； 3）体重指标，包括TBW，理想体重（IBW），瘦体重（LBW）和BMI； 4）肌酐清除率（CRCL）； 5）进入重症监护病房（ICU； ICU = 1，普通医疗病房= 0）。在逐步正向包含过程中，降低模型目标函数值（OFV）> 3.84（p <0.05; O2分布; 1 df）的协变量被认为与模型中的药代动力学参数显着相关。在后向消除过程中，如果消除了协变量，则将模型OFV增加0.025时，将其移除；氧分布1 df）。使用最终的药代动力学模型，对三个4小时的给药方案进行了Monte Carlo模拟，以使用≥50％fT> MIC来计算靶标达成（PTA）的概率。总体而言，共有27例患者（11例为非肥胖）和16个肥胖者）进行了研究。 TBW为60公斤至211公斤，体重指数为19.7公斤/平方米至72.9公斤/平方米，肌酐清除率（CRCL）为23毫升/分钟至260毫升/分钟。非肥胖组和肥胖组的患者人口统计[中位数（范围）]为：年龄，53岁（27-76岁）对比48岁（35-69岁）； CRCL，88（23-148）vs. 111（28-260）mL / min；高度：175（163-190）厘米与175（157-190）厘米； TBW：74（60-100）公斤； 151（98-211）公斤； LBW：54（39-72）公斤：78（50-94）公斤； IBW，71（55-84）公斤。71（50-84）公斤； BMI，24.8（19.7-29.4）vs. 50.1（32.7-72.9）kg / m2。在非肥胖中，男性患者为七名，在肥胖患者中为十名；在非肥胖和肥胖患者中，重症监护病房（ICU）的入院患者分别为七名。与非肥胖患者相比，肥胖患者的TBW，LBW和BMI显着更大（p <0.05）。非肥胖和肥胖患者的其他人口统计学特征相似。观察到的哌拉西林和他唑巴坦的血药浓度-时间曲线最好用零舱输入和一阶线性消除的一室模型来描述。哌拉西林的最终模型为：清除率（CL; L / h）= 11.3 + [0.0646 *（CRCL-105）] + [0.0579 *（BMI-35）];分布体积（V; L）= 31.3 + [0.132 *（TBW-120）]。他唑巴坦的最终模型为：CL（L / h）= 10.1 + [0.0272 *（CRCL-105）]；并且V（L）= 34.3。对于哌拉西林和他唑巴坦，与非肥胖患者相比，肥胖患者的CL和V显着升高。非肥胖与肥胖患者的药代动力学参数[中位数（范围）]为：哌拉西林CL 9.0（4.8-14.2）对13.1（6.8-20.0）L / h（p = 0.026）；哌拉西林V，24.6（17.1-37.8）vs. 32.5（19.8-69.8）L（p = 0.014）;他唑巴坦CL，6.8（4.4-15.5）对13.1（5.6-26.4）L / h（p = 0.005）;和他唑巴坦V分别为17.1（9.4-70.3）和45.5（10.5-116.6）L（p = 0.019）。基于蒙特卡罗模拟的药效学分析，他唑巴坦存在下哌拉西林MICs≥16 mg / L（这是肠杆菌科和铜绿假单胞菌的敏感性临界点），对于非肥胖患者，4小时输注剂量方案的PTA> 90％，非肥胖患者为3.375 g q8h，肥胖患者为4.5 g q8h。使用前瞻性收集的来自我们研究小组的三项先前研究（研究3，研究4和研究5）的血清浓度-时间数据进行了回顾性分析。住院的成年患者，如果需要对怀疑或记录的细菌感染进行抗微生物治疗，则有资格参加所有三项研究。尽管CRCL低于50 mL / min的患者有资格参加研究3，但由于研究目标不同，他们被排除在研究4和5中。在研究3中，仅招募BMI≥40 kg / m2的患者，在研究4中，仅招募BMI≥40 kg / m2或TBW≥100磅IBW的患者。患者分为肥胖（BMI≤30 kg / m2）或非肥胖（BMI <30 kg / m2）。在研究3中，患者接受了下列美罗培南给药方案：如果CRCL> 60 mL / min，则每6h服用500 mg；如果CRCL为40至60 mL / min，则每8h 500 mg；如果CRCL为10到39 mL / min，则每12h 500 mg。在研究4中，所有患者每6h服用500 mg或1000 mg。在研究5中，所有患者每8h服用1000 mg。在所有研究中，所有给药方案均在30分钟内注入。经过2天或更多天的治疗后，按照每次研究的时间表从留置的静脉导管中采集系列血样：在给药前即刻（输注结束）0.5、0.75、1、1.5、2、3、4、5在研究3中开始输液后的第6、8（如果接受q8h或q12h给药方案）和12小时（如果接受q12h给药方案）；在研究4中，开始给药后0.5，（输注结束），1、2、3、4和6小时开始给药；在研究5中，开始输注后0.5，（输注结束），输注开始后的1、1.5、2、3、4、5、6和8小时（输注结束）。