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NephropharmacologyCJASN ePress. Published on July 24, 2018 as doi: 10.2215/CJN.05150418 for the Clinician

Clinical in Disease Application to Rational Design of Dosing Regimens

Darren M. Roberts ,1,2,3 Jacob Sevastos,4,5 Jane E. Carland,1,5 Sophie L. Stocker,1,5 and Tom N. Lea-Henry2,6

Abstract A change in pharmacokinetics can alter exposure and predispose the patient to either over- or underdosing, potentially resulting in adverse drug reactions or therapeutic failure. Kidney disease is characterized by multiple 1Departments of physiologic effects, which induce clinically significant changes in pharmacokinetics. These vary between Clinical and individuals and may be quantitated in certain instances. An understanding of pharmacokinetic concepts is, , and therefore, important for a rational approach to the design of drug dosing regimens for the delivery of personalized 4Nephrology and medical care. Whether kidney disease is acute or chronic, drug decreases and the Renal Transplantation, may remain unchanged or increase. AKI is defined by dynamic changes in kidney function, which complicates St. Vincent’s Hospital, attempts to accurately quantify drug clearance. In contrast, changes in drug clearance progress more slowly with Darlinghurst, New South Wales, CKD. In general, kidney replacement therapies increase drug clearance, but the extent to which this occurs depends Australia; on the modality used and its duration, the drug’s properties, and the timing of drug administration. However, the 2Department of Renal changes in drug handling associated with kidney disease are not isolated to reduced kidney clearance and an , The appreciation of the scale of potential derangements is important. In most instances, the first administered in Canberra Hospital, Woden, Australian patients with kidney disease is the same as in patients with normal kidney function. However, in some cases, a higher Capital Territory, (loading) initial dose is given to rapidly achieve therapeutic , followed by a lower , Australia; 3Medical as is well described when prescribing anti-infectives to patients with sepsis and AKI. This review provides an School, Australian overview of how pharmacokinetic principles can be applied to patients with kidney disease to personalize dosage National University, regimens. Patients with kidney disease are a vulnerable population and the increasing prevalence of kidney disease Acton, Australian Capital Territory, means that these considerations are important for all prescribers. Australia; Clin J Am Soc Nephrol 13: ccc–ccc, 2018. doi: https://doi.org/10.2215/CJN.05150418 5Department of Medicine, St. Vincent’s Clinical School, University of Introduction As discussed in part 1 (2), although there are New South Wales, Pharmacokinetic concepts underlie the rational pre- guidelines available for dosage adjustment in patients Sydney, Australia; and 6 scribing of . Drugs are commonly prescribed in with kidney disease, these guidelines may be incon- Nephrology and the management of patients with both chronic and Transplantation Unit, sistent (4) or not applicable to all clinical contexts, John Hunter Hospital, acute kidney disease, and this population may have particularly in AKI where drug clearance can change Newcastle, New South an increased risk of adverse drug reactions (1). Kidney rapidly. Wales, Australia diseases cause a range of changes to pharmacoki- Acommonapproachtodrugdosingwhenthereis netics, as discussed in part 1 of this series (2), so these uncertainty in its dosage or pharmacokinetics in Correspondence: must be considered when designing appropriate patients with kidney disease is to use a conservative Dr.DarrenM.Roberts, dosage regimens. “ ” Department of start low and go slow iterative approach. Depend- Clinical The usual method of dosage adjustment in patients ing on the rate of dose escalation, this approach will Pharmacology and with kidney disease is defined by the product label, attain a target clinical effect (e.g., BP or glycosylated Toxicology, St. Vincent’s Hospital, but this can have limitations. During , hemoglobin A1c) in a delayed fashion, which is rea- dosing regimens are initially determined in patients with sonable for drugs that yield a clinical benefitfrom Victoria Street, Darlinghurst, NSW normal or mildly impaired kidney function. The drugs treatment over months or years (e.g., antihypertensives 2010, Australia. Email: are then trialed in a smaller number of patients with or oral hypoglycemics). However, this approach is less darren.roberts@svha. more severe kidney disease before registration. Data for useful for drugs requiring a rapid onset of effect, such as org.au patients with ESKD treated with dialysis are particularly anti-infective or immunosuppressive drugs. limited before registration, with only a minority of new are inappropriately dosed in patients with decreased drug applications to the US Food and Drug Adminis- GFR, and this may contribute to poorer outcomes in tration (FDA) being evaluated in this patient population those requiring kidney replacement therapy (5,6). (3). Indeed, because of complex pharmacokinetics The purpose of this review is to provide an over- in a small number of cases or other safety concerns, view of how the pharmacokinetic principles outlined manufacturers may recommend that the drug is con- in part 1 of this series (2) can be applied to patients traindicated in patients with advanced kidney disease, with kidney disease to personalize dosage regimens hindering access to a potentially beneficial drug. and to appropriately monitor drug therapy. It should,

