Drug Dosing Consideration in Patients With Acute and Chronic Kidney Disease

A Clinical Update From Kidney Disease: Improving Global Outcomes (KDIGO)

Gary R Matzke; George R Aronoff; Arthur J Atkinson Jr; William M Bennett; Brian S Decker; Kai-Uwe Eckardt; Thomas Golper; Darren W Grabe; Bertram Kasiske; Frieder Keller; Jan T Kielstein; Ravindra Mehta; Bruce A Mueller; Deborah A Pasko; Franz Schaefer; Domenic A Sica; Lesley A Inker; Jason G Umans; Patrick Murray

Disclosures

Kidney Int. 2011;80(11):1122-1137.

The Controversy

The pharmacokinetic era that began in the 1960s provided many methods to quantify drug concentrations and tools to characterize the influence of multiple factors including kidney function on the disposition of drugs.^[5,6] In subsequent years the pharmaceutical industry began to investigate the relationship of kidney function and the PK as well as the PD of the drugs they had in development. There was no regulatory agency guidance during the 1970s to early 1990s that provided a framework for when investigations should be conducted and with what degree of rigor. Thus, much of the information on the PK/PD of drugs in patients with renal insufficiency was the result of clinician-initiated postmarketing studies. These studies often employed small sample sizes and resulted in the publication of frequently inconsistent or in some cases even conflicting recommendations regarding the need for drug dosage regimen adjustment. Comprehensive evaluations of clinical PK and PD of drugs and the resultant drug dosage regimen adjustment recommendations for CKD patients has been the topic of hundreds of articles in the past two decades and has become a standard feature in almost all clinical pharmacology and therapeutics textbooks. This wealth of data and expert opinion has fueled controversy regarding almost every step in the process of drug therapy individualization. The critical questions range from: What patient assessment considerations should be factored into the decision-making process? What is the most accurate and reliable index of 'kidney function' for drug dosing? What are the determinates of the desired therapeutic end points that guide therapy, the significance of risk associated with the accumulation of excessive drug and/or metabolite concentrations, and the degree of impact of AKI or CKD on the PK or PD of a drug? How to make pharmaceutical company-derived drug PK and PD readily available to clinicians? What is the predictive performance of the various methodologies to calculate the desired dosage regimen? What are the essential criteria that need to be met to reliably quantify the influence of RRTs on a drug PK and PD, which mathematical methods should be used to individualize drug therapy for those receiving RRTs, and finally what educational efforts should be developed to enhance drug prescribing for patients with AKI and CKD?

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Table 1. Mathematical approaches to estimate GFR that have been proposed to guide drug dosage adjustment
Equations	Units	Reference
Cockcroft and Gault CL_cr=(140−age (years) × weight (kg) × 0.85 [female])/(Scr (mg/dl) × 72)	ml/min	13
MDRD (four-variable) Study equation GFR=186.3·Scr ^−1.154·Age ^−0.2031.212 [black]·0.742 [female]	ml/min per 1.73 m²	19
MDRD (four-variable) Study equation for IDMS serum creatinine GFR=175.6·Scr ^−1.154·Age ^−0.2031.212 [black]·0.742 [female]	ml/min per 1.73 m²	19
CKD-EPI^a GFR _α=141·min (Scr/κ,1)^α·max (Scr/κ,1)^−1.209·0.993^Age·1.159 [black]·1.018 [female]	ml/min per 1.73 m²	17

Abbreviations: CKD-EPI, Chronic Kidney Disease-Epidemiology Collaboration; CL_cr, creatinine clearance; GFR, glomerular filtration rate; IDMS, isotope dilution mass spectroscopy; MDRD, Modification of Diet in Renal Disease.
^a Here, κ is 0.7 for females and 0.9 for males, α is −0.329 for females and −0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1 and age is measured in years.