血清美罗培南的浓度通过上述分析方法确定：研究3和研究4中的HPLC;以及研究5中的超高效液相色谱法。使用NONMEM估计群体药代动力学参数，并通过逐步逐步包容和后向消除过程评估协变量对美罗培南药代动力学参数的影响，建立最终的药代动力学模型。测试的协变量包括：1）年龄； 2）性； 3）身体大小描述符，包括TBW，IBW，LBW和BMI； 4）CRCL； 5）进入ICU（ICU = 1，普通医疗病房= 0）。在逐步前入过程中，降低模型OFV> 3.84的协变量（p <0.05; O2分布; 1 df）被认为与模型中的药代动力学参数显着相关。在后向消除过程中，如果消除了协变量，则将模型OFV增加0.025时，将其移除；氧分布1 df）。使用最终的药代动力学模型，对5种不同的美罗培南给药方案进行了Monte Carlo模拟，以使用40％fT> MIC来计算PTA。每种给药方案均模拟为30分钟输注，q6h方案为3小时输注，q8h和q12h方案为4小时输注。总体而言，研究了40位患者（11位非肥胖和29位肥胖）的便利性样本。 TBW为57 kg至305 kg，BMI为19.2 kg / m2至88.8 kg / m2，CRCL为15 mL / min至186 mL / min。非肥胖组和肥胖组的患者人口统计学[中位数（范围）]为：年龄（59岁（20-79岁）对57岁（26-76岁））。 CRCL，58（15-182）vs. 87（20-186）mL / min；高度：170（165-183）厘米； 170（150-193）厘米； TBW：72（57-88）公斤； 149（73-305）公斤； LBW：49（40-66）公斤。66（38-114）公斤； IBW，64（57-78）公斤。64（34-87）公斤； BMI，25.0（19.2-28.6）vs. 53.7（30.6-88.8）kg / m2。在非肥胖中，男性患者为7名，在肥胖患者组中为13名，进入重症监护病房（ICU）的患者在非肥胖中为7名，在肥胖患者组中为18名。与非肥胖患者相比，肥胖患者的TBW，LBW和BMI显着更大（p <0.05）。非肥胖和肥胖患者的其他人口统计学特征相似。美罗培南的观察到的血清浓度-时间曲线最好用两室模型来描述，该模型具有零级输入和从中央室进行的一级线性消除。最终的美罗培南模型为：CL（L / h）= 8.62 *（CRCL / 85）0.533;中央隔室中的分配体积（V1; L）= 13.6;室间分配许可（Q; L / h）= 11.8;外围隔室中的分配体积（V2; L）= 14.5。非肥胖和肥胖患者组之间的CL，V1，Q和V2没有显着差异。非肥胖与肥胖患者的美罗培南药代动力学参数[中位数（范围）]为：CL，5.5（3.3-17.7）vs. 8.2（3.0-18.1）L / h； V1，14.3（10.1-20.7）和12.3（5.6-47.4）大升； Q，10.8（5.0-25.9）vs. 14.6（0.6-66.4）L / h；和V2，分别为12.6（9.7-20.1）和14.5（5.6-27.1）L。基于蒙特卡罗模拟的药效学分析，在MICs≥2 mg / L（铜绿假单胞菌的敏感性临界点）下，PTA>对于非肥胖和肥胖患者组，每500毫克q8h的给药方案为90％，每8小时一次；对于头孢吡肟，使用前三项研究（研究6，研究7和研究）的前瞻性收集的血清浓度-时间数据进行了回顾性分析。 8）由我们的研究小组出版。住院的成年患者，如果需要对怀疑或记录的细菌感染进行抗微生物治疗，则有资格参加所有三项研究。在研究8中，只有BMI≥40 kg / m2的患者入选，而在研究6和研究7中，纳入和排除标准中没有体重限制。患者分为肥胖（BMI≤30 kg / m2）或非肥胖（BMI <30 kg / m2）。在研究6中，如果CRCL≥60 mL / min，则患者每6h服用头孢吡肟1 g q6h；如果CRCL <60 mL / min，则接受1 g q8h或q12h。在研究7中，患者分别接受了1 g q8h，在研究8中，接受了2 g q8h。在研究6中，在30分钟内注入了所有剂量，在研究7和研究8中，在4小时内注入了所有剂量。在治疗2天或更长时间后，按照每次研究的时间表，从静脉内留置的静脉导管中收集了连续的血液样本：在研究6中开始输注后，分别为0.5（输注结束），0.75、1、1.5、2、3、4、6、8（如果接受q8h给药方案）和12小时（如果接受q12h给药方案）；在研究7和8中，在开始给药后的1、2、3、4（输注结束），5、6、7和8小时开始给药之前。血清头孢吡肟的浓度通过先前描述的HPLC方法测定。