Clinical Pharmacokinetics in Kidney Disease PDF

Nephropharmacology for the Clinician Clinical Pharmacokinetics in Kidney Disease Fundamental Principles Tom N. Lea-Henry,1,2 Jane E. Carland,3,4 Sophie L. Stocker,3,4 Jacob Sevastos,4,5 and Darren M. Roberts 2,3,6 Abstract Kidney disease is an increasingly common comorbidity that alters the pharmacokinetics of many drugs. Prescribing 1 to patients with kidney disease requires knowledge about the drug, the extent of the patient’s altered physiology, Nephrology and Transplantation Unit, and pharmacokinetic principles that influence the design of dosing regimens. There are multiple physiologic John Hunter Hospital, effects of impaired kidney function, and the extent to which they occur in an individual at any given time can be Newcastle, New South difficult to define. Although some guidelines are available for dosing in kidney disease, they may be on the basis of Wales, Australia; 3 limited data or not widely applicable, and therefore, an understanding of pharmacokinetic principles and how to Departments apply them is important to the practicing clinician. Whether kidney disease is acute or chronic, drug clearance of Clinical Pharmacology decreases, and the volume of distribution may remain the same or increase. Although in CKD, these changes and Toxicology and progress relatively slowly, they are dynamic in AKI, and recovery is possible depending on the etiology and 5 Nephrology and treatments. This, and the use of kidney replacement therapies further complicate attempts to quantify drug Renal Transplantation, clearance at the time of prescribing and dosing in AKI. The required change in the dosing regimen can be estimated St. Vincent’s Hospital, Darlinghurst, or even quantitated in certain instances through the application of pharmacokinetic principles to guide rational New South Wales, drug dosing. This offers an opportunity to provide personalized medical care and minimizes adverse drug Australia; events from either under- or overdosing. We discuss the principles of pharmacokinetics that are fundamental for 4 Department of the design of an appropriate dosing regimen in this review. Medicine, St. Vincent’s Clinical Clin J Am Soc Nephrol 13: 1085–1095, 2018. doi: https://doi.org/10.2215/CJN.00340118 School, St. Vincent’s Hospital, University of New South Wales, Introduction only 57% of new drug applications to the Food and Sydney, New South Drugs are an important and frequently used treatment Wales, Australia; Drug Administration (FDA) examined pharmacoki- 2 Department of Renal for patients with kidney disease. Knowledge of basic netics in kidney impairment, and only 44% of those Medicine, The pharmacokinetic principles is important for all pre- with data in kidney impairment evaluated patients on Canberra Hospital, scribers, but it is particularly important for nephrol- hemodialysis (1). This reﬂects the FDA policy that Woden, Australian ogists and other physicians who routinely see patients manufacturers are not required to determine the effect Capital Territory, Australia; and with organ dysfunction that affects drug handling. of kidney disease on drug dosing (2). 6 Medical School, Prescribing to patients with kidney disease is In many cases, it is reasonable to simply prescribe Australian National complicated, because kidney disease has multiple the dose recommended by the manufacturer, partic- University, Acton, effects on pharmacokinetics, and these effects are ularly if the drug has a wide therapeutic index, the Australian Capital Territory, Australia dependent on both the drug and the clinical context. duration of therapy is short, the dose is low (e.g., For example, kidney disease may be chronic (slowly prophylaxis dosing), and/or there is the ability to titrate Correspondence: progressive over months or years) or acute (rapidly the dose on the basis of clinical and laboratory pro- Dr. Darren M. Roberts, evolving), and each scenario requires a different ap- gression. Other dosing guidance is available through Department of Clinical proach to drug dosing. Understanding how changes to textbooks, online references, and local procedures for Pharmacology and physiology affect the pharmacokinetics of a given drug many drugs but not all, and there may be signiﬁcant Toxicology, St. Vincent’s Hospital, is essential to rational drug use and the optimization of differences in the suggested change in dose between Victoria Street, treatment regimens. different resources (3). Unfortunately, limited data or Darlinghurst, NSW Failure to properly account for the effect of kidney other safety concerns may simply lead the manufacturer 2010, Australia. Email: disease when designing appropriate drug-dosing to declare that the drug is contraindicated in patients darren.roberts@svha. regimens can predispose an individual to treatment with advanced kidney disease, which can deprive org.au failure or adverse drug events. Guidelines for adjust- patients with kidney disease of important drug options. ment of the dosing regimen in varying stages of CKD In recent years, the application of pharmacokinetic are provided by the manufacturer. principles to drugs in the postmarketing phase has Furthermore, dose recommendations in the setting raised the prospect of using drugs that were pre- of kidney disease are frequently on the basis of limited viously considered contraindicated in patients