Table 2. Assessment of kidney function
Recommendations
Clinical practice	1. Glomerular filtration rate (GFR) should be the standard measure to evaluate kidney function for staging of CKD and drug dosing purposes
	2. Clinicians should use the most accurate method/tool to assess kidney function for the individual patient (i.e., eCL_cr or eGFR or mGFR)
	3. Timed clearances of creatinine and urea may be particularly of value for patients with AKI
	4. Metrics to determine the most accurate eGFR methodology include rigor of development process, comparison to gold standard, and measures of bias, precision, and accuracy in multiple patient populations
	5. Clinical laboratories should report eGFR in ml/min as well as ml/min per 1.73 m²
Research	1. Studies are needed to determine the best method to individualize drug dosing to body size
	2. In AKI, studies are needed to establish the role of new biomarkers in detecting early changes in GFR
Regulatory	1. GFR should be measured directly with an inert tracer (e.g., inulin, iohexol, iothalamate, etc.) to determine the relationship between pharmacokinetic or pharmacodynamic alterations due to kidney dysfunction and GFR
	2. If GFR is measured directly during pharmacokinetic and pharmacodynamic studies, then whatever method of eGFR that is used clinically for drug dosing will always be referenced to a measured GFR
	3. Drug labels should refer to measured or estimated GFR without specifying the methodology to be used for drug dosing

Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; eCL_cr, estimated creatinine clearance; eGFR, estimated glomerular filtration rate; mGFR, measured glomerular filtration rate.

Table 3. Stepwise approach to adjust drug dosage regimens for patients with CKD and AKI
Step 1	Obtain history and relevant demographic/clinical information	Assess demographic information, past medical history including history of renal disease, and current clinical and laboratory information, including DNA polymorphisms to ascertain drug therapy needs
Step 2	Estimate GFR	Use most appropriate tool to assess eGFR or CL_cr for the patient based on age, body size, ethnicity, and concomitant disease states
Step 3	Review current medications	Identify drugs for which individualization of the treatment regimen will be necessary
Step 4	Calculate individualized treatment regimen	Determine treatment goals (see text); calculate dosage regimen based on pharmacokinetic characteristics of the drug and the patient's volume status and eGFR or CL_cr
Step 5	Monitor	Monitor parameters of drug response and toxicity; monitor drug levels if available/applicable
Step 6	Revise regimen	Adjust regimen based on drug response or change in patient status (including renal function) as warranted

Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; CL_cr, creatinine clearance; eGFR, estimated GFR; GFR, glomerular filtration rate.

Table 4. Drug dosing considerations for patients with CKD
Recommendations
Clinical practice	1. A single tool to evaluate kidney function for determination of CKD and drug dosing purposes would enable delivery of high-quality care
	2. It should be recognized that drug dosing recommendations developed in the era of high serum creatinine variability will be applied differently than intended in the original pharmacokinetic study
	3. Clinicians should use the most appropriate tool to assess kidney function for individual patient (i.e., measured vs. estimated)
	4. Metrics to determine most accurate eGFR include rigor of development process, comparison to gold standard, and measures of bias, precision, and accuracy
	5. Clinical laboratories should also report eGFR in ml/min
	6. Drug dosages should be adjusted according to FDA- or EMA-approved product labeling
	7. When there is no information in the product label, peer-reviewed literature recommendations should be used to guide drug dosage regimen adjustments
	8. Obese CKD and AKI patients and those with large variations in serum protein levels should have their drug dosage individualized based on the best available evidence
Research	1. Rigorously conducted PK/PD studies are needed to evaluate the impact of CKD on all drugs. The analysis of these studies should generate dosage regimen recommendations based on continuous relationship between GFR and clearance as well as V _D when evident
	2. Categorical dosage recommendations should be based on pharmacokinetic and exposure response, not predetermined categories of kidney function
	3. Evaluate the relationship between steady-state drug and metabolite exposure when appropriate on drug safety and efficacy in patients with CKD enrolled in phase II and III and/or postmarketing studies
	4. Evaluate the impact of interactions of all drugs commonly used in CKD patients (e.g., phosphate binders, PPI)
	5. Design and test methods to translate knowledge of PK/PD and drug interactions into clinical practice (e.g., clinical decision support systems)
	6. Develop database of patients with CKD with PK/PD data and outcomes (safety/efficacy) data
	7. Examine differences in dosing efficacy and safety related to the use of various kidney function indices
Regulatory	1. Drug labeling should state the strength of evidence for dosing modifications for CKD patients
	2. Pharmacokinetic studies in healthy normal volunteers and CKD stage 1–5 patients should be conducted for all renally eliminated drugs
	3. Reduced PK studies should be performed for all drugs. Study population should include patients on HD and the study should be initiated on a non-HD day
	4. Measured GFR should be the standard for renal function and the relationship between PK/PD parameters and multiple estimating equations should be assessed
	5. Pharmacokinetic data from CKD patients provided to FDA should be publicly available and accessible in user-friendly format
	6. Drug labels should indicate the dosage recommendations based on measured GFR rather than a specific estimation equation
	7. Further evaluations of the safety and efficacy of the proposed dosage regimens should be assessed in postmarketing studies in patient populations not sufficiently represented in premarketing studies

Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated GFR; EMA, European Medicines Agency; FDA, US Food and Drug Administration; GFR, glomerular filtration rate; HD, hemodialysis; PD, pharmacodynamics; PK, pharmacokinetics; PPI, proton pump inhibitors; V _D, volume of distribution.

