Introduction: Angiotensin II may reduce muscle ischemia during intermittent hemodialysis and thereby decrease the incidence and/or intensity of intradialytic muscle cramps. We aimed to test whether angiotensin II infusion during intermittent hemodialysis is safe, feasible, and effective in the attenuation of muscle cramps. Methods: We performed a pilot, single-blinded, randomized crossover trial of patients receiving intermittent hemodialysis who frequently experience intradialytic muscle cramps. Patients were randomly allocated to receive either intravenous angiotensin II or placebo for the duration of their first dialysis session of the week. They crossed over to the alternate arm each week for four weeks. The primary outcome was safety. Secondary outcomes included cramp-related symptoms, hemodynamic parameters, dialysis prescription alterations, and biomarkers. Results: We studied 24 sessions in 6 patients. Intradialytic hypertension (systolic blood pressure >180mmHg) occurred more often with angiotensin II than with placebo (33% vs 17% sessions, P=0.64). There were no other adverse events. Compared with placebo, muscle cramps were less frequent (33% vs. 92% sessions, P=0.009) and of lower intensity with angiotensin II (median Brief Pain Inventory score 1.4 vs. 5.3; P<0.001; maximal Brief Pain Inventory score 1.2 vs. 6.0; P<0.001). Fluid bolus administration for cramps was less common during angiotensin II infusion than placebo (0% vs. 42% sessions, P=0.037). Conclusion: Angiotensin II increased blood pressure and heart rate but not cardiac output or levels of troponin, creatine kinase or renin. In conclusion, angiotensin II infusion during intermittent hemodialysis appears safe and effective at reducing intradialytic muscle cramps. These observations justify further investigation in larger controlled studies.

Alterations in pharmacokinetics, which quantitatively describes the time course of drug disposition in the body, may lead to clinically significant changes in systemic exposure and corresponding response to drugs in patients with impaired kidney function, including those with acute and chronic kidney disease (CKD). Pharmacokinetic changes should be considered -when selecting and dosing medications in CKD patients to optimize the risk:benefit ratio. While changes in absorption, distribution, and renal clearance are well described for most drugs, changes in nonrenal clearance are less predictable. This chapter broadly reviews the effect of kidney disease on pharmacokinetics and presents strategies for drug dosing in patients with impaired kidney function.

The extracorporeal clearance created by renal replacement therapy adds another route for drugs to be eliminated. Total drug clearance in patients receiving this therapy can be calculated as the sum of extracorporeal clearance plus the preexisting renal and nonrenal clearances. The A-V difference method and recovery method are described as two ways for calculating extracorporeal clearance in patients during hemodialysis. Drug clearance for patients receiving continuous renal replacement therapy is calculated on the basis of the dialysis saturation factor and ultrafiltration coefficient. Three methods are provided for estimating drug replacement doses for patients receiving renal replacement therapy. The use of these methods for treating drug intoxications is also discussed.

Clinical Pharmacology & TherapeuticsVolume 109, Issue 6 p. 1388-1389 Tribute Tribute: Sir Colin Terence Dollery, MB, Ch, MD (Hon) Arthur J. Atkinson Jr., Corresponding Author Arthur J. Atkinson Jr. Art_Atkinson@msn.com Department of Pharmacology, Feinberg Medical School, Northwestern University, Chicago, Illinois, USA Correspondence: Arthur J. Atkinson (Art_Atkinson@msn.com)Search for more papers by this author Arthur J. Atkinson Jr., Corresponding Author Arthur J. Atkinson Jr. Art_Atkinson@msn.com Department of Pharmacology, Feinberg Medical School, Northwestern University, Chicago, Illinois, USA Correspondence: Arthur J. Atkinson (Art_Atkinson@msn.com)Search for more papers by this author First published: 12 February 2021 https://doi.org/10.1002/cpt.2150Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume109, Issue6June 2021Pages 1388-1389 RelatedInformation

The author declared no competing interests for this work.

