Pharmacokinetics and dosage adjustment in patients with renal dysfunction

Introduction  Chronic kidney disease is a common, progressive illness that is becoming a global public health problem. In patients with kidney dysfunction, the renal excretion of parent drug and/or its metabolites will be impaired, leading to their excessive accumulation in the body. In addition, the plasma protein binding of drugs may be significantly reduced, which in turn could influence the pharmacokinetic processes of distribution and elimination. The activity of several drug-metabolizing enzymes and drug transporters has been shown to be impaired in chronic renal failure. In patients with end-stage renal disease, dialysis techniques such as hemodialysis and continuous ambulatory peritoneal dialysis may remove drugs from the body, necessitating dosage adjustment. Methods  Inappropriate dosing in patients with renal dysfunction can cause toxicity or ineffective therapy. Therefore, the normal dosage regimen of a drug may have to be adjusted in a patient with renal dysfunction. Dosage adjustment is based on the remaining kidney function, most often estimated on the basis of the patient's glomerular filtration rate (GFR) estimated by the Cockroft–Gault formula. Net renal excretion of drug is a combination of three processes: glomerular filtration, tubular secretion and tubular reabsorption. Therefore, dosage adjustment based on GFR may not always be appropriate and a re-evaluation of markers of renal function may be required. Discussion  According to EMEA and FDA guidelines, a pharmacokinetic study should be carried out during the development phase of a new drug that is likely to be used in patients with renal dysfunction and whose pharmacokinetics are likely to be significantly altered in these patients. This study should be carried out in carefully selected subjects with varying degrees of renal dysfunction. In addition to this two-stage pharmacokinetic approach, a population PK/PD study in patients participating in phase II/phase III clinical trials can also be used to assess the impact of renal dysfunction on the drug's pharmacokinetics and pharmacodynamics. Conclusion  In conclusion, renal dysfunction affects more that just the renal handling of drugs and/or active drug metabolites. Even when the dosage adjustment recommended for patients with renal dysfunction are carefully followed, adverse drug reactions remain common.     

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。     

Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment

Objective To evaluate the effect of moderate liver impairment on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093, ESL), a novel voltage-gated sodium channel blocker currently in clinical development. Methods The pharmacokinetics of ESL following an administration regimen of 800 mg once-daily for 8 days was characterized in patients with moderate liver impairment (n = 8) and in subjects with normal liver function (n = 8, control group). Results Eslicarbazepine acetate was rapidly and extensively metabolized by first-pass metabolism to its main active metabolite, eslicarbazepine (S-licarbazepine). There were more subjects with measurable plasma concentrations of the parent drug (ESL) in the hepatic impairment group than in the control group, suggesting that first-pass metabolism was slightly decreased by liver impairment. However, ESL plasma concentrations remained very low, representing only about 0.01% of total systemic exposure. No differences in the pharmacokinetics of eslicarbazepine or its metabolites were found between the hepatic impairment and control groups. Urinary excretion of eslicarbazepine and its glucuronide form was similar in the liver impaired and control subjects. The sum of drug moieties recovered in the urine corresponded to 91% of the administered dose in the control group and to 84% of the administered dose in the liver impairment group. Conclusion The pharmacokinetics of ESL was not affected by moderate hepatic impairment. Therefore, patients with mild to moderate liver impairment treated with ESL do not require dosage adjustment.     

危重症患者万古霉素给药方案调整的研究进展

万古霉素是目前临床耐甲氧西林金葡菌感染治疗的一线药物,准确建立和适时调整万古霉素给药方案是临床治疗的关键,针对危重症患者特殊的病理生理状态的个体化治疗尤为重要。本文综述影响危重症患者万古霉素药动学性质的各因素和方案调整。     

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。     

Effect of hepatic insufficiency on pharmacokinetics and drug dosing

The liver plays a central role in the pharmacokinetics of many drugs. Liver dysfunction may not only reduce the plasma clearance of a number of drugs eliminated by biotransformation and/or biliary excretion, but it can also affect plasma protein binding which in turn could influence the processes of distribution and elimination. In addition, reduced liver blood flow in patients with chronic liver disease will decrease the systemic clearance of flow limited (high extraction) drugs and portalsystemic shunting may substantially reduce their presystemic elimination (firstpass effect) following oral administration. When selecting a drug and its dosage regimen for a patient with liver disease additional considerations such as altered pharmacodynamics and impaired renal excretion (hepatorenal syndrome) of drugs and metabolites should also be taken into account. Consequently, dosage reduction is necessary for many drugs administered to patients with chronic liver disease such as liver cirrhosis.     