Table 5. Drug dosing considerations for patients with AKI
Recommendations
Clinical practice	1. The KDIGO AKI, AKIN, RIFLE, or pRIFLE criteria should be prospectively utilized to optimize the identification of patients at highest risk of developing AKI
	2. High-risk medications, those with known nephrotoxicity, or other potential toxicities associated with supratherapeutic serum concentrations should be identified proactively, for example, computerized order entry, so that the prescribing clinician can closely monitor patient response
	3. The volume of distribution of several medications is dramatically increased in the presence of AKI and thus larger loading doses may need to be administered to avoid subtherapeutic responses due to the achievement of lower than desired serum concentrations
	4. When possible, therapeutic drug monitoring should be utilized for those medications where serum drug concentrations can be obtained in a clinically relevant time frame
	5. Trends in renal function indices such as serum creatinine and urine output along with volume status should be utilized to guide drug dosing when rapidly measurable indices are unavailable
	6. For those medications where therapeutic drug monitoring is not possible, close monitoring of drug PD may prove to be a useful surrogate
	7. Evaluation of risk for drug–drug and drug–nutrient interactions should be facilitated by incorporating validated electronic drug interaction tools into EMRs
	8. A patient-centered team approach that includes an ICU pharmacist is recommended to prevent medication-related problems and enhance safe and effective medication use
	9. EMRs should maintain records for discontinued medications for up to 7 days to make it possible to assess potential residual effects on the patient's current condition
Research	1. Evaluate the sensitivity and reliability of biomarkers to predict risk for the development of AKI and quantify the degree of injury
	2. Formulation and validation of rapid and reliable direct measurement methods or estimating formulas for kidney and liver function are definitively needed to prospectively ascertain the trajectory of the patient's kidney or liver function
	3. Generate guidelines for the frequency of prospective monitoring of kidney function and drug dosing adjustments in patients with AKI
	4. If estimating equations are to be used, these should be validated against measured values determined via state-of-the-art standard techniques for assessing kidney function
	5. Clinical studies of nonrenal clearance of the most commonly used metabolized medications and the most important hepatic enzymes, CYP2D6, 2C9, 2C19, and 3A4 in AKI are imperative given the emerging evidence that the activity of these enzymes are altered in the presence of CKD
	6. Specific and rapid drug assays (LC-MS/MS) for high-risk medications should be developed and widely available so that pharmacokinetic studies of medications used in AKI patients receiving and not receiving various RRTs can be conducted
	7. Development and validation of 'standardized ICU drug assay panels' (e.g., multiple antibiotics) to facilitate therapeutic drug monitoring to optimize patient outcomes. Validation should include assessment of assay interference with commonly used medications in AKI patients
	8. Encourage further development of electronic tools/decision-making software to guide drug dosage individualization and detect, ascertain causality, and prevent drug interactions
	9. Create open-access databases, based on FDA Medwatch system, to collect information regarding potential drug adverse events and drug interactions in AKI patients
	10. Develop a longitudinal medication history to aid in the identification of residual effects of drugs on the pharmacokinetics, dynamics as well as the patient's sensitivity to the development of adverse events
	11. Create a mechanism to enroll AKI patients upon ICU admission into PK and PD studies across the spectrum of AKI
Regulatory	1. PK and PD studies of all medications in patients with stage 3–5 AKI should be conducted so that reliable drug dosing recommendations can be developed
	2. The innovator of a new drug likely to be used in the ICU setting should during the drug development process establish methodologies for the analysis of drug concentrations in the clinical setting so that the value of TDM in AKI patients can be assessed
	3. Drug labeling should state the level of evidence for the safe and effective use in AKI
	4. Mandate changes in drug labeling to reflect measurement techniques used for establishing the patient's organ clearance that are the foundation of drug dosing individualization
	5. Mandate postmarketing studies to validate drug clearance relationships with 'standard' organ function assessments performed in stable patients with chronic disease are relevant in the setting of MODS

Abbreviations: AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; CKD, chronic kidney disease; EMRs, electronic medical records; FDA, US Food and Drug Administration; ICU, intensive care unit; KDIGO, Kidney Disease: Improving Global Outcomes; LC-MS/MS, liquid chromatography/mass spectrometry; MODS, multiorgan dysfunction syndrome; PD, pharmacodynamics; PK, pharmacokinetics; RRT, renal replacement therapy; RIFLE, risk, injury, failure, loss, end-stage kidney disease; pRIFLE, pediatric risk, injury, failure, loss, end-stage kidney disease; TDM, therapeutic drug monitoring.