The increasing emphasis on patient-centered care has refocused research interests, and hemodialysis patients have identified symptom management as a top research priority.1Manns B. Hemmelgarn B. Lillie E. et al.Setting research priorities for patients on or nearing dialysis.Clin J Am Soc Nephrol. 2014; 9: 1813-1821Crossref PubMed Scopus (176) Google Scholar,2Palmer S.C. de Berardis G. Craig J.C. et al.Patient satisfaction with in-centre haemodialysis care: an international survey.BMJ Open. 2014; 4: e005020Crossref PubMed Scopus (23) Google Scholar A recent study analyzed the top 3 prioritized physical symptoms of insomnia, muscle cramps, and fatigue from the standpoint of their current state, barriers, and knowledge gaps impeding progress and a possible path forward.3Flythe J.E. Hilliard T. Lumby E. et al.Fostering innovation in symptom management among hemodialysis patients: paths forward for insomnia, muscle cramps, and fatigue.Clin J Am Soc Nephrol. 2019; 14: 150-160Crossref PubMed Scopus (25) Google Scholar In keeping with the importance of this topic, a survey of our dialysis center patients was conducted to characterize the frequency, severity, and timing of dialysis-related cramps. Dialysis-related cramps can be extremely painful and can compromise the efficacy of hemodialysis therapy, but their pathophysiology is unclear.4Rocco M.V. Burkart J.M. Prevalence of missed treatments and early sign-offs in hemodialysis patients.J Am Soc Nephrol. 1993; 4: 1178-1183PubMed Google Scholar,5Batlle D.C. von Riotte A. Lang G. Delayed hypotensive response to dialysis in hypertensive patients with end-stage renal disease.Am J Nephrol. 1986; 6: 14-20Crossref PubMed Scopus (25) Google Scholar The central role of volume removal as the trigger for susceptible patients seems evident from the fact that intradialytic cramps are usually associated with hypotension and that prompt correction of hypotension by saline administration and discontinuation of ultrafiltration often improve the cramping. Here we propose a central role of relative angiotensin II deficiency as the cause of decreased muscle blood flow during dialysis and therefore a key contributor to this painful complication of dialysis. Of the 149 participants surveyed, 79 (53%) self-identified as diabetic. In all, 79% of the participants (117 of 149) reported having experienced cramps at least once during dialysis (Table 1). Of these 117 patients, 63 (54%) stated that cramps occurred during only dialysis days, whereas 54 (46%) reported cramps during both dialysis and nondialysis days. None of the patients reported cramps on nondialysis days only. A total of 73% (85 of 117) reported cramps during the last hour and 26% (30 of 117) in the middle of dialysis (Table 1). Severity of cramps was rated using a scale from 1 to 10 and then classified in 3 categories: minor (1−3), moderate (4−6), and severe (7−10). Two patients were not able to estimate the severity of their cramps. Among the 117 participants who experienced cramps, 14% (n = 16) rated the pain as minor and 38% (n = 44) as moderate, whereas almost half (47%, n = 55) reported severe cramps (Table 2). Patients who reported severe pain were subcategorized for the analysis into moderately severe (pain scale rating of 7−8) and extremely severe (pain scale rating of 9−10). In all, 41 of the 55 patients (75%) reporting severe pain scored the pain as moderately severe, and 14 of 55 patients (25%) scored the pain as extremely severe.Table 1Reported muscle cramps frequency and characteristicsSurvey questionResponse, n (%)Response, n (%)Response, n (%)Have you ever had muscle cramps during dialysis?Yes117 of 149(79)No32 of 149(21)Which days do you usually experience muscle cramps?Dialysis days only63 of 117(54)Nondialysis days0 of 117(0)Both54 of 117(46)When you have cramps during dialysis, when do they usually occur?Initiation (first h)1 of 117(1)Middle30 of 117(26)End (last h)85 of 117(73)Has the dialysis session sometimes been interrupted because of the cramps?Yes92 of 117(79)No24 of 117(21)How often does dialysis interruption occur?More than 50%aAs many of 10% of the patients (9 of 92) reported that they almost always had the session interrupted because of cramps.15 of 92(16)Less than 50%bThe majority (64%) of the patients (59 of 92) reported that interruptions in the dialysis session happened rarely.77 of 92(84)a As many of 10% of the patients (9 of 92) reported that they almost always had the session interrupted because of cramps.b The majority (64%) of the patients (59 of 92) reported that interruptions in the dialysis session happened rarely. Open table in a new tab Table 2Reported muscle cramps frequency and characteristicsSurvey questionResponse, n (%)Response, n (%)Response, n (%)Response, n (%)How severe are the cramps?Mild16 of 117(14)Moderate44 of 117(38)Severe55 of 117(47)Unable to estimate2 of 117(2)What treatment is usually being done for dialysis cramps?Decrease fluid removal/infuse fluid back89 of 117(76)Bring toes up60 of 117(51)Massage or squeeze the extremities56 of 117(48)Stop dialysis prematurely22 of 117(19) Open table in a new tab Most patients surveyed (76%) reported that fluid removal by dialysis was decreased, was stopped, and/or fluid was given back as the main intervention used to alleviate their cramps (Table 2). Half of the patients stated that “bringing the toes up” was tried as a way to ameliorate the cramps. When asked about all interventions to alleviate dialysis cramps, the most frequent response (29%) was a combination of decreasing fluid removal, raising the lower extremities, and massaging the extremities. Stopping dialysis prematurely was 1 of the measures reported by some (22 of 117), either alone or in combination with other measures (19%). Pain from intradialytic cramps was frequently reported as severe and a cause for premature termination of dialysis in 19% of the cramping patients we surveyed, a percentage similar to the 17.9% termination rate previously reported.4Rocco M.V. Burkart J.M. Prevalence of missed treatments and early sign-offs in hemodialysis patients.J Am Soc Nephrol. 