Quantitative analysis of drug handling by the kidney using a physiological model of renal drug clearance

Summary Published data on the renal clearance of creatinine, p-aminohippuric acid (PAH) and kanamycin in relation to glomerular filtration rate (GFR) in patients with various renal diseases were analysed by a physiological model of renal clearance. Fitting of the data by the general linear equation representing the model proposed by Levy [10] resulted in insignificant intercepts with the ordinate, indicating the unsuitability of the model for the detection of tubular secretory activity. Use of this model also did not lead to significant improvement in goodness of fit compared to simple proportionality of renal clearance and GFR. On the other hand, parameter estimates of the physiological model obtained from the data by nonlinear regression analysis revealed statistically significant tubular secretion both of PAH and creatinine. The much lower tubular secretory activity estimated from the kanamycin data did not reach statistical significance. For compounds exhibiting statistically significant tubular secretion, use of the physiologically based relationship between renal clearance and GFR significantly improved the goodness of fit to the data as compared to simple proportionality of both variables. It is concluded that analysis of the relationship between renal clearance of drugs and GFR using the physiological model of renal clearance can contribute to our knowledge of drug handling by the kidney, and may facilitate drug classification according to total extraction by this organ.     

Effect of acute water deprivation on renal function in rats

The effect of acute water deprivation for 96 h on renal function was studied in male Sprague-Dawley rats. The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) were estimated using inulin and p-amino hippuric acid (PAH), respectively, as model compounds. Acute water deprivation caused a significant decrease (44 per cent) in the GFR without altering the ERPF. These results indicate that a proper dosage adjustment may have to be made in the dehydration condition, especially for drugs whose disposition is dependent on GFR.     

Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines

Introduction: The incidence of kidney dysfunction increases with age and is highly prevalent among patients with hypertension. Since many therapeutic compounds are primarily eliminated through the kidneys, impaired renal function can have negative consequences on drug disposition, efficacy and safety. Therefore, regulatory agencies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued detailed guidelines for new drug applications to determine posology requirements for patients with renal impairment.

Areas covered: The current review highlights and contrasts agency requirements for pharmacokinetic renal impairment clinical studies. While many of the guidelines are similar among the two agencies, glomerular filtration rate (GFR) determination and reporting differ. Design considerations for a reduced, full or dialysis renal impairment study, as well as modifications to the FDA’s draft guidance are discussed. Furthermore, scenarios where pharmacokinetic modelling analysis can benefit a drug development program are also reviewed. Moreover, practical solutions for patient recruitment challenges are addressed.

Expert commentary: We summarize how ‘one size does not fit all’ for GFR assessment, and recommend when to use certain modalities. Finally, we highlight the need for the pharmaceutical industry to engage therapeutic experts to assist in protocol development for renal impairment studies, as these experts understand the nuances of this special population and recommended guidelines.     

儿童肾功能评估公式和更昔洛韦清除率的相关性确证与剂量优化

目的:采用群体药动学分析方法考察不同肾小球滤过率(GFR)公式估计更昔洛韦清除率的适用性,并用于更昔洛韦给药剂量优化。方法:收集100例患者的血药浓度数据和临床资料,采用基于不同生物标志物的公式计算GFR。建立儿童患者静脉滴注更昔洛韦的群体药动学模型,考察体质量和肾功能对药动学参数的影响,并对最终模型进行内部验证。在建模过程中探索不同公式获取的GFR和更昔洛韦清除率之间的相关性。确定最适用的GFR公式后,根据体质量和肾功能对给药剂量进行个体化设计。结果:具有一级消除的一房室模型能够很好地描述更昔洛韦在儿童群体中的药动学特征。验证结果显示最终模型稳定可靠,预测性能较好。综合可视化检验和协变量分析结果,可确定Flanders Metadata公式计算获得的GFR与更昔洛韦清除率相关性较高,临床适用性较好。在此基础上提出了基于GFR和患者体质量的个体化给药方案。结论:本研究确证了最适用于预测儿童群体更昔洛韦清除率的GFR公式,为该药物治疗提供了一种基于建模手段的个体化给药策略。     

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。     

Pregnancy and renal failure: the case for application of dosage guidelines.