Table 6. Drug dosing considerations—hemodialysis
Recommendations
Clinical practice	1. The dose should be given after dialysis (D _hd) to ensure active drug levels until next dosing. Consider a supplementary (D _sup) dose in addition to the dose adjusted to kidney failure (D _fail) after dialysis to replace the fraction removed by dialysis (F _r) D _hd=D _fail+D _sup where D _sup=F _r (D _start−D _fail)
	2. The D _sup derived from studies of low-flux nonsynthetic membranes should empirically be increased by at least 50% when patients are dialyzed with high-flux synthetic dialyzers
	3. Extended dialysis regimens with high diffusive membranes have been associated with extensive drug clearances and thus the D _sup may need to be increased
Research	1. Develop accurate and reproducible methods to quantitate dialysate and ultrafiltration flow rates and collect representative aliquots because the clinical utility of pharmacokinetic studies in HD patients is critically dependent on the accuracy of these procedural variables
	2. Develop methodologies to quantitate the degree of drug adsorption to the dialyzer membrane and associated elements in the extracorporeal circuit as this route of drug removal impacts the overall dialyzer clearance
	3. The drug should be administered intravenously at a sufficient interval before HD is instituted so that predialysis distribution and elimination PK can be fully characterized
	4. The dialyzer model and all the components of the dialysis prescription should be reported for each individual studied. The dialysis prescription should be standardized as much as clinically feasible to enhance the generalizability of the data
	5. The time course and the extent of the postdialysis rebound in drug serum concentrations should be assessed and the resultant data incorporated into the drug dosage regimen recommendation
Regulatory	1. FDA and EMA should mandate that the PK/PD including determination of the HD clearance be evaluated for all drugs that will likely be used in ESRD patients
	2. In vitro and in vivo dialysis studies should use a standard array of model substrates such as creatinine, vitamin B12 or vancomycin, and β2-microglobulin. This will facilitate extrapolation of the results with one hemodialyzer to another as it is impractical to mandate studies be done with all commercially available dialyzers

Abbreviations: EMA, European Medicines Agency; ESRD, end-stage renal disease; FDA, US Food and Drug Administration; HD, hemodialysis; PD, pharmacodynamics; PK, pharmacokinetics.

Table 7. Drug dosing considerations for AKI patients receiving CRRT/EDD
Recommendations
Clinical practice	1. ESRD dosing recommendations should be used only as an initial guide for the initiation of therapy in an AKI patient receiving CRRT when no other information is available
	2. The existing maintenance dosing recommendations for ESRD patients receiving HD often result in the achievement of subtherapeutic concentrations and treatment failures for patients with severe AKI requiring RRT
	3. The most effective dosing optimization strategy is to use therapeutic drug monitoring for drugs like aminoglycosides and vancomycin to achieve the desired therapeutic goals. However, very few drugs have clinically useful (quick turnaround time, FDA/EMA approved) assays available
	4. When CRRT or EDD clearance data are available, the current literature recommendations should be the logical starting dose for therapy. Different treatment intensities for CRRT or EDD result in marked variability in drug removal and thus this literature may not be generalizable across the multiple CRRT and EDD prescriptions that are used in practice
	5. Another alternative is to calculate the 'total creatinine clearance' (CL_cr) based on the addition of the patient's residual renal clearance and expected extracorporeal clearance. This value can then be used to estimate a maintenance dosing regimen based on medication dosing guidelines specified for that resultant total CL_cr range. Using this method, most drugs will fall in the CL_cr 25–50 ml/min range
	6. A fourth method starts with the dose and dosing interval for a patient with a GFR <10 ml/min (anuric dose), and makes dosage adaptations based on the drug fraction expected to be removed by extracorporeal therapy (Fr_EC)
	i. Maintenance dose=anuric dose/[1−Fr_EC]
	ii. Dosing interval=anuric dosing interval × [1−Fr_EC]
	7. A fifth method starts with a normal dose (D_n) and reduces dose based on normal clearance (Cl_norm), non-renal clearance (Cl_nonrenal), effluent rate (Q_eff), and sieving coefficient (SC)
	b. Dose =Dose_n × [Cl_nonrenal+(Q_eff × SC)]/Cl_norm
	8. CRRT and EDD education should be an integral part of critical care and nephrology fellowship training programs
Research	1. CRRT or EDD clearance data derived from in vitro studies or those conducted in ESRD patients are needed to guide clinical studies in AKI patients
	2. Studies should be conducted in AKI patients to characterize the influence of CRRTs because the PK parameters observed in ESRD patients are not generalizable to ICU patients
Regulatory	1. FDA and EMA should mandate PK/PD studies at a given, predefined CRRT or EDD intensity level during the preapproval process or in phase IV studies
	2. FDA and EMA should make PK/PD studies a mandatory requirement for antimicrobials and renally excreted drugs that are likely to be extensively used in the ICU setting
	3. Available and future PK/PD data in this patient population should be compiled in a publicly accessible data repository
	4. The effect of other extracorporeal techniques should be investigated in terms of their ability to remove/adsorb drugs
	5. The results of PK/PD studies conducted in patients receiving CRRT/EDD and dosing guidelines for these therapies should be presented in a drug's package insert