使用NONMEM评估群体药代动力学参数，并通过逐步向前包容和后向消除过程评估协变量对头孢吡肟药代动力学参数的影响，建立最终的药代动力学模型。测试的协变量包括：1）年龄； 2）性； 3）身体大小描述符，包括TBW，IBW，LBW和BMI； 4）CRCL； 5）进入ICU（ICU = 1，普通医疗病房= 0）。在逐步前入过程中，降低模型OFV> 3.84的协变量（p <0.05; O2分布; 1 df）被认为与模型中的药代动力学参数显着相关。在后向消除过程中，如果消除了协变量，则将模型OFV增加0.025时，将其移除；氧分布1 df）。使用最终的药代动力学模型，对5种不同的头孢吡肟给药方案进行了Monte Carlo模拟，以使用60％fT> MIC来计算PTA。每种给药方案模拟为30分钟输注，q6h方案输注3小时，q8h和q12h方案输注4小时。总体上，研究了30例患者的便利性样本（10例非肥胖和20例肥胖） 。 TBW为54 kg至276 kg，BMI为18.5 kg / m2至92.5 kg / m2，CRCL为20 mL / min至205 mL / min。非肥胖组和肥胖组的患者人口统计[中位数（范围）]为：年龄，44岁（21-70岁）对比59岁（32-81岁）； CRCL，101（56-180）vs. 92（20-205）mL / min；身高178（147-190）厘米171（147-183）厘米; TBW：74（54-97）公斤； 110（81-276）公斤； LBW：60（36-71）公斤：64（42-96）公斤； IBW，73（41-84）公斤：64（41-78）公斤； BMI，22.5（18.5-29.8）vs. 39.2（30.9-92.5）kg / m2。在非肥胖中，男性患者为八名，在肥胖患者组中为13名，在非肥胖中接受重症监护病房（ICU）的患者为四名，在肥胖患者组中为十二名。与非肥胖患者相比，肥胖患者的年龄明显更大，并且TBW和BMI显着更大（p <0.05）。非肥胖和肥胖患者的其他人口统计学特征相似。观察到的头孢吡肟的血清浓度-时间曲线最好通过零间隔输入和一阶线性消除的一室模型来描述。最终的头孢吡肟模型为：CL（L / h）= 8.06 + [0.0598 *（CRCL-90）]；并且V（L）= 39.2 + [0.323 *（TBW-95）]。与非肥胖患者相比，肥胖患者的V显着增加（p <0.05），但非肥胖和肥胖患者的CL相似。非肥胖与肥胖患者的头孢吡肟药代动力学参数[中位数（范围）]为：CL，8.0（5.0-12.6）vs. 7.5（3.6-27.9）L / h； V为27.6（22.1-48.8）vs. 50.0（19.3-94.5）L。基于蒙特卡罗模拟的药效学分析，在MICs≥2 mg / L（肠杆菌科易感性临界点）时，PTA> 90非肥胖和肥胖患者组中每12小时1 g的给药方案百分比。在MIC为4 mg / L的情况下，非肥胖患者剂量方案≥1 g q8h，PTA> 90％，肥胖患者≥1 g q12h。 MIC为8 mg / L，这是铜绿假单胞菌的敏感性临界点，对于非肥胖患者，每次输注1 g q6h和2 g q8h的30分钟，PTA≥90％，给药方案为肥胖患者1 g q8h。当将输注时间延长至3至4小时时，在非肥胖和肥胖患者组中，MIC≥4 mg / L时，每次1 g q12h的给药方案PTA> 90％。对于非肥胖和肥胖患者，长期输注方案≥1 g q8h MIC的PTA> 90％，结论是，哌拉西林和他唑巴坦的药代动力学会发生改变，并且肥胖与接受4小时输注3.375 g q8h剂量的非肥胖患者相比，肥胖患者可能需要在4小时内输注4.5克q8h的剂量才能提供相似的暴露。相反，肥胖和非肥胖患者中美罗培南的药代动力学相似，因此相同的剂量为肥胖和非肥胖患者之间的易感生物体提供了相当的药效学暴露。尽管在肥胖症中头孢吡肟的药代动力学发生了改变，但对于肥胖和非肥胖患者，相同的给药方案对易感生物体的药效学暴露相似。

著录项

  • 作者

    Chung, Eun Kyoung.;

  • 作者单位

    Purdue University.;

  • 授予单位 Purdue University.;
  • 学科 Pharmaceutical sciences.;Pharmacology.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 357 p.
  • 总页数 357
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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