Pregnancies in women with renal disease, undergoing dialysis treatment or with kidney transplants are increasingly observed. Serious problems with drug dose adjustment may arise in pregnant women with renal impairment. This review gives a practical overview on the risks of drug use during gestation, the recommended drugs of choice (e.g. methyldopa, cyclosporin), and provides some proposals for dosage adjustments in pregnant women with renal impairment. In normal pregnancy, the glomerular filtration rate and plasma volume increase, whereas plasma protein binding and liver function may be impaired. An increase in dosage is needed for cyclosporin and for methadone because of increased hepatic clearance. The dosage of erythropoetin must be increased because of lower potency in pregnant women. Little more is known on the impact of gestation on drug dose, since pharmacokinetic studies are rarely done in pregnant women. The dosages of magnesium, lithium and morphine must be reduced in renal impairment. Dose adjustment to renal function is critical and is essential for anti-infective agents (e.g. ceftazidime, ganciclovir). Basing drug dose on estimated creatinine clearance might be the most practical solution in pregnant women with renal impairment.     

Pro-active provision of drug information as a technique to address overdosing in intensive-care patients with renal insufficiency

Purpose  To correct overdosing of drugs requiring adjustment based on renal function in intensive-care patients. Methods  In a prospective intervention study, we estimated individual glomerular filtration rate and assessed whether medication required dose adjustment based on renal function. Senior clinicians received a structured report containing recommendations as to whether and how to adjust dosage in the individual patient (intervention). Prevalence of overdosed drugs (primary outcome), extent of overdoses, and reasons for nonacceptance of recommendations (secondary outcomes) were assessed. Results  Of 138 screened intensive-care patients, 68 (49%) had renal impairment, and 110 (14%) of the 805 prescribed drugs required consideration of renal function. A potential overdose was found in 53/110 drugs (48%) and this rate decreased to 26/110 (24%, P < 0.001) after the intervention. The average extent of overdose was reduced from 54% before to 31% after the intervention (P < 0.001). The main reasons expressed by the physicians for nonacceptance of recommendations were a large therapeutic index or minor overdoses of the involved drugs. Conclusions  In intensive-care patients, overdosing of drugs requiring adjustment based on renal function is still very common. Drug information counselling significantly decreased the prevalence and extent of overdose.     

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.     

Influence of renal function on the steady-state pharmacokinetics of the antiarrhythmic propafenone and its Phase I and Phase II metabolites

The aim of this study was to investigate the disposition of propafenone and its Phase I and II metabolites in relation to kidney function under steady-state conditions. The mechanism of the renal handling of propafenone glucuronides (filtration, secretion) was also examined. Racemic (R/S) propafenone was administered to 7 young volunteers, to 5 older patients with a normal glomerular filtration rate and to 4 patients with chronic renal failure. No difference was found in the plasma concentrations of propafenone and 5-hydroxypropafenone between the three groups. The propafenone glucuronide (PPFG) concentration was elevated in the older compared to the younger subjects (S-PPFG: 544 vs. 222 nmol · ml^–1 · mol^–1; R-PPFG: 576 vs. 304 nmol · ml^–1 · mol^–1). Although Glomerular filtration rate did not differ, the renal clearance of propafenone glucuronides was reduced in the former group, which could be attributed to their impaired renal secretion. A dramatic increase in propafenone glucuronide concentration was observed in the patients with renal failure (S-PPFG: 2783 nmol · ml^–1 · mol^–1; R-PPFG: 7340 nmol · ml^–1 · mol^–1). In summary, the disposition of propafenone and of its active metabolite 5-hydroxypropafenone was not affected by kidney dysfunction, indicating that no dose adjustment is necessary in patients with renal failure. The accumulation of drug glucuronides in older patients with apparently normal kidney function should be taken into account as a possible factor modifying drug therapy.     