www.cjasn.org Vol 13 August, 2018 Copyright © 2018 by the American Society of Nephrology 1 2 Clinical Journal of the American Society of Nephrology

Figure 1. | The same daily dose of administered as different dosage regimens has differing effects on the –time profile in a patient with CKD. Three different dosage regimens (each equivalent to 1000 mg/d) are simulated in a patient with an GFR of 20 ml/min. The concentration–time profiles are shownrelativeto aproposed target concentration of 2–3 mg/L. This dosage is anticipated to bean overdose on the basis of a suggested initial dose of 750 mg/d for patients with an GFR of 30 ml/min (42). Each regimen achieves steady-state concentrations within 70 hours and the same average plasma concentration, but more frequent dosing is associated with less variability in plasma concentration (the difference between Cmax and the minimum plasma concentration). therefore, be possible to optimize drug therapy in this exists, present even in apparently homogenous patient vulnerable patient population, utilizing this knowl- populations. This is further complicated in a cohort of edge both at the bedside and when designing research patients with CKD, which incorporates a heterogeneous projects. mix of etiologies. So, although the methods described below appear somewhat precise, there are substantial and Rational Design of Dosing Regimens unpredictable errors within the calculations that warrant General Principles close monitoring. Fortunately, many of the drugs currently fi The important principles to consider include the thera- used have a good safety pro le, and therapeutic drug peutic target, the initial dose, the maintenance dose, the monitoring (TDM) is (or should be) performed for drugs dose frequency, and when a dosage adjustment should be requiring more precision. performed. The key changes in pharmacokinetics that occur in a patient with kidney disease have been discussed Defining the Therapeutic Target elsewhere (2). Prescribing a dose that maximizes benefits and mini- These principles require the prescriber to obtain pub- mizes risks is the goal of rational drug dosing. Serum drug lished pharmacokinetic data from patient populations with concentration targets are derived from concentration– similar causes of kidney disease, its severity, and manifes- efficacy and/or concentration– relationships and tations, to the patient receiving treatment. Appropriate may reflect a therapeutic target or the avoidance of drug data are often difficult to ascertain, and assumptions are accumulation and adverse events (Figure 1). The specific commonly required to assess their clinical applicabil- therapeutic target (optimal plasma concentration range) ity. Furthermore, interpatient pharmacokinetic variability depends on the drug being prescribed, and sometimes on

Figure 2. | A decreases the time to achieve the target concentration. When the plasma t1/2 is prolonged (for example, because of kidney disease), the time to reach steady state or the target concentration increases proportionally. Administration of a loading dose reduces the time to achieve the therapeutic plasma concentration, and in this simulation the loading dose is double the maintenance dose. Clin J Am Soc Nephrol 13: ccc–ccc, August, 2018 Pharmacokinetics and Drug Dosing: Applications, Roberts et al. 3