Abbreviations: AKI, acute kidney injury; CRRT, continuous renal replacement therapy; CVVH, continuous venovenous hemofiltration; EDD, extended daily dialysis; EMA, European Medicines Agency; ESRD, end-stage renal disease; FDA, US Food and Drug Administration; GFR, glomerular filtration rate; HD, hemodialysis; ICU, intensive care unit; PD, pharmacodynamics; PK, pharmacokinetics; RRT, renal replacement therapy.

Table 8. Drug dosing considerations—peritoneal dialysis
Recommendations
Clinical practice	1. As most pharmacokinetic studies establishing peritoneal antibiotic doses have used 4- to 8-h loading periods, it is recommended to perform antibiotic loading by an extended cycle in both CAPD and APD patients. For intermittent maintenance dosing, a long nighttime dwell should be used in CAPD and a long daytime dwell in APD patients
	2. Intermittent antibiotic dosing has not been unequivocally successful in eradicating bacterial growth, partially questioning the concept of antibiotic back diffusion into the peritoneal cavity. Transperitoneal drug movement may be less effective in the post acute phase of peritoneal infection when inflammation-related capillary hyperperfusion subsides
	3. Short dwell times in APD patients may prevent accumulation of antibiotic in the peritoneal cavity to concentrations exceeding the minimal inhibitory concentrations
	4. Monitoring of drug blood levels is advocated in patients receiving intraperitoneal antibiotics because they are at increased risk for under- and over-dosing, that is, those with significant residual renal function and those on intense APD schedules, respectively. Monitoring of dialysate concentrations may provide even more relevant information
Research	1. CAPD patients are a suitable group for PK and PD studies in end-stage renal disease as they represent a steady-state clinical condition
	2. Peritoneal dialysis drug clearance may need to be characterized for many more drugs than in the past due to the introduction of high- and continuous-flow peritoneal dialysis variants, which are likely to become available for both acute and chronic patients in the foreseeable future
	3. Although the intraperitoneal route is a well-established administration mode for some agents, especially antibiotics in patients with peritoneal dialysis-associated peritonitis, several aspects of this dosing approach require further research. These include assessment of the degree of equivalence of drug absorption across a noninflamed vs. inflamed peritoneum and the determination of the optimal administration schedule to achieve adequate systemic drug exposure
	4. Simulation studies of bidirectional transperitoneal drug transport would be particularly relevant in intermittently treated patients on automated peritoneal dialysis, in whom alternating phases of rapid nocturnal cycling and daytime rest might result in complex pharmacokinetic patterns
	5. Finally, the efficacy and safety of intermittent and continuous dosing protocols should be studied in clinical trials
Regulatory	1. The limited and continuous drug clearance achieved with many modes of peritoneal dialysis does not warrant a mandate to conduct PK/PD studies of all new drugs
	2. However, as the transperitoneal route is a well-established administration mode mainly for antibiotics and antifungal agents in patients with peritoneal dialysis-associated peritonitis, it is recommended that PK studies of new agents in these classes be conducted in the postmarketing period

Abbreviations: APD, automated peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis; PD, pharmacodynamics; PK, pharmacokinetics.

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