Drug therapy in patients undergoing peritoneal dialysis. Clinical pharmacokinetic considerations

Peritoneal dialysis has become an accepted treatment modality for end-stage renal disease. The introduction of continuous ambulatory peritoneal dialysis (CAPD) has further popularised this technique. The need for adjustment of drug dosage in patients with endstage renal disease and the need for supplemental dosages following haemodialysis are well recognised. Little documentation exists concerning the need for supplemental drug dosage in patients on peritoneal dialysis. Knowledge of the influence of peritoneal dialysis on the elimination of specific drugs is essential to the rational design of dosage regimens in patients undergoing this dialysis technique. This review addresses the clinical pharmacokinetic aspects of drug therapy in patients undergoing peritoneal dialysis and considers: the efficiency of the peritoneal membrane as a dialysing membrane; the effects of peritoneal dialysis on the pharmacokinetics of drugs; the pharmacokinetic models and estimation methods for peritoneal dialysis clearance and the effects of peritoneal dialysis on drug elimination; the influence of the pharmacokinetic parameters of drugs on drug dialysability; and the application of pharmacokinetic principles to the adjustment of drug dosage regimens in peritoneal dialysis patients. Data on drugs which have been studied in peritoneal dialysis are tabulated with inclusion of pharmacokinetic and dialysability information.     

Quantitative estimation of renal clearance of N-acetylprocainamide in rats with various experimental acute renal failure.

The dosage regimen of a drug eliminated predominantly through the kidney need to be adjusted for the patients with renal disease. The objective of the present study was to establish a quantitative approach to precisely predicting the renal clearances of basic drugs using N-1-methylnicotinamide (NMN). A variety of experimental acute renal failure (ARF) in rats were prepared and N-acetylprocainamide (NAPA) was used as a model drug. The renal clearances of NAPA were significantly decreased in rats with ARF, resulting in significantly increased plasma concentrations. Remarkable reduction in clearance ratios (CL(ratio)) was observed, indicating that the impairment in tubular and glomerular function did not proceed in a parallel manner. The renal clearance of NAPA (CL(rNAPA)) was better predicted from the renal clearance of NMN (CL(rNMN)) than from GFR. A mathematical equation was also constructed to estimate the CL(rNMN) from the NMN plasma concentration. Therefore, the renal clearance of basic drugs excreted predominantly from the kidney can be easily and more accurately estimated based on the concentrations of endogenous NMN to provide a precise dosage regimen for patients with renal failure.     

血液透析患者头孢吡肟及左氧氟沙星中毒的分析及警示

对1例药物中毒病例进行分析,对于肾功能不全或肾功能衰竭进行血液透析的患者,用药时应充分考虑药物在体内的排泄途径,经肾脏排泄的药物要根据肌酐清除率调整给药剂量,血液透析的患者要考虑所用药物能否经血液透析透出体外,否则按常规剂量给药,可导致药物中毒。     

肾功能不全癌症疼痛患者阿片类药物的应用

阿片类药物是控制癌症疼痛(简称癌痛)的重要药物,若品种及剂量使用不当,将会进一步造成肾脏损伤.癌症患者由于疾病本身或并发症的进展,可能会伴有肾功能不全.因此存在肾功能不全风险的癌痛患者,必须正确评估肾功能状态,结合疼痛程度和阿片类药物特性,正确选择药品品种和剂量.该文综述常用阿片类药物的药动学特征、肾功能不全患者和透析...     

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。     

Antiretroviral drugs and the kidney: dosage adjustment and renal tolerance

BACKGROUND: Acquired immunodeficiency syndrome (AIDS)-related kidney disorders concern 30% of those patients and can lead to end-stage renal disease (ESRD; 0.6 to 1%). Therefore, administration of antiretroviral drugs in human immunodeficiency virus (HIV) patients with nephropathy is not uncommon. AIM OF THE REVIEW: Since renal insufficiency is not uncommon among HIV-infected patients treated with antiretroviral drugs, guidelines on how to use these drugs in the pattern of an altered renal function are mandatory. This review provides such guidelines established on the basis of pharmacokinetic and clinical studies reported in the international literature. In addition, some of these drugs may be nephrotoxic. Mechanisms and clinical and/or biological manifestations are reviewed to help monitor renal tolerance in patients receiving these drugs. CONCLUSION: Antiretroviral drugs' dosage in HIV-infected patients with altered renal function should be cautiously determined. Drug dosage should not be systematically reduced since dosage adjustment is not mandatory for all therapies (ie. protease inhibitors). Furthermore, when dose reduction is necessary, pharmacokinetic and clinical data from the literature allows to establish practical guidelines on how to use these drugs in such patients.     