t Figure 3. | An increase in a drug’s 1/2 prolongs the time to achieve steady-state plasma concentrations with maintenance dosing. The effect of the same dose given to three simulated patients with CKD. The increasing elimination t1/2 are because of decreasing endogenous clearance, which is noted with increasing severity of CKD. Increasing the t1/2 delays the time to steady-state plasma concentrations and results in higher # plasma concentrations. Failure to reduce the dose or frequency in patients with the longer t1/2 may predispose to adverse drug reactions. indicates the time when steady-state conditions are achieved for the respective profile. These conditions are present when the concentration–time profile plateaus, for example, when the Cmax (maximum plasma concentrations) are no longer increasing. the indication and individual being treated and the inten- circumstances where no other pharmacokinetic parameters ded duration of therapy. In many instances, it is possible to are changed, a reduction in drug clearance by the kidney measure not only the pharmacokinetic outcomes but also does not alter the loading dose given. The loading dose is the desired therapeutic outcomes in both the short- and proportional to the Vd and is calculated by rearranging the long-term. For example, changes to an antidiabetic regimen equation for determining maximum plasma concentration can be readily measured by monitoring plasma glucose (Cmax) from part 1 (2) (where LD is loading dose and F is concentration, as well as a long-term assessment of the effect ), on hemoglobin A1c. À Á Some drugs, such as anti-infectives, immunosuppres- target concentration mg= 3 Vd ðLÞ LD ðmgÞ 5 L : sants, and , are prescribed to maximize the F effect of the initial dose, although the full therapeutic (Equation 1) benefit may not be observed for days, weeks, or even months. Antibiotics also need to target a concentration– Maintenance Dose. For drugs administered as multiple time profile related to the markers of bacterial susceptibil- doses, the maintenance dose depends on clearance (where ity, such as the minimum inhibitory concentration. For MD is maintenance dose): other drugs, a reasonable starting point is to prescribe a dosage regimen that will target the mean or median drug MD ðmg=hÞ 5 clearanceðL=hÞ 3 target concentration ðmg=LÞ: concentration that was demonstrated to be effective in (Equation 2) clinical trials. These and other examples are discussed in more detail in part 1 of this series (2). A potential complexity with Equation 2 is determining drug clearance in an individual patient at the time of prescribing, Equations which is discussed in part 1 (2) and below for each patient group. Pharmacokinetics is a quantitative science, meaning that This maintenance dose is directly applied to continuous each parameter can be measured. These data can be intravenous infusions. For intermittent dosing, the main- incorporated into relatively simple equations to tenance dose to be administered over the desired dosing determine a dosing regimen. interval is Loading Dose. A loading dose is a deliberately larger initial dose given to a patient to rapidly attain a target MD ðmg=doseÞ 5 MD ðmg=hÞ 3 dosing interval ðh=doseÞ: concentration (Figure 2). This may be used in cases when (Equation 3) there is an expanded apparent volume of distribution (Vd) (for example, sepsis or nephrotic syndrome) or where a A decrease in drug clearance with kidney disease prompts a delayed may be detrimental (for example, decrease in either the maintenance dose or an increase in the waiting until steady-state plasma concentrations are dosing interval (Equations 2 and 3). The dosing frequency fi achieved with long t1/2 drugs), as discussed in part 1 of depends on the toxicity pro le of the drug. For example, a this series (2) and reiterated in Figure 2. Because the aim of relatively long dosing interval will require a relatively high the loading dose is to achieve a target serum concentration Cmax to maintain an acceptable mean drug concentration after the first dose, changes in drug clearance do not (Figure 1). Therefore, in most instances, a reduction in dose influence the loading dose given (Equation 1). Therefore, in rather than an increase in the dosing interval is appropriate, 4 Clinical Journal of the American Society of Nephrology

Table 1. Biochemical and clinical markers of a potentially clinically significant decrease in drug clearance by the kidney

Minimum criteria that indicate the potential for impaired kidney function as proposed by the Extracorporeal Treatments in Poisoning (EXTRIP) group

eGFR,45 ml/min per 1.73 m2 Stage 2 or 3 AKI In adults without a baseline plasma creatinine, plasma creatinine .2 mg/dl (176 mmol/L) in adults or .1.5 mg/dl (132 mmol/L) in the elderly or those with low muscle mass Plasma creatinine greater than two times the upper limit of normal for age and weight in children without a baseline plasma creatinine concentration The presence of oligoanuria

with the uncommon exception of drugs where high peak clear how applicable these data are to other patients, so serum concentrations are beneficial, such as ciprofloxacin. increased monitoring is required. The complexities of As the decrease in clearance also prolongs the elimina- interpreting changes in area under the concentration– tion t1/2 (Equation 4 from part 1 [2]), the time until time curve and Cmax with regards to reduced clearance – achieving steady state (achieved after 3 5 t1/2) is delayed or increased bioavailability are discussed in part 1 of this compared with patients with normal kidney function series (2). (Figure 3). An expansion in Vd is reported with advanced CKD because of subsequent fluid retention, , and decreased protein binding. However, Vd may also Design of Dosing Regimens in Patients with Kidney decrease in the context of sarcopenia, which is more Disease Kidney disease encompasses a heterogeneous range of conditions of differing severity, but also differing effects on the kidney vasculature, glomeruli, and tubulointerstitium. Each condition and corresponding treatment(s) have the potential to exert different effects on a drug’spharmaco- kinetics. Criteria that indicate the potential for a clinically signif- icant decrease in kidney function due to either AKI or CKD were proposed by the Extracorporeal Treatments in Poi- soning (known as EXTRIP) group (see Table 1). These criteria were proposed to aid bedside decision-making for the treatment of poisonings, such as (7), methanol (8), and metformin (9), but the underlying considerations are similar to those for therapeutic drug dosing. It is important to note that these criteria have not been vali- dated.