1993; 4: 1178-1183PubMed Google Scholar Among the 117 patients with cramps, 15 (12.8%) were receiving angiotensin II receptor blockers (ARBs), and 21 (17.9%) were receiving angiotensin-converting enzyme (ACE) inhibitors (Figure 1). In total, the 2 classes of renin−angiotensin system (RAS) blockers were used by 36 of the 117 patients with cramps (30.7%) and only 4 of the 32 patients without cramps (12.5%). This difference was statistically significant by the Fisher exact test (P = 0.028). There were no significant differences in the percentage of cramping and noncramping patients receiving β-blockers or calcium channel blockers (Figure 1). Attempts to develop a rational approach for treating muscle cramps are clearly hampered by an incomplete understanding of its pathophysiology. The efficacy of fluid replacement as a palliative measure supports the key role of fluid removal as the initiating event. Yet, for similar degrees of fluid removal, some patients experience severe cramps whereas others do not. This suggests that an abnormal response to fluid removal is involved in those patients who experience cramps. Our survey also revealed that some patients experience cramps on nondialysis days, which may suggest a predisposition unrelated to fluid removal. A delayed effect of fluid removal during dialysis, however, may be responsible for their cramping much in the same way that some patients experience a delayed hypotensive response after hemodialysis.5Batlle D.C. von Riotte A. Lang G. Delayed hypotensive response to dialysis in hypertensive patients with end-stage renal disease.Am J Nephrol. 1986; 6: 14-20Crossref PubMed Scopus (25) Google Scholar Mechanisms that have been proposed to be responsible for dialysis-related cramps include hypoxia caused by hypotension and vasoconstriction, osmotic shifts, hyponatremia, hypomagnesemia, and carnitine deficiency.4Rocco M.V. Burkart J.M. Prevalence of missed treatments and early sign-offs in hemodialysis patients.J Am Soc Nephrol. 1993; 4: 1178-1183PubMed Google Scholar A clue to the nature of the pathogenesis of cramps was provided by using a tilt table to study the hemodynamic response of cramping and noncramping dialysis patients to postural change.6Kaplan B. Wang T. Rammohan M. et al.Response to head-up tilt in cramping and noncramping hemodialysis patients.Int J Clin Pharmacol Ther Toxicol. 1992; 30: 173-180PubMed Google Scholar From this study, it was concluded that intradialytic skeletal muscle cramps result at least in part from a sympathetic nervous system response to dialysis-induced volume stress. We now propose a key role of angiotensin II as a main contributor to muscle cramping during dialysis. Specifically, we hypothesize that the lack of an appropriate increase in angiotensin II activity during fluid removal by hemodialysis results in decreased muscle blood flow, which in turn causes cramps. Normally, within seconds of changing from a recumbent to a standing position, hemorrhage, or other stress that causes a perceived reduction in intravascular volume, such as fluid removal during dialysis, there is release into the circulation of renin secreted by the kidney juxtaglomerular apparatus.7Tang J. Wysocki J. Ye M. et al.Urinary renin in patients and mice with diabetic kidney disease.Hypertension. 2019; 74: 83-94Crossref PubMed Scopus (18) Google Scholar This leads to the rapid formation of angiotensin I by cleavage of angiotensinogen by renin and concurrent angiotensin II formation. When appropriately regulated during volume removal by hemodialysis, angiotensin II may ensure adequate muscle blood flow and helps to prevent cramping. In support of the proposed angiotensin II hypothesis of cramping during dialysis is the key finding of Fliser et al.8Fliser D. Dikow R. Demukaj S. Ritz E. Opposing effects of angiotensin II on muscle and renal blood flow under euglycemic conditions.J Am Soc Nephrol. 2000; 11: 2001-2006PubMed Google Scholar that infusions of angiotensin II caused a marked increase in skeletal muscle blood in normal volunteers, which has been confirmed by others. The action of angiotensin II on muscle blood flow is in contrast to the vasoconstrictive properties of this peptide and the decreased renal blood flow consistently reported after infusions of this peptide. Why would a blunted angiotensin II response be involved in dialysis cramping? An appropriate response of angiotensin II to fluid removal is dependent on several factors: namely, renin secretion, which is often decreased in patients with end-stage kidney disease as a result of chronic volume overload and sclerosis of the juxtaglomerular apparatus in some cases.7Tang J. Wysocki J. Ye M. et al.Urinary renin in patients and mice with diabetic kidney disease.Hypertension. 2019; 74: 83-94Crossref PubMed Scopus (18) Google Scholar What we are hypothesizing is that the more impaired the RAS response is, the more likely it is that cramping occurs as a result of inappropriately low angiotensin II levels. When dogs with intact kidneys were dialyzed, they exhibited a normal RAS response to fluid removal as shown by an increase in plasma renin activity and did not exhibit capillary derecruitment.9Bowsher D.J. Krejcie T.C. Avram M.J. et al.Reduction in slow intercompartmental clearance of urea during dialysis.J Lab Clin Med. 1985; 105: 489-497PubMed Google Scholar Peripheral vasoconstriction from sympathetic activation is likely to occur in all patients during hemodialysis, leading to derecruitment of skeletal muscle capillaries. Muscle cramping is more likely in patients whose sympathetic system activation during hemodialysis is not accompanied by an appropriate activation of the RAS during fluid removal and the attendant increase in renin and therefore plasma angiotensin II. Our survey findings moreover are consistent with the angiotensin II hypothesis of dialysis cramping proposed here, as patients treated with RAS blockers experienced cramps more often than those who were not treated with these agents (Figure 1). Weaknesses of our survey that should be noted include an open recall period (from initiation of dialysis to the survey period), which creates variability in the intervals being surveyed. Another weakness is the lack of data on blood pressure during dialysis. Lack of validation of our questionnaire and our use of the Stanford Pain Scale, which is not specific to dialysis-related cramps pain, are additional limitations. Further studies are needed to confirm our observations from larger databases before it can be recommended that RAS blockers be avoided in patients with cramps. Now that angiotensin II is commercially available for treating patients with shock that is refractory to norepinephrine infusions, it may be possible to study whether infusions of this natural peptide or novel agonists may be effective in preventing intradialytic skeletal muscle cramps. AJA holds U.S. patent number 9,919,022 relating to the use of AII receptor agonists to prevent or reduce hemodialysis-associated skeletal muscle cramps. DB is a co-inventor of U.S. patent number 10,443,049 relating to the use of ACE2 truncates and also the founder of Angiotensin II therapeutics Inc. All the other authors declared no completing interests. This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK104785 . We wish to thank all the dialysis patients at the Northwestern/Fresinius Dialysis Unit who participated in our surveys to evaluate cramping during dialysis.