RENAL EXTRACTION OF ATRIAL NATRIURETIC PEPTIDE IN UNILATERAL RENAL ARTERY STENOSIS

1. Elevated peripheral atrial natriuretic peptide (ANP) levels were observed in 12 patients with unilateral renal artery stenosis (U-RAS). 2. Renal extraction of ANP was higher across the affected than the unaffected kidney in U-RAS, provided the glomerular filtration rate in the affected kidney was not severely reduced (> 12 mL/min). As ANP is a high clearance compound, reduced flow on the affected side may result in increased renal extraction of ANP. 3. When glomerular filtration rate (GFR) in the affected kidney was severely reduced (<12 mL/min), renal extraction of ANP was also reduced, possibly contributing to increased circulating ANP levels in this subgroup. 4. Overall, renal extraction of ANP was inversely correlated to peripheral ANP levels in patients with U-RAS. This might be explained by progressive sodium retention as GFR falls leading to volume expansion and increased ANP secretion.     

Drug therapy in patients undergoing haemodialysis. Clinical pharmacokinetic considerations

Haemodialysis is utilised therapeutically as supportive treatment for end-stage renal disease (ESRD). In conjunction with haemodialysis therapy, ESRD patients frequently receive a large number of drugs to treat a multitude of intercurrent conditions. Because of the impaired renal function in ESRD patients, dosage reduction is often recommended to avoid adverse drug reactions, particularly for drugs and active metabolites with extensive renal excretion. On the other hand, if the removal of a drug by haemodialysis during concomitant drug therapy is significant, a dosage supplement would be required to ensure adequate therapeutic efficacy. Knowledge of the impact of haemodialysis on the elimination of specific drugs is therefore essential to the rational design of the dosage regimen in patients undergoing haemodialysis. This review addresses the clinical pharmacokinetic aspects of drug therapy in haemodialysis patients and considers: (a) the effects of ESRD on the general pharmacokinetics of drugs; (b) dialysis clearance and its impact on drug and metabolite elimination; (c) the definition of dialysability and the criteria for evaluation of drug dialysability; (d) pharmacokinetic parameters which are useful in the prediction of drug dialysability; and (e) the application of pharmacokinetic principles to the adjustment of dosage regimens in haemodialysis patients. Finally, drugs commonly associated with haemodialysis therapy are tabulated with updated pharmacokinetics and dialysability information.     

Effects of renal impairment on transporter‐mediated renal reabsorption of drugs and renal drug–drug interactions: A simulation‐based study

Renal impairment (RI) significantly impacts the clearance of drugs through changes in the glomerular filtration rate, protein binding and alterations in the expression of renal drug transport proteins and hepatic metabolizing enzymes. The objectives of this study were to evaluate quantitatively the effects of renal impairment on the pharmacokinetics of drugs undergoing renal transporter‐mediated reabsorption. A previously published semi‐mechanistic kidney model incorporating physiologically relevant fluid reabsorption and transporter‐mediated active renal reabsorption (PMID: 26341876) was utilized in this study. The probe drug/transporter pair utilized was γ‐hydroxybutyric acid (GHB) and monocarboxylate transporter 1 (SCL16A1, MCT1). γ‐Hydroxybutyric acid concentrations in the blood and amount excreted into urine were simulated using ADAPT 5 for the i.v. dose range of 200–1500 mg/kg in rats and the impact of renal impairment on CL_R and AUC was evaluated. A 90% decrease in GFR resulted in a > 100‐fold decrease in GHB CL_R. When expression of reabsorptive transporters was decreased and f_u was increased, CL_R approached GFR. The effect of renal impairment on CL_R was reduced when the expression of drug metabolizing enzymes (DME) was increased as a result of increased metabolic clearance; the converse held true when the DME expression was decreased. In conclusion, this study quantitatively demonstrated that the effects of renal insufficiency on the clearance of drugs is modulated by transporter expression, contribution of renal clearance to overall clearance, expression of drug metabolizing enzymes, fraction unbound and drug–drug interactions with inhibitors of renal transporters that may be increased in the presence of renal impairment.     