CKD CKD is a progressive decline in GFR such that kidney function is reasonably stable over weeks or months. Drug absorption from the gastrointestinal tract may be highly variable in patients with CKD. Although it is commonly Figure 4. | Dose adjustments in patients with CKD are based on the thought that absorption decreases in edematous states change in the concentration-time profile for the drug of interest. because of gut wall edema, animal and human studies Compared with patients with no kidney disease, those with advanced indicate that drug absorption may actually increase be- CKD receiving oral (upper panel; substrate of CYP2D6 cause of impairment of the gut wall barrier function or a and CYP3A4) showed a decrease in clearance and an increase in the decrease in function and/or expression of efflux trans- mean area under the concentration–time curve and Cmax of 70% and porters, such as P-glycoprotein (10). Furthermore, for drugs 29%. To achieve concentrations similar to those in patients without with a low bioavailability because of hepatic first-pass kidneydisease,thedosingintervalshouldbeprolongedbutthedosedoes , the decrease in cytochrome-P (CYP) 450 not need to be changed. In contrast, for oral (lower panel; and transporter activity (see part 1 [2]) may substrate of CYP3A4, CYP2C8, and organic anion transporting poly- peptide OATP1B1, in patients with advanced CKD the mean area under increase bioavailability. For example, significant increases – the concentration–time curve and Cmax increase 232% and 82% in both the area under the concentration time curve and compared with patients with no kidney disease. Here, to achieve plasma Cmax have been demonstrated for both dihydrocodeine concentrations similar to those in patients without kidney disease, both and repaglinide in patients with advanced CKD (Figure 4) the dosing interval should be prolonged and a lower dose should be (11,12). It is important to be cognizant of this phenomenon prescribed. Figure panels are approximate representations of data when prescribing these and other drugs. However, it is not published by Barnes et al. (11) and Marbury et al. (12). Clin J Am Soc Nephrol 13: ccc–ccc, August, 2018 Pharmacokinetics and Drug Dosing: Applications, Roberts et al. 5

Table 2. AKI, CKD, and from kidney replacement therapy have differing effects on pharmacokinetics

Pharmacokinetic Parameter AKI CKD Kidney Replacement Therapy

Absorption Poorly quantified, may Poorly quantified, may increase Limited effect decrease or decrease Volume of distribution No change or increase No change or increase No change or decrease Metabolism Poorly quantified, Decreased clearance by several May increase post-KRT compared clearance by CYPs observed with pre-KRT, but the duration and CYP3A4/5 may extent of the change is poorly decrease quantified Kidney: decreased, Kidney: decreased, relatively Kidney: no change rapidly changing stable Nonkidney: unknown Nonkidney: poorly quantified, Nonkidney: uncertain possibly decreased Elimination Increased because of drug removal by KRT the extent depends on properties of both the drug, the KRT regimen and its duration

CYP, cytochrome-P 450 enzyme.

