Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction

The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with β-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.     

Disposition kinetics of disopyramide in patients with renal insufficiency

The pharmacokinetics of an intravenous injection of disopyramide was studied in five normal subjects and six patients with varying degrees of renal impairment. The elimination rate constant (β) was related to the endogenous creatinine clearance (Cl_cr). However, a decrease in β was not observed until the Cl_cr was reduced below 40 ml min^?1. Below 40 ml min^?1 a linear relationship existed between β and Cl_cr. Similarly, the plasma elimination half-life (t_½β) showed a significant increase when the Cl_cr was less than 30 ml min^?1. Hence, dosage modification for disopyramide is necessary only when renal function is severely impaired. Overall, the apparent volume of distribution in patients with renal insufficiency was reduced to two-thirds of that in normal subjects. Therefore, in patients with Cl_cr less than 40 ml min^?1 both the loading and maintenance dose of disopyramide should be reduced.     

抗癫痫药物在肝肾功能不全患者中使用的研究进展

临床常用抗癫痫药物根据其药动学特点可分为主要经肝代谢、主要经肾排泄和肝肾双通道清除。肝功能不全患者尽量选择主要经肾排泄的抗癫痫药物,如加巴喷丁、普瑞巴林,或评估肝功能不全的程度,适当的减少剂量。肾功能不全的患者尽量选择主要经肝代谢的抗癫痫药物,如丙戊酸钠、卡马西平、拉莫三嗪,或评估患者的肌酐清除率（CLcr）,根据CLcr进行剂量调整。对于透析的患者,结合血药浓度监测透析后补充剂量有助于个体化治疗。肝肾功能不全患者抗癫痫药物的选择、剂量调整应综合考虑患者肝肾功能情况、药物代谢特点、合并疾病、个体耐受性等因素,在抗癫痫药物使用过程中,加强对药物相互作用、药物不良反应等的监护,结合血药浓度监测,以提高临床用药的有效性与安全性。     

细胞毒性药物在肝肾功能不全患者中的剂量调整

目的：探索细胞毒性药物在肝肾功能不全患者中的剂量调整。方法：以"细胞毒性药物","肝功能不全","肾功能不全"为关键词对Pubmed,EMbase,Cochrane Library,中国知网,万方,维普等数据库进行检索,以整理和归纳细胞毒性药物在肝肾功能不全患者中的剂量调整策略。结果：肝肾功能不全可影响药物的代谢动力学,进而影响药物的安全性和有效性。45种常见细胞毒性药物,当肝功能不全时,有41种药物需要进行剂量调整;当肾功能不全时,有33种药物需要进行剂量调整。结论：应重视细胞毒性药物在肝肾功能不全患者中的剂量调整,以保障患者用药的安全性和有效性。     

慢性肾脏病患儿抗菌药物剂量调整方案分析

目的探讨慢性肾脏病患儿应用抗菌药物的肾功能不全剂量调整指南。方法比较头孢呋辛、甲硝唑、头孢哌酮舒巴坦和复方磺胺甲噁唑在3种剂量调整指南(德国乌尔姆大学肾衰竭剂量调整表格、《热病》附表、透析患者剂量调整表)和英国儿童处方集中剂量调整方法,并结合实例进行分析。结果3种指南均针对成人设计。结论肾功能不全剂量调整指南在应用于儿童时,需要结合临床疗效进行调整。     

高血压病人的肾功能储备与早期肾损害

目的研究原发性高血压(EH)病人的肾功能储备,探讨发现早期肾功能损害的指标.方法27例1级与2级EH病人,收缩压20.84±1.62kPa,舒张压12.41±1.17kPa,停用降压药2周后收集24小时尿.晨采血5nl后,输入复方氨基酸500ml,2小时内滴完,1小时后再采血留尿.测定氨基酸负荷前后的血压、血尿素氮、血肌酐、尿肌酐、内生肌酐清除率、尿微量白蛋白、尿α1微球蛋白、尿β2微球蛋白、尿视黄醇结合蛋白.结果以超过正常对照组95%上限值为异常,EH病人输入氨基酸前,尿微量白蛋白异常17/27例(63%),尿α1微球蛋白16/27例(59.3%),尿β2微球蛋白14/27例(51.9%),尿视黄醇结合蛋白25/27例(92.6%);而血尿素氮、血肌酐、肌酐清除率均正常.氨基酸负荷后,肌酐清除率较前增高30%是尿量增多、肌酐排泄率升高所致,而血压及其他指标无明显变化(P＞0.05).结论(1)尿微量白蛋白、尿α1微球蛋白、尿β2微球蛋白、尿视黄醇结合蛋白测定可作为EH病人早期肾功能受损的指标.氨基酸负荷后这些指标并无明显变化,说明短期的高滤过未加重肾损害.(2)本组病人肾功能储备仍高达氨基酸负荷前肌酐清除率的30%,用来监测早期肾功能损害,肾功能储备不如上述指标敏感.     