with data, and they may not adequately account for in- eGFR,30 ml/min per 1.73 m2, including metformin terindividual variability or acute changes, such as (4) and novel-acting oral anticoagulants (NOACs) during AKI. For example, between 2002 and 2007, or direct-acting oral anticoagulants (DOACs; for www.cjasn.org Vol 13 July, 2018 Copyright © 2018 by the American Society of Nephrology 1085 1086 Clinical Journal of the American Society of Nephrology example, apixaban) (5). There may also be circumstances Reasons to Optimize Dosing Regimens when additional adjustments to the dosing regimen may be Either sub- or supratherapeutic dosing can occur when required in a patient (for example, a change in clearance due appropriate dose adjustments are not made in patients with to a coprescribed drug that induces or inhibits elimination kidney disease, and both have negative effects on patient pathways of the index drug). outcomes, including morbidity, prolonged hospital admis- Therefore, it is necessary to have a rational approach sions, and potentially, death. Subtherapeutic dosing increases to prescribing in patients with kidney disease. This the risk of treatment failure, which may be life threatening requires knowledge about pharmacokinetic princi- (e.g., anti-infectives) or organ threatening (e.g., immuno- ples, properties of the drug, and how the drug will be suppressive drugs). The risk of supratherapeutic exposure handled by an individual patient. The purpose of this from drugs (or their active or toxic metabolites) that rely on review is to provide an overview of pharmacokinetic kidney elimination is ampliﬁed when the drug has a narrow principles that affect the design of a dosing regimen therapeutic index, such as digoxin or lithium. In many cases, and provide the basis for discussions regarding the accumulation develops over weeks, and the onset of drug delivery of personalized medicine to those with kidney toxicity is insidious. These principles are reﬂected in the disease. examples below. Relationship between Dosing Regimen and the Effect Selected Examples of Drugs That Require Special of a Drug Consideration When Prescribing to Patients with An individual’s response to a drug is determined by both Kidney Disease the pharmacokinetics and pharmacodynamics of that drug. Antibiotics Pharmacodynamics is concerned with the effect of the drug The efﬁcacy of antibiotics depends on their concentration on the body, including interactions between the drug, its relative to the minimum inhibitory concentration (MIC) of target, and downstream biochemical effects. Pharmacoki- the culprit bacteria. Three pharmacokinetic-pharmacodynamic netics describes the effect of the body on a drug and reﬂects targets describe features of the concentration-time proﬁle that the physiologic processes of absorption, distribution, me- maximize antibiotic efﬁcacy. tabolism, and excretion. Each of these processes may be altered in patients with kidney disease and affect thera- (1) The ratio of maximum free drug plasma concentration to peutic outcomes. MIC (concentration dependent; e.g., aminoglycosides) The concentration-time proﬁle of a drug reﬂects the net (2) The ratio of the AUC to MIC (AUC:MIC; e.g., vanco- effects of these pharmacokinetic processes after drug mycin) administration (Figure 1). The concentration-time proﬁle (3) The proportion of time that the plasma concentration approximates the clinical effect of most drugs, and drug exceeds the MIC (time-dependent killing; e.g., b-lactam exposure relates to the maximum plasma concentration antibiotics) (Cmax) and/or the area under the concentration-time curve (AUC). In general, high drug exposures increase Therefore, the actual target depends on the speciﬁc the risk of adverse drug reactions, and low drug exposures antibiotic and the MIC of the culprit bacteria (6). Plasma are ineffective. concentrations below the target concentration predispose When the changes in pharmacokinetics due to kidney to therapeutic failure and development of multiresistant disease and other conditions are understood, the dosing organisms. Although prescribing higher doses increases the regimen can be adjusted so that the concentration-time likelihood of achieving pharmacokinetic-pharmacodynamic proﬁle is optimized for the individual. targets, it also increases the risk of adverse events, including in drugs considered to have a wide therapeutic index, like b-lactam antibiotics (7). Lithium and Digoxin Lithium excretion depends on kidney function. The most common cause of adverse reactions to lithium is chronic poisoning, which typically occurs in the setting of reduced kidney function as a result of dehydration or dose adjustment with inadequate monitoring (8,9). The resultant neurotoxicity can be severe and persist for days or weeks, and in rare instances, it can be irreversible (9). Similarly, digoxin has a narrow therapeutic index and accumulates when there is impaired kidney function if the dose is not decreased (10). Digoxin poisoning is reasonably common, being associated with prolonged hospital admissions Figure 1. | Plasma concentration-time profile after oral adminis- tration of a single dose. The components relevant to the pharmaco- and high resource utilization, including antidigoxin Fab (11). kinetics of a drug’s concentration-time profile are the peak or maximum Both agents commonly undergo therapeutic