common with advanced CKD. Overall, the change in Vd different GFRs, kidney diseases, or other drugs, but the from interdialytic weight gain is low relative to total body general principles are summarized in Tables 2 and 3. water and is not clinically significant. The effect of severe edema on Vd is inconsistent, with studies finding that Vd AKI could either double (13) or remain unchanged (14) in the AKI commonly occurs in critically ill patients. Here, setting of marked extracellular fluid expansion. Fluid dosage adjustments are complicated because of multiple overload is more likely to affect the Vd of hydrophilic marked and dynamic changes in , including drugs (for example, aminoglycoside, b-lactam, and glyco- organ dysfunction and volume status. Subsequently, drug peptide antibiotics) compared with lipophilic drugs, but concentrations can either increase or decrease if the dose is these rules are not always applicable. not properly adjusted. For example, AKI is a common The decrease in GFR with CKD decreases kidney drug consequence of bacterial sepsis and a substantial propor- clearance. A practical approach to adjusting drug doses in tion of critically ill patients receive inadequate CKD is to assume that kidney drug clearance will decrease concentrations within the critical first 48 hours of treatment in proportion to GFR, and that nonkidney clearance is (18,19). Although some drugs used for chronic conditions unchanged (see Figure 2 in part 1 [2]). However, this can be withheld in the context of AKI (20), others such as otherwise convenient approach is limited by changes to anticoagulants, immunosuppressants, antihyperglycemics, nonkidney clearance that occur with kidney disease and and analgesics are often continued. In each case, dosage are difficult to quantify at the individual level (2). It also adjustment is required to limit the risk of adverse effects ignores the role of intact kidney tubules in the handling of without compromising efficacy. many drugs and that tubular elimination likely increases The Vd often increases in AKI; for example, in critically ill relative to glomerular clearance in some types of kidney patients with sepsis and AKI, antibiotic Vd varies ten-fold disease. For example, kidney clearance is 25% lower in or more (21). This occurs because of intravenous fluid patients with CKD involving tubular dysfunction relative loading during resuscitation, vasoplegia, and capillary leak to those with isolated GN (15). causing edema, pleural effusions, or ascites, as well as In patients with GN, proteinuria, and hypoalbuminemia changes in protein binding (22). but creatinine clearance (CrCL) .90 ml/min, apparent The RIFLE (Risk, Injury, Failure, Loss, ESKD) and AKIN clearance of (substrate of P-glycoprotein and (AKI Network) criteria categorize AKI severity on the basis other transporters) is decreased 40% compared with of the increase in plasma creatinine concentration or healthy controls with a comparable GFR (16). Further, decrease in output, but they do not quantify GFR. the elimination t1/2 of fexofenadine is prolonged in patients Changes in creatinine lag behind those of GFR (23), and with GN compared with patients with ESKD and healthy intravenous fluids and dialysis temporarily decrease the controls, suggesting an increased Vd with GN (16). Yet, plasma creatinine concentration, understating the severity flurbiprofen (CYP2C9 substrate) had similar pharmacoki- of AKI. Alternatives methods to quantitate changes in netics in patients with GN and CrCL.90 ml/min as in kidney function in AKI include an abbreviated CrCL in patients with ESKD. clearance is increased patients without anuria over 2–12 hours (24), or measuring three-fold in patients with FSGS and nephrotic-range GFR using an exogenous compound; however, these only proteinuria despite normal eGFR, compared with healthy determine kidney function at a single time point. The rate controls (17). Therefore, it is not possible to generalize these of increase in creatinine plasma concentration is a further findings of altered pharmacokinetics to patients with alternative (25,26), but is uncommonly used. 6 Clinical Journal of the American Society of Nephrology

Table 3. AKI, CKD, and kidney replacement therapy have differing effects on drug dosing

Dosage AKIa CKDa Kidney Replacement Therapy Component

Initial dose Potential changes to oral Potential changes to oral Rarely requiredin addition to thosefor and need for a bioavailability are bypassed bioavailability are bypassed with AKI or CKD, which are the loading dose, with intravenous intravenous administration. indications for KRT. see Equation 1 administration. A loading dose may be required A loading dose may be required in in patients with sepsis and some patients, but clinical marked fluid overload, indicators are poorly defined. particularly for hydrophilic Consider for hydrophilic drugs that drugs that require a rapid require a rapid onset of effect, such onset of effect, such as as antibiotics. antibiotics. Decreased clearance prolongs Decreased clearance prolongs the time the time to achieve steady- to achieve steady-state state concentrations, which concentrations, which may prompt may prompt a loading dose. a loading dose. Maintenance Kidney excretion decreases by Kidney excretion decreases by $50%b: Intermittent hemodialysis is efficient dosage, see $50%b: decrease amount or decrease amount or frequency of but usuallyof short duration. Ithas a Equations 2 frequency of dose dose proportionally. minimal effect when the drug is and 3 proportionally. Dose- administered after the treatment. adjustments are required frequently in response to changes in GFR. Kidney excretion decreases by Kidney excretion decreases by ,50%b: Continuous KRT often requires an ,50%b: no change. no change. increase in maintenance dosing. However, the extent of change varies markedly depending on the drug, KRT regimen, and endogenous clearance. Limited data regarding dose- Reductions may be required for drugs Peritoneal dialysis has minimal adjustment for drugs with predominantly secreted in the additional effects on chronic drug predominantly nonkidney proximal tubule in patients with therapy. excretion. kidney tubulointerstitial disease, regardless of GFR. Therapeutic drug monitoring Dosage reductions may be required Therapeutic drug monitoring can can assist dosage adjustment. for drugs that undergo assist dosage adjustment. predominantly nonkidney clearance when GFR,60 ml/min, but data are limited or contradictory. Therapeutic drug monitoring can assist dosage adjustment.