Patient-centered care is refocusing research interests and hemodialysis patients have identified symptom management as a top priority.Cramps from dialysis are one of the top three symptoms thus identified, are painful, lead to disruption of dialysis and inefficient treatments.We designed and undertook a survey of our outpatient dialysis patients to characterize the frequency, severity, and timing of dialysis related cramps.The pathophysiology of dialysis related cramps is incompletely understood.Angiotensin II can increase muscle blood flow and here we propose as hypothesis a key role of relative angiotensin II deficiency in dialysis related cramps.A total of 149 chronic hemodialysis patients at our outpatient center were surveyed using a questionnaire developed to capture the frequency, timing and intensity of cramps.A single coordinator delivered the questionnaire we designed.A total of 117 patients (out of 149 surveyed) reported cramps during dialysis.Most of them (73%) reported cramps in the last hour.Almost half (47%) noted severe cramps (a pain score of 7-10).Most (76%) had improvement with decreased fluid removal or return of fluid while 1/3rd identified a combination of fluid return, raising limb or massage as effective.Of all the patients with cramps, 30.7% were on either ACE inhibitors or ARBs while only 12.5% of those without cramps were on medications other than RAS blockers.Our results are generally consistent with prior reported high frequency of dialysis-related cramps.There is lack of a clear understanding of the pathophysiology of dialysis-related cramps but plasma volume contraction during fluid removal seems to often be the inciting event.Increased muscle blood flow after angiotensin II administration and during exercise has been documented in normal volunteers.We now propose a role of relative angiotensin II deficiency as a key contributor of muscle cramping during dialysis.We suggest that the lack of an appropriate increase in angiotensin II activity during fluid removal by hemodialysis results in decreased muscle blood flow, which in turn, causes cramps.