小剂量EP方案治疗小细胞肺癌肝转移合并严重肝功能异常患者的疗效观察

目的：探讨小剂量EP方案（依托泊苷＋顺铂）治疗小细胞肺癌肝转移合并严重肝功能异常患者的肝功能改善情况。方法：收集2007—2012年我院肿瘤科收治的小细胞肺癌肝转移初治患者,且治疗前血清生化检查天门冬氨酸氨基转移酶（AST）≥正常值上限5倍及／或丙氨酸氨基转移酶（ALT）≥正常值上限5倍。总胆红素（TBIL）≥正常值上限3倍。应用依托泊苷100mg静脉滴注,d1～5;顺铂20mg,d1～5,21d为1周期,进行化疗2周期后,再次检测患者的肝功能指标。结果：共有8名患者纳入本研究,经过化疗后,所有患者肝功能指标均下降。结论：在无其他肝脏疾病的前提下,小剂量EP方案对于小细胞肺癌肝转移合并肝功能严重异常的患者较为安全,对改善患者肝脏功能有一定效果,临床疗效有待进一步探索。     

A hand-held calculator program for individualized dosage adjustment of intravenous theophylline in acute asthma

Summary Despite general development of drug assay services and increasing interest in pharmacokinetics, proper dosage regimen calculations are not often made in routine clinical practice. This could be due, in part, to unfamiliarity with pharmacokinetic theory, the consequent difficulty of collaboration and the inevitable delay while data are processed on a computer. The present program for a hand-held calculator (TI-59) was written to minimize these problems, and was designed for the use of intravenous theophylline in the management of acute asthma, where there is a need for individualisation of dosage. Calculations are based on the one compartment open model. With 3–4 plasma drug concentrations taken early in the treatment, the program gives a measure of goodness of fit, the elimination rate constant (k_el), the volume of distribution (V_d) and the suggested infusion rate to achieve a given steady-state level. Data from 10 severe acute asthmatic patients were used to test the model and the estimated parameters were: V_d=0.26±0.029 l/kg (mean±SEM) and k_el=0.20±0.045 h^–1. The average standard deviation (s) for differences between the model and observations was 0.96±0.21 mg/l, of which at least 0.5 mg/l was due to assay error. In seven patients where the infusion period was extended, the predicted steady state plasma concentration agreed reasonably with that observed (r=0.83, df=5, 0.01<p<0.05).     

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 diacerein in patients with liver cirrhosis

The pharmacokinetics of diacerein following a single oral dose of 50 mg was studied in 12 healthy volunteers, 10 patients with a mild liver cirrhosis (Child Pugh's grade A), and 6 patients with a more severe liver cirrhosis (Child Pugh's grade B to C). Statistical analysis using a Kruskal- Wallis test showed no significant differences between the three groups for the following parameters: median C_max was 3.9 mg l^?1 for the cirrhotic patients group I (CPI) and 3.2 mg l^?1 for the cirrhotic patients group II (CPII) versus 3.2 mg l^?1 for the healthy volunteers (HV); median t_1/2 was 4.9 h for CPI and 4.3 h for CPII versus 4.3 h for HV; median Cl/F was 2.1 l h^?1 for CPI and 2.5 l h^?1 for CPII versus 1.6 l h^?1 for HV; median Vdss/F was 12.6 l for CPI and 14.01 for CPII versus 13.2 l for HV. The urinary parameters were comparable. It was concluded that, from a pharmacokinetic point of view, no reduction in the initial dosage of diacerein need be proposed in liver cirrhosis.     

Aminoglycoside dosage adjustment in renal failure: A hand-held calculator program

Summary Several problems occur when devising dosage guidelines for aminoglycoside antibiotics in patients with renal failure. To rationally address these problems, dosage guidelines require several steps involving complex calculations, use of graphic charts and/or use of sophisticated computer systems. We describe a practical program for modifying doses of aminoglycosides using a programmable hand-held calculator; this program is based both on pharmacokinetic theory and on applicability to varied clinical settings. The program compiles a series of equations to provide recommended doses, dosing intervals and predictions of serum concentrations of aminoglycosides at various times after a dose. It is hoped that patient care can be improved by using this simple, convenient and low-cost approach which retains efficiency and accuracy as a bed side method of dosage adjustment for aminoglycosides.     

成人获得性噬血细胞综合症肝功能损害临床资料分析

目的探讨成人获得性噬血细胞综合症（hemophagocyticsyndrome,HPS）肝功能损害的临床特点。方法回顾性分析郑州大学附属肿瘤医院2010年3月-2012年8月收治的24例成人获得性嗜血细胞综合症合并肝功能损害的患者,了解肝功能损害的特点,以及肝功能损害与获得性HPS病因和预后之间的关系。结果获得性HPS患者肝功能损害的特点为乳酸脱氢酶（LDH）及门冬氨酸转氨酶（AST）升高、低蛋白血症、高脂血症和黄疸。肿瘤继发HPS组乳酸脱氢酶（LDH）水平明显高于非肿瘤继发HPS组（P〈0．05）。门冬氨酸转氨酶（AST）增高、白蛋白（ALB）降低提示预后不良（P〈0．05）。24例患者中12周内共死亡15例,占62．50％。结论肝功能损害是获得性HPS常见的器官功能损害,其肝功能损害程度可能与获得性HPS的病因和预后相关。     