aA 50% decrease in GFR is chosen because this decrease has the potential to be clinically significant in most instances. bTo estimate the decrease in kidney excretion for a drug at a point in time, multiply the decrease in GFR by the proportion that is eliminated by the kidney. For example, for a drug that is 50% eliminated by the kidney, GFR would need to be around 1 ml/min for there to be a 50% net decrease in kidney drug clearance.

AKI decreases kidney drug clearance, which prompts a There are limited data about the effect of AKI on reduction in the maintenance dose (Equations 2 and 3). nonkidney clearance, but the clearance of Unfortunately, the principles discussed for CKD cannot be (CYP3A4/5 substrate) is noted to decrease in AKI, sug- readily applied to AKI because drug clearance (and gesting that CYP450 and other nonkidney processes may distribution) vary widely in short time frames (over hours also be impaired (29,30). Changes in bowel, hepatic, and or days) and it is difficult to practically quantify GFR kidney perfusion with critical illness may also alter drug (21,22). Wide interpatient pharmacokinetic variability also absorption and disposition. means that extrapolation from other studies is not always Ultimately, the high interpatient variability in pharma- possible. For example, in patients with sepsis treated with cokinetics with AKI is a significant challenge and compli- moxifloxacin, the mean clearance and Vd were similar to cates attempts to provide a generic approach to drug healthy patients, but interpatient variability in clearance dosing. Because an increase in Vd is commonly noted, the (up to 60%) and Vd (30%) was greater in patients with initial dose should be increased if a prompt response is sepsis (27). Furthermore, changes in the clearance of desired, particularly for hydrophilic antibiotics (e.g., pen- b-lactam antibiotics correlate poorly with fluctuations in icillins). These principles are summarized in Tables 2 and 3. CrCL (28). Thus, TDM is the best way to ensure the More research is required to guide repeat dosing, especially attainment of pharmacokinetic targets in AKI. for drugs that are subject to nonkidney clearance or those Clin J Am Soc Nephrol 13: ccc–ccc, August, 2018 Pharmacokinetics and Drug Dosing: Applications, Roberts et al. 7

Table 4. Important parameters that increase drug clearance with different kidney replacement therapies (31)

Diffusive therapies (e.g., HD) Convective therapies (e.g., HF)

Small solutes, e.g., lithium High Qb High Qb and Quf High Qd (ratio Qd:Qb .2.5) Postfilter volume replacement High-efficiency filter diffusion High SA filter preferred over convection

Medium-sized solutes, e.g., High Qb High Qb and Quf High flux filter Postfilter volume replacement High SA filter High flux filter High SA filter Convection preferred over diffusion Highly protein bound drugs, e.g., sodium High Qd High flux filter (low clearance is anticipated) High SA filter High SA filter Clearance possibly increased by prefilter volume replacement so convection may be preferred over diffusion

HD, hemodialysis; HF, hemofiltration; Qb, flow rate; Quf, ultrafiltration rate; Qd, dialysate flow rate; SA, surface area.