Dose optimization of piperacillin/tazobactam in patients with renal dysfunction based on population pharmacokinetic and pharmacodynamic simulations

In the present study, we aimed to investigate the optimal dosage regimens of piperacillin/tazobactam in patients with chronic kidney disease according to their different classes of renal function based on bacterial resistance. A total of 2700 simulationswere applied based on a published population pharmacokinetic and pharmacodynamic model using nonlinear mixed effects modeling (NONMEM) software. Permissible optimal dosage regimens were defined as those associated with a less than 10% of patients whose probabilities of target attainment (PTA) were not attain target. For patients with mild to moderate renal injury, 4/0.5 g of piperacillin/tazobactam every 12 h in 30 min intermittent infusion could attain the target. If the MIC (minimum inhibitory concentration) for the pathogen was 8 mg/L or 16 mg/L, either an 8-h or 6-h dosing interval or extended 2–6 h infusion regimen had to be used to achieve the outcome of the therapy. Regarding MIC was up to above 32 mg/L, a high dose of piperacillin (12–24 g/d) in continuous infusion was the only approach that could achieve the effective target in patients with renal dysfunction. A low dose with extended 4–6 h infusion regimen was recommended for patients with severe renal injury. Our study identified permissible optimal piperacillin/tazobactam dosage regimens for patients with renal dysfunction with an MIC up to 64 mg/L. The findings of this study would be helpful for precise administration of piperacillin/tazobactam in clinical practice.     

重症患者肾功能亢进现象及药物剂量调整的研究进展

目的：综述重症患者肾功能亢进现象的研究现状及肾功能亢进状态下药物剂量调整的方法,为重症患者治疗用药提供参考。方法：查阅近年国内外有关文献,对已报道的有关肾功能亢进状态及肾功能亢进状态下药物剂量调整相关研究进行归纳和总结。结果：在重症患者中肾功能亢进是一个普遍发生的临床现象,表现为肌酐清除率升高,CrCl>130 mL/min/1.73 m²,对于一些主要经过肾脏排泄和代谢的药物来说,肾功能亢进会导致药物代谢增加,若按照常规剂量给药无法达到目标血药浓度,会导致治疗失败。结论：医生在制定给药方案时需考虑肾功能亢进对药效的影响,对于有高危因素的患者应避免使用经肾脏排泄的药物或进行治疗药物监测。     

Pharmacodynamics of meropenem in critically ill patients with febrile neutropenia and bacteraemia

The bactericidal activity of β-lactams is determined by the time that concentrations in tissue and serum are above the minimum inhibitory concentration (T > MIC) for the pathogen. The aim of this study was to compare the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for meropenem between administration by bolus injection and a 3-h infusion. The study was a randomised, three-way, cross-over design in eight febrile neutropenic patients with bacteraemia. Each subject received meropenem in three regimens consecutively: (i) a bolus injection of 1 g every 8 h (q8h) for 24 h; (ii) a 3-h infusion of 1 g q8h for 24 h; and (iii) a 3-h infusion of 2 g q8h for 24 h. For pathogens with an MIC of 4 μg/mL, the PTA of achieving 40% T > MIC following administration of meropenem by a bolus injection of 1 g q8h, a 3-h infusion of 1 g q8h and a 3-h infusion of 2 g q8h was 75.7%, 99.24% and 99.96%, respectively. Only the 3-h infusion of 2 g q8h achieved a PTA >99% for 40% T > MIC for a MIC of 8 μg/mL. By referral to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) MIC distributions, the three regimens of meropenem were predicted to achieve a CFR ≥ 90% against Escherichia coli and Klebsiella spp. In conclusion, a 3-h infusion of 2 g of meropenem q8h resulted in the highest PTA rates. The three regimens of meropenem had high probabilities of achieving optimal impact against E. coli and Klebsiella spp.     

Evaluation of applying drug dose adjustment by physicians in patients with renal impairment

ObjectiveTo determine whether appropriate dose adjustment was taken into account or not by the physicians when prescribing drugs in patients with renal impairment.DesignA retrospective chart review was performed and included 98 adult in-patients, diagnosed with renal impairment based on clinical evaluation and laboratory data, in King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia, who was admitted to the hospital from September 2005 to January 2011. Data of the patients were noted and recorded including baseline demographics, clinical data, laboratory data, renal state, treatment data and medications.ResultsThe initial number of the patients was reduced to 80 where a total of 502 drugs were investigated in the present study with an average of six drugs per patient. Of these 502 studied drugs, 196 (39%) required dose adjustment where 92 (46.9%) were adjusted and 104 (53.1%) were not adjusted. It was found also that most of the drugs requiring dose adjustment were antibiotics (39.8%).ConclusionThe current study confirms that physicians still do not take into account sufficiently patients’ renal function when prescribing drugs. Continuous medical education and collaboration with clinical pharmacist should be encouraged for quality improvement in patients with renal impairment.     