In the conventional concept of translational research, investigations flow from the laboratory bench to the bedside. However, clinical research can also serve as the starting point for subsequent laboratory investigations that then lead back to the bedside. This article chronicles the evolution of a series of studies in which a detailed analysis of pharmacokinetics in hemodialysis patients revealed new physiological insight that, through a systems approach incorporating kinetic, physicochemical, physiologic, and clinical trial results, led to an elucidation of the pathophysiology of intradialytic skeletal muscle cramps. Based on this understanding, a therapeutic path forward is proposed.

Adding to the complexity of caring for critically ill patients is the fact that many of them have a creatinine clearance that exceeds 130 mL/min/1.73 m2. This phenomenon, termed augmented renal clearance (ARC), has only recently been widely recognized and its pathogenesis remains incompletely understood. However, ARC has been shown to result in increased dose requirements for drugs that are primarily eliminated by renal excretion, including many antimicrobial agents and enoxaparin. Recognition of ARC is hampered by the fact that the standard creatinine-based equations used to estimate renal function are not accurate in this clinical setting and the diagnosis is best established using both serum and urine creatinine measurements to calculate clearance. So a high index of clinical suspicion and awareness is usually required before this step is taken to confirm the diagnosis of ARC.

Among the various routes of drug administration, perhaps the least studied is intracerebroventricular (ICV) administration. This route has been shown to be particularly useful in administering to the central nervous system (CNS) drugs that do not cross the blood-brain barrier readily. As such, the ICV route is a valuable option for providing therapeutic CNS drug concentrations to treat patients with CNS infectious and neoplastic diseases. This route of drug administration also has the advantage of minimizing systemic toxicity.

The bioavailability of a drug is usually assessed in healthy subjects. However, it is reasonable to expect that significant alterations in bioavailability may occur in actual patients with different diseases or in individuals belonging to special populations. Relatively few studies have been conducted to examine this possibility. The stable isotope method is well suited to compare absolute bioavailability in patients and healthy subjects. Studies in which this method was used indicate that significant changes in the bioavailability of some drugs are particularly likely in patients with advanced liver disease and in those whose splanchnic blood flow is reduced. The expectation is that bioavailability in neonates, children, and pregnant women may also differ from that in non-pregnant adults.

The therapeutic technique of hemodialysis and the concept of clearance have both followed a long but instructive course of development. In addition, it recently has been shown that physiological changes occurring during hemodialysis have important clinical consequences both in the treatment of drug toxicity and in the selection of appropriate replacement doses of therapeutic drugs. Two major approaches for calculating hemodialysis clearance are currently used. The first approach, termed the recovery method is the "gold standard" that is recommended for use in the current US FDA draft guidance on the conduct of pharmacokinetic studies in patients with impaired renal function. The second approach, termed the A-V difference method, is used more commonly. Unfortunately, this method results in erroneous plasma clearance estimates when improper values for dialyzer flow are chosen. This constitutes a major pitfall that should be avoided in future studies.