Renal effects of antihypertensive drugs

Antihypertensive drugs have disparate effects on renal haemodynamics, tubular function, plasma electrolytes, and hormonal responses. Calcium entry blockers and angiotensin-converting enzyme (ACE) inhibitors are unique in that they may increase glomerular filtration rate (GFR) and renal blood flow in patients with hypertension. Both classes of drugs are distinctive in that they prevent salt retention because of their inhibitory effect on tubular sodium reabsorption. In addition to these attributes, which are desirable in terms of lowering systemic blood pressure, these 2 classes of drugs exert important intrarenal effects which may participate in limiting the progression of renal disease. ACE inhibitors have been shown to protect against the development of glomerulosclerosis in various experimental models of renal insufficiency. Importantly, there is emerging evidence from human studies supporting a distinctive beneficial effect of these agents on renal function in patients with hypertension, mild chronic renal insufficiency and diabetes mellitus. Calcium entry blockers have also been shown to exert some beneficial effect in limiting the progression of experimental kidney disease but neither an improvement in glomerular sclerosis nor a decrease in proteinuria have been clearly documented. At present ACE inhibitors appear the most attractive agents in terms of arresting the progression of renal disease. Acute deterioration in renal function may occur following the administration of ACE inhibitors, calcium entry blockers, and beta-blockers. This complication should be considered in every patient on antihypertensive therapy who suffers an unexplained deterioration in renal function. In particular, the sudden deterioration in renal function following initiation of therapy with an ACE inhibitor is a clue to the possible presence of bilateral renal artery stenosis or stenosis of a solitary functioning kidney. Renal damage may also occur in patients with unilateral renal artery stenosis even though total (2-kidney) GFR may not be appreciably reduced. In this setting, a captopril renal scan with hippuran and diethylenetriamine pentaacetic acid (DTPA) provides physiological information regarding the renal blood flow and GFR of each kidney. In patients with unilateral renal artery stenosis the impact of ACE inhibitor therapy on GFR may be discerned by the use of the DTPA scan, which may demonstrate a reduction in GFR in the stenotic kidney that is not apparent by evaluation of total kidney GFR. This suggests that despite adequate control of systemic blood pressure and unchanged plasma creatinine progressive kidney damage in the stenotic kidney ensues.     

Pharmacokinetic predictions for patients with renal impairment: focus on peptides and protein drugs

AIM

Drug dosage adjustments in renal impairment are usually based on estimated individual pharmacokinetics. The extent of pharmacokinetic changes in patients with renal impairment must be known for this estimation. If measured data are not available, an estimate based on drug elimination in urine of healthy subjects or patients with normal renal function is commonly made. This is not reliable, however, if renal drug metabolism is involved, as is presumably the case for many peptide and protein drugs. In the present study a new method to predict pharmacokinetic changes for such drugs based on molecular weight was derived.

METHODS

Articles reporting measured pharmacokinetics of peptide and protein drugs in patients with severe renal impairment or end-stage renal disease were identified from the scientific literature, the pharmacokinetic parameter values were extracted and a statistical data synthesis was performed. A sigmoid E_max model was applied and fitted to the data and the prediction error was analyzed.

RESULTS

Overall, 98 peptide and protein drugs were identified. Relevant pharmacokinetic data in patients with renal impairment were found for 21 of these drugs. The average drug clearance was 30% and the average prolongation in half-life was 3.1-fold for low molecular weight peptides or proteins. The median root squared percentage of the prediction error was 18% (drug clearance) and 12% (half-life).

CONCLUSION

An apparently continuous non-linear relationship between molecular weight and pharmacokinetic alterations in patients with severe renal impairment was found. The derived equations could be used as a rough guide for decisions on drug dosage adjustments in such patients.