用蒙特卡洛模拟优化耐甲氧西林金黄色葡萄球菌感染的肾功能不全低龄患儿万古霉素的给药方案

目的 应用蒙特卡洛模拟评价万古霉素在肾功能正常与不全低龄耐甲氧西林金黄色葡萄球菌(MRSA)感染患儿中的给药方案.方法 收集2013—2014年成都地区万古霉素对MRSA菌株的最低抑菌浓度值(MIC)和其在2个月 ～2岁中国低龄患儿中药动学资料,经Crystal Ball软件模拟5000例次得到相应目标获得概率(PTA)与累计反应分数(CFR).结果 万古霉素对MRSA的MIC分布频率,MIC为0.03、0.06、0.12、0.25、0.50 mg·L-1时各占12.79％,MIC为1、2 mg·L-1时各占29.07％ 、6.98％.万古霉素达满意抗菌活性的最低剂量:肾功能正常者(A组),MIC为0.03～0.06、0.12和0.25 mg·L-1时分别予30、37.5和80 mg·kg-1·d-1,MIC为0.5～2 mg·L-1时即使80 mg·kg-1·d-1也不能达满意抗菌活性;肾功能轻度不全者[B组,估算的肾小球滤过率(eGFR)为60～89 mL·min-1·1.73 m-2],MIC为0.03～0.12、0.25和0.5 mg·L-1时分别予30、40和80 mg·kg-1·d-1,MIC为1～2 mg·L-1时即使80 mg·kg-1·d-1也不能达满意抗菌活性;肾功能中度不全者(C组,eGFR为30～59 mL·min-1·1.73 m-2),MIC为0.03～0.25、0.5 mg·L-1时分别予30、50 mg·kg-1·d-1,MIC为1～2 mg·L-1时即使80 mg·kg-1·d-1也不能达满意抗菌活性.各方案下A、B组对MRSA的CFR均<90％.结论 感染MR-SA的肾功能正常与轻度不全低龄患儿经验性应用万古霉素时可考虑联合用药,结合各MIC分布频率和达满意抗菌活性的最低剂量可知,大多数肾功能正常低龄患儿按40 mg·kg-1·d-1给药剂量偏低,绝大多数肾功能中度不全者应用50～80 mg·kg-1·d-1可获得满意抗菌活性.     

Method for the rapid estimation of the total body drug clearance and adjustment of dosage regimens in patients during a constant-rate intravenous infusion

A simple method is proposed to estimate the total body clearance and biological half-life of drugs in patients by determining two blood or plasma levels of drugs separated by an appropriate interval during the constant-rate intravenous infusion. The method is based on the assumptions that the drug disposition in the body can be adequately described by the linear onecompartment open model and its apparent volume of distribution can be estimated with a reasonable degree of accuracy from the literature data. The validity of this newly proposed method was demonstrated in three rabbits using theophylline as a test drug. Results of theoretical error analyses indicate that the method is potentially useful in providing an early guide for dosing adjustments for those potent drugs whose elimination rates have been shown to vary greatly in patients. The method may be particularly useful in patients with changing elimination kinetics of drugs. Effects of the accuracy in V_d estimate, plasma level assay, and sampling time interval on the error of total body clearance estimation are discussed.     

Pharmacokinetics of tocainide in patients with renal dysfunction and during haemodialysis

Summary The disposition of tocainide was studied in 15 patients with renal dysfunction. In 9 with total renal failure, the plasma half-life ranged from 16.6 to 42.7 h and total plasma clearance from 35 to 94 ml/min. The longest half-lives were found in 1 patient with cirrhosis, 3 taking the enzyme inhibitor allopurinol, and 1 on cimetidine. The mean half-life in the remaining patients was 22.3±4.8 h (±SD). During a 4 h haemodialysis, the half-life in the 9 patients decreased to 8.5±4.6 h, which was calculated to correspond to removal of 25±14% of the drug from the body. In 6 patients with impaired renal function (creatinine clearance 10–55 ml/min) the tocainide half-life ranged from 13.2 to 22.0 h and total plasma clearance from 72 to 122 ml/min. One patient was taking allopurinol and 1 dihydralazine, and the mean half-life in the others was 19.2±4.0 h. The apparent volume of distribution was similar to that found previously in healthy subjects. The results suggest that tocainide elimination is predictably reduced in patients with renal disease.     