with a narrow , for which TDM is hemodialysis, where a large dose can be administered particularly useful. immediately before dialysis to optimize the concentration– time profile (Figure 5). Intermittent Hemodialysis Drug clearance by kidney replacement therapies is addi- Continuous KRT and Hybrid Techniques tive to endogenous clearance (see Equation 2 in part 1 [2]), so Similar principles as outlined for intermittent hemodi- it should be accounted for in determining the appropriate alysis can be applied to continuous KRT, noting that dosing regimen. Unfortunately, a complexity with doing so is continuous KRT is applied for a longer duration. Un- that data concerning the effect of dialysis on drug clearance is fortunately, there are minimal data regarding drug clear- often highly variable or simply not available. Limitations ance during continuous KRT and much of it is limited to relate to advances in dialysis technology (data published antibiotics. It is apparent (and predicted) that drug clear- decades ago are of questionable present-day relevance), the ance by continuous KRT is less efficient than intermittent use of inadequate pharmacokinetic methods, or differences in hemodialysis. However, the prolonged duration of contin- the dialysis regimen used between published studies and local uous KRT means that it is more likely to remove a practice (blood and dialysate flow, filter size and type, etc.; significant amount of the drug over the course of treatment. Table 4) (31). In some cases, it may be possible to estimate Reported continuous KRT clearances are quite variable drug clearance on the basis of the clearance of endogenous given the heterogeneity of continuous KRT prescribing , such as urea (a small ) or b2-microglobulin (blood, dialysate, and ultrafiltration rates; Table 4) and (a medium-sized molecule) from experimental studies. techniques used. This complicates the prediction of phar- Fortunately, it is possible to manage the effect of in- macokinetics and individual drug dosing. termittent hemodialysis on the drug regimen by adminis- Depending on the technique used, the clearance rate of tering drugs relative to the timing of hemodialysis. small water-soluble drugs with minimal protein binding by Although high clearances are reported (even exceeding continuous KRT is approximately 20%–30% of that from 200 ml/min, which far exceeds endogenous clearance of intermittent modalities. Small-molecule clearance by contin- many drugs eliminated by the kidney), hemodialysis is of a uous KRT appears to most strongly correlate with the effluent relatively short duration. Therefore, the practical approach flow rate (32), which is the sum of dialysis fluid, replacement is to administer drugs that are cleared during dialysis after fluid, and net ultrafiltration rates (see Table 4). Changes in the dialysis treatment and to tolerate low concentrations blood flow rates affect drug and solute clearance in convec- during dialysis. If subtherapeutic concentrations during tive continuous KRT to a greater extent than in diffusive dialysis are not tolerated, then a small additional dose therapies (33) (Table 4). The effect of hybrid techniques (e.g., (calculated using Equation 1) can be given midway through sustained low-efficiency dialysis or prolonged intermittent dialysis. However, for patients where dialysis is removing KRT) on pharmacokinetics is even less defined. uremic toxins that interfere with nonkidney clearance (see It is, therefore, difficult to make precise recommenda- discussion in part 1 of this series [2]), there may be an tions for the prescribing of most drugs during continuous increase in drug clearance soon after dialysis that is KRT. Given that continuous KRT is generally prescribed to nonsustained during the interdialytic period. These prin- patients with AKI for which pharmacokinetic data are ciples are summarized in Tables 2 and 3. already uncertain, continuous KRT compounds the vari- One possible exception to this approach is the prescribing ability in drug clearance. Whether continuous KRT signif- of aminoglycosides to patients with ESKD on intermittent icantly increases the total clearance also depends on the 8 Clinical Journal of the American Society of Nephrology

Figure 5. | The timing of administration affects the concentration-time profile in patients using hemodialysis. Simulation on the basisofa30-minuteintravenousinfusionof200or80mggentamicin,usingmedianvaluesfromSowinskietal.(43)includingVdof13.5L,endogenous elimination t1/2 of 39.4hours,andeliminationt1/2 duringhemodialysis(HDx) of 1.6hours.Administration prehemodialysismaximizestheCmax:MIC ratio(ratioofCmaxtotheminimuminhibitoryconcentrationofthebacteria;seepart1[2])anddecreasestheoverallexposure.Thisdemonstratesthata large dose can be administered immediately predialysis to take advantage of the concentration-dependent killing and postantibiotic effect of this antibiotic class. This maximizes the antibiotic concentration–time profile and drug effect, and the clearance achieved by dialysis allows for the aminoglycoside to be rapidly cleared to a less toxic concentration. Other antibiotics that also have a concentration-dependent killing and therefore may also benefit from a large dose immediately before dialysis are (44) and the fluoroquinolones (45,46). pharmacokinetics of the drugs of interest. For example, in where dosing is guided by plasma concentration monitoring patients with AKI receiving continuous hemodiafiltration, (37). Therefore, comparing outcomes solely on the basis of the continuous KRT was more likely to significantly contribute type of antibiotic (38), without considering dosing regimen, to total clearance for vancomycin and , but may be suboptimal. less likely for ciprofloxacin and (21). Given the lack of certainty, TDM remains the only reliable method of TDM fi con rmingattainmentoftargetconcentrationsinthis The risk of sub- or supratherapeutic drug concentrations setting. in clinical practice prompts the use of methods that confirm that the desired drug concentrations are achieved, such as Peritoneal Dialysis TDM. Here, drug concentrations are measured in the Similar principles as those outlined for continuous KRT patient and if the concentration is outside the desired apply to peritoneal dialysis (PD). Although there are therapeutic range, the dosing regimen is adjusted accord- different techniques with differing clearances and there ingly. Dosage adjustments may be iterative, but modifica- are minimal data regarding drug clearance during PD, its tions can be improved with the above-discussed methods overall additional effect on total clearance is probably low. or computer-based approaches, including those using An important consideration is antibiotic dosing for PD- Bayesian methodology (39). TDM-based approaches over- associated peritonitis, for which dosing recommendations are come interindividual variation in pharmacokinetics and commonly made on the basis of uncontrolled observational guide the delivery of individualized drug therapy. This studies using multiple antibiotics and without TDM (34). tailored approach has advantages because much of the Further, some pharmacokinetic studies of intraperitoneal (IP) previously mentioned data were on the basis of population antibiotics were reported in patients without PD-associated mean or median results, yet interindividual variability in peritonitis and did not report IP antibiotic concentrations or results was often significant, particularly in critically ill the effect of antibiotic-free PD exchanges. Therefore, it is not patients. clear whether regimens made on the basis of these data TDM should be performed routinely for anti-infectives achieve optimal antibiotic concentrations. because the concentration is the key determinant of their For example, until recently either cefalothin or effect (see part 1 of this series [2]). TDM is now an accepted were the recommended first-line empirical antibiotics and standard of care and a key indicator for the appropriateness were dosed identically (35), but it is now known that of antibiotic use and stewardship (40). cefalothin is undetectable in IP fluid and plasma for at least A complexity with TDM is ensuring that the appropriate 12 hours with once daily IP administration (36). This is plasma sample(s) are collected at the correct time. A because .30% of cefalothin clearance is by nonkidney limitation of TDM for many drugs is the slow turnaround metabolism, whereas cefazolin is predominantly cleared by time of assay results, such that drug concentrations are not the kidney. This is in contrast to vancomycin and gentamicin, available in a clinically useful time frame. Regardless, it is a Clin J Am Soc Nephrol 13: ccc–ccc, August, 2018 Pharmacokinetics and Drug Dosing: Applications, Roberts et al. 9

superior method of dosage adjustment and is also useful in including the effect of KRT, to inform drug dosing. The research when exploring the dose-response relationship, collection of this data are within the reach of most clinicians particularly in the setting of altered physiology. and hospital departments.

Acknowledgments Future Research Directions D.M.R. is a recipient of the Jacquot Research Establishment There are limited data to guide the prescribing of drugs Fellowship, Royal Australasian College of Physicians and the Cli- in kidney impairment and widely used dosing recommen- nician “Buy-Out” Program, St. Vincent’s Centre for Applied Medical dations are often made on the basis of outdated data and/ Research. or theoretical extrapolation. Despite concerns regarding the effect of sub- and supra- Disclosures therapeutic drug concentrations, TDM and Bayesian-style None. computer-based dosing are not currently performed rou- tinely for most drugs administered to patients receiving References KRT. Furthermore, physiologically-based pharmacokinetic 1. Corsonello A,Pedone C,LattanzioF,OnderG,AntonelliIncalziR; modeling is an approach that is increasingly used to predict Gruppo Italiano di Farmacovigilanza nell’Anziano (GIFA): As- the effect of changes in kidney function on pharmacoki- sociation between glomerular filtration rate and adverse drug netics and to guide rational drug dosing. Data obtained reactions in elderly hospitalized patients: The role of the esti- from routine TDM may help inform appropriate drug mating equation. Drugs Aging 28: 379–390, 2011 2. Lea-Henry TN, Carland JE, Stocker SL, Sevastos J, Roberts DM: dosing in this understudied patient population. The lack of Clinical pharmacokinetics in kidney disease (part 1): Funda- data for some drugs in some circumstances is so extreme mental principles. Clin J Am Soc Nephrol 13: 1085–1095, 2018 that even a single case report, with proper sample collec- 3. 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