The idea of body compartments has its origins in physiology and antedates their use in both physio logically-based predictive pharmacokinetic models and in the simpler compartmental models used to analyze pharmacokinetic data. Whereas physiologically-based pharmacokinetics has evolved to use increasingly sophisticated organ-based models, most compartmental models for data analysis are used without regard for their underlying physiological basis. However, detailed analysis of inulin and urea kinetics has offered some understanding of the physiological basis underlying some three-compartment pharmacokinetic models. In addition, these simple models have yielded new insight into physiological phenomena.

A biomarker has been defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic process, or pharmacologic responses to a therapeutic intervention.” This comprehensive definition of biomarkers arose from the April 1999 US Food and Drug Administration (FDA)/National Institutes of Health consensus conference on “Biomarkers and Surrogate Endpoints: Advancing Clinical Research and Applications,” and emphasized that biomarkers are medical measurements, including physiological measurements, blood tests, molecular analyses of biopsies, genetic or metabolic data, and measurements from images. Research on biomarkers—organized and propelled by this definition—has skyrocketed, with over 200,000 PubMed citations in the last five years.

Although therapeutic drug monitoring, pharmacokinetics, and pharmacogenetics/ pharmacogenomics are conventionally considered in isolation, when applied to patient care, they are really three chapters in a continuing story that has as its theme the optimization of pharmacotherapy. This has been variously referred to as rational drug therapy, individualization of drug therapy, and personalized medicine. However, the goal of improved drug therapy has been the same.

Mitochondrial medicine is an evolving discipline whose importance derives from the central function of mitochondria in adenosine triphosphate (ATP) production, generation of reactive oxygen species, and cell death by necrosis or apoptosis. Consequently, mitochondrial dysfunction plays an important role in the progression of aging and the pathophysiology of many common diseases and off-target drug effects. This provides an impetus for the development of mitochondrial pharmacology, and some promising therapeutic targets for mitochondrial protective therapy have been identified.

As science matures, it becomes more mathematical, progressing from enumeration to the use of equations to the formulation of models. Clinical pharmacology has developed to the stage where models play an increasingly important role in predicting and analyzing drug pharmacokinetics and pharmacodynamics, and even in characterizing disease progression and therapeutic response. Useful models have two characteristics that are in ostensible conflict: (i) they must accurately represent the essential features of the underlying system and (ii) the representation must be sufficiently simplified to enable its salient features to be identified and investigated through further experimentation.

In their semimechanistic analysis of trastuzumab emtansine (T-DM1) pharmacokinetics, Chudasama et al., as reported in this issue, modeled the process of T-DM1 deconjugation with a series of transit compartments representing plasma volume and a single peripheral compartment. The implausibility of the two-compartment distribution model used in this study as well as in other recent attempts to analyze the distribution kinetics of trastuzumab and other macromolecules reflects the fact that this modeling has been guided primarily by statistical rather than physiological considerations.

Chronic kidney disease, or renal impairment (RI) can increase plasma levels for drugs that are primarily renally cleared and for some drugs whose renal elimination is not a major pathway. We constructed physiologically based pharmacokinetic (PBPK) models for 3 nonrenally eliminated drugs (sildenafil, repaglinide, and telithromycin). These models integrate drugdependent parameters derived from in vitro, in silico, and in vivo data, and system‐dependent parameters that are independent of the test drugs. Plasma pharmacokinetic profiles of test drugs were simulated in subjects with severe RI and normal renal function, respectively. The simulated versus observed areas under the concentration versus time curve changes (AUCR, severe RI/normal) were comparable for sildenafil (2.2 vs 2.0) and telithromycin (1.6 vs 1.9). For repaglinide, the initial, simulated AUCR was lower than that observed (1.2 vs 3.0). The underestimation was corrected once the estimated changes in transporter activity were incorporated into the model. The simulated AUCR values were confirmed using a static, clearance concept model. The PBPK models were further used to evaluate the changes in pharmacokinetic profiles of sildenafil metabolite by RI and of telithromycin by RI and co‐administration with ketoconazole. The simulations demonstrate the utility and challenges of the PBPK approach in evaluating the pharmacokinetics of nonrenally cleared drugs in subjects with RI.