Pharmacokinetics of nisoldipine in renal dysfunction

Summary The pharmacokinetics of nisoldipine have been studied after oral administration of one 10 mg tablet to 3 groups of patients: Group A (n=8) with a mean creatinine of 90 ml/min, Group B (n=8) with a mean creatinine clearance of 12 ml/min and Group C of 12 patients on maintenance haemodialysis. All of them were studied off-dialysis and 7 were also studied on a dialysis day.No significant differences were observed between Groups A, B and C (on an interdialysis day) in AUC (0–7h), t_max, C_max and plasma protein binding. Unchanged nisoldipine could not be recovered from the urine in any patient. Haemodialysis did not significantly affect AUC, t_max and C_max, and nisoldipine could not be detected in the dialysate.The results indicate that the dose of nisoldipine need not be changed in patients with renal dysfunction, and that a supplementary dose is not required after haemodialysis. Blood pressure in the uraemics fell more than in the patients with good renal function.     

代偿性肾功能不全对心功能不全患者B型尿钠肽浓度的的影响

目的 研究代偿性肾功能不全对心功能不全患者B型尿钠肽(BNP)浓度的影响.方法 选择190例有心肌梗死病史的患者,测定血浆BNP、肌酐(Cr)浓度,超声心动图检查测定左心室射血分数(LVEF),记录性别、身高、体重,计算肾小球滤过率(GFR).结果 肾功能不全发生率为29%.肾功能不全患者BNP为(130±19)pg/ml,显著高于肾功能正常者的(65×6)pg/ml(P<0.05).单因素及多因素变量分析BNP与GFR均相关(P<0.05).结论 BNP浓度受到轻中度肾功能不全的影响.     

169例肾综合征出血热不同分期患者肾功能损害观察

目的探讨肾综合征出血热不同分期患者肾功能损害情况。方法 2006年1月至2010年6月收治的肾综合征出血热患者169例,根据患者的发热程度、血压、尿量、出血量、肾脏损害情况、并发症等临床表现进行分期,观察在各期内进行尿蛋白定性检查、肾功能(BUN、Cr)检测,统计并观察。结果 169例肾综合征出血热患者病例经积极救治,死亡5例,病死率为2.95。低血压期、少尿期尿蛋白定性、BUN、Cr检测与发热期、恢复期比较差异有统计学意义(P<0.05)。结论肾综合征出血热患者肾功能损害情况观察,指导临床医生对肾综合征出血热患者应对检查肾功能定期检查,可以及早发现和了解肾脏损伤情况,掌握各期肾功能损伤程度,对治疗起到重要的引导作用。     

Pharmacokinetics and anti-inflammatory pharmacodynamics of prednisolone in cynomolgus monkey

1. The purpose was to investigate whether the pharmacokinetics and pharmacodynamics of prednisolone in the non-human primate was an appropriate surrogate for man.

2. After single intravenous doses of 0.03, 0.3, and 3?mg kg^?1, prednisolone demonstrated a dose-dependent clearance and volume of distribution. When corrected for concentration-dependent protein binding, the free clearance was linear at the tested dose levels. The protein binding-corrected volume of distribution was similar across doses. The serum half-life was estimated as being between 2 and 4?h. Prednisolone exhibits near complete inhibition of the cytokines TNF-α, IL-1β, IL-6 and IL-8 with very similar IC₅₀ estimates from 0.09 to 0.16 μg ml^?1 (from 0.24 to 0.44 μM).

3. The monkey demonstrated a similar pharmacokinetics–pharmacodynamics profile of prednisolone when compared with man (from the literature).

     

Pharmacokinetics of intravenously administered ciprofloxacin in intensive care patients with acute renal failure

The pharmacokinetics of ciprofloxacin after a single intravenous administration of 100 mg were studied in intensive care patients with an acute renal impairment. There was no correlation found between the creatinine clearance and the renal clearance of ciprofloxacin. This applies to the entire group of patients. The decrease in renal clearance of ciprofloxacin was, however, more pronounced than the change in the elimination half-life, suggesting an important extra-renal elimination of the drug.     

Pharmacokinetics of atenolol in patients with renal impairment

Summary The pharmacokinetics of atenolol, a new cardioselective -adrenoceptor blocking agent, were determined following both acute and chronic dosing in 33 hypertensive patients with widely differing levels of renal impairment. In patients with normal renal function the atenolol half-life was calculated to be about six hours following single 100 mg oral doses. This value increased markedly in patients with renal insufficiency and the blood clearance of atenolol was found to have a significant correlation with the glomerular filtration rate. This demonstrated the importance of the kidneys in the elimination of the drug. After 8 weeks oral treatment with atenolol (100 mg twice daily) a significant decrease in blood pressure, heart rate and plasma renin activity was observed, but no correlation was established between the blood levels of atenolol and any of its pharmacodynamic effects. A positive correlation was found however between the anti-hypertensive action of atenolol and the pretreatment value of the plasma renin activity.