肝炎标志物阴性老年肝功能异常患者114例病因分析

目的分析肝炎标志物阴性的老年肝功能异常患者的病因特点。方法选取年龄≥60岁的肝功能异常患者164例作为老年组,其中肝炎标志物阴性者114例(老年肝炎阴性亚组);另选年龄<60岁的肝功能异常者152例作为非老年组,其中肝炎标志物阴性者90例(非老年肝炎阴性亚组)。比较2组肝功能异常率及2亚组肝功能异常原因。结果老年组肝功能异常发生率为69.51%(114/164),非老年组为59.21%(90/152),2组差异无统计学意义(P>0.05)。老年肝炎阴性亚组以药物性肝损害、胆源性肝损害、肿瘤为病因的发病率高于非老年肝炎阴性亚组,以病毒感染为病因的发病率低于非老年肝炎阳性亚组,差异均有统计学意义(P<0.05)。结论老年肝功能异常由非病毒性肝炎引起者所占比例较高,在病因构成上老年组与中青年无明显差异,但在构成比上有老年人自身的特点。     

Comparative antihypertensive activities of losartan and HM70186 in rats with hepatic dysfunction

HM70186, a medoxomil ester of EXP3174 which is an active metabolite of angiotensin II receptor blocker losartan, was synthesized, and its antihypertensive efficacy was evaluated in rats with hepatic dysfunction. Male Wistar rats were intraperitoneally injected with 0.5 mL/kg of carbon tetrachloride to cause hepatic injury, and implanted with an osmotic minipump containing angiotensin II (0.4 mg/kg/day) to induce hypertension. After confirmation of both hepatic damage and hypertension, the rats were orally administered losartan or HM70186, and then blood pressure and heart rate were monitored for 24 h. In normal animals, angiotensin II-induced hypertension was lowered by losartan, resulting in an ED_{−30 mmHg} of 9.05 mg/kg. HM70186 also immediately decreased the blood pressure in a dose-dependent manner, exhibiting an ED_{−30 mmHg} of 0.89 ng/kg (10,000 times the potency observed with losartan). Moreover, HM70186 (3 ng/kg) exerted a strong antihypertensive effect even in rats with hepatic injury, while losartan (10 μg/kg) was ineffective. These results suggest that HM70186 could be a promising candidate for the treatment of hypertension accompanied by hepatic dysfunction.     

Dosage adjustment for ceftazidime in patients with impaired renal function

Summary Ceftazidime has good antibacterial activity against many Gram-negative micro-organisms including Ps. aeruginosa.The aim of the present study was to calculate a dosage adjustment regimen for renal failure patients and to test it in a second group of patients. A study was made of the pharmacokinetics of ceftazidime 1 g given as a single bolus i.v. injection in 20 patients in an intensive care unit with varying degrees of renal function, including patients on regular haemodialysis. The serum half-life of elimination (t_1/2) varied from 1.6 to 45 h depending on renal function. During haemodialysis the mean t_1/2 was 4.7 h. A good correlation between the renal clearance of creatinine and ceftazidime was observed. In most patients protein binding was lower than previously observed. From the pharmacokinetic data, a dosage adjustment regimen for patients with renal insufficiency was calculated, which studies in 7 further patients showed to be effective.Abbreviations C_t serum concentration at time t - and slopes of the bi-exponential curve of the fast and the slow disposition (overall elimination) processes - A and B intercepts of the distribution slope and elimination slope extrapolated to the ordinate - t_1/2 serum half-life of elimination - k₁₂ distribution rate constant for transfer from the central to the peripheral compartment - k₂₁ distribution rate constant for transfer from the peripheral to the central compartment - k₁₃ elimination rate constant from the central compartment - k_N and elimination rate constants from the central compartment in normal and impaired renal function, respectively - AUC area under the serum concentration-time curve from zero to infinity - V_t total apparent volume of distribution (area method) - V₁ and V₂ distribution volumes in the central and the peripheral compartments, respectively - CL total body clearance of ceftazidime - CL_R renal clearance of ceftazidime - CL_CR renal clearance of creatinine - T and dosing intervals in normal and impaired renal function - (m) pe (mean) prediction error - rmspe root mean squared prediction error     

Pharmacokinetics of sildenafil after intravenous and oral administration in rats: hepatic and intestinal first-pass effects

Pharmacokinetics of sildenafil after intravenous and oral administration at various doses and first-pass effect at 30 mg/kg were evaluated in rats. After intravenous administration (10, 30, and 50 mg/kg), the dose-normalized AUC values were proportional to intravenous doses studied. However, after oral administration (10, 30, and 100 mg/kg), the dose-normalized AUC values increased significantly with increasing doses, possibly due to saturation of metabolism of sildenafil in rat intestinal tract. After oral administration (30 mg/kg), approximately 0.626% was not absorbed and F was 14.6%. The AUC after intragastric administration was significantly smaller (71.4% decrease) than that after intraportal administration, however, the values were not significantly different between intragastric and intraduodenal administration. The above data suggested that intestinal first-pass effect of sildenafil was approximately 71% of oral dose in rats. The AUC values after intraportal administration were significantly smaller (49% decrease) than that after intravenous administration. This suggested that hepatic first-pass effect of sildenafil after absorption into the portal vein was approximately 49% of oral dose in rats (approximately 49% was equivalent to approximately 13.7% of oral dose). The low F of sildenafil at a dose of 30 mg/kg in rats could be mainly due to considerable intestinal first-pass effect.     

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.     

Pharmacokinetics of sabeluzole and dextromethorphan oxidation capacity in patients with severe hepatic dysfunction and healthy volunteers

AIMS: The primary objective of this study was to determine how the pharmacokinetics of sabeluzole, an investigational drug with specific effects on memory and learning abilities, are affected by chronic liver disease. Since sabeluzole is metabolised by CYP2D6, a secondary objective was to study the correlation between CYP2D6 activity (as assessed by the dextromethorphan dextrorphan metabolic ratio) and hepatic dysfunction. METHODS: The single-dose pharmacokinetics of sabeluzole (10 mg) was compared in 10 healthy Caucasian subjects and 10 patients with severe hepatic dysfunction. The urinary dextromethorphan/dextrorphan (DMP/DRP) metabolic ratio was determined after intake of 20 mg dextromethorphan (NODEX capsules). RESULTS: The terminal half-life of sabeluzole was significantly prolonged in subjects with severe hepatic dysfunction vs healthy subjects (respectively 39.3 +/- 11.5 h; 17.5 +/- 10.2 h (mean +/- s.d.)). The areas under the curve (AUC) were significantly higher in subjects with severe hepatic dysfunction than in healthy volunteers (681 +/- 200 ng ml(-1) h vs 331 +/- 282 ng ml(-1) h). There was a significant correlation between the AUC(0,infinity) and the DMP/DRP metabolic ratio in healthy volunteers and subjects with severe hepatic dysfunction. AUC was greater and elimination of sabeluzole slower in poor metabolizers compared with extensive metabolizers. CONCLUSIONS: These results suggest that a) sabeluzole dose should be reduced in patients with severe hepatic dysfunction and b) the AUC of sabeluzole is linked to individual CYP2D6 activity.     

儿童丙戊酸血药浓度与给药剂量

目的 研究儿童癫痫服用丙戊酸后血药浓度与给药剂量的关系.方法 对48例癫痫失神性发作儿童患者服用丙戊酸,用荧光偏振免疫法(FPIA)监测血药浓度.结果 达稳态后给药剂量与血药浓度的变化有着密切的关系.结论 监测血药浓度,及时调整给药剂量,对控制儿童患者癫痫失神发作至关重要.     

Pharmacokinetics of verapamil and its major metabolite, nor-verapamil from oral administration of verapamil in rabbits with hepatic failure induced by carbon tetrachloride

The aim of this study was to investigate the pharmacokinetic changes of verapamil and its major metabolite, norverapamil, after oral administration of verapamil (10 mg/kg) in rabbits with slight, moderate and severe hepatic failure induced by carbon tetrachloride. The plasma verapamil concentrations in all groups of hepatic failure were significantly higher (p < 0.01) than the control. However, the plasma norverapamil concentrations in severe hepatic failure were significantly higher (p < 0.05) than the control. The peak concentrations (Cmax) and the areas under the plasma concentration-time curve (AUC) of verapamil in the rabbits were significantly (p<0.01) higher than the control. The absolute bioavailability (F(A.B)) and the relative bioavailability (F(R.B)) of verapamil in the rabbits with hepatic failure were significantly higher (13.6-22.2% and 150-244%, respectively) than the control (9.1% and 100%, respectively). Although the AUC and Cmax of its major metabolite, norverapamil, in slight, moderate hepatic failure were not significantly lower than the control, the metabolite-parent AUC ratio in all groups of hepatic failure was decreased significantly (p < 0.05, in slight group; p < 0.01, in moderate and severe group) than the control. This could be due to decrease in metabolism of verapamil in the liver because of suppressed hepatic function in the hepatic failure groups because verapamil is mainly metabolized in the liver. From our data, it would seem appropriate that in patients with liver disease, doses of verapamil should be decreased by degree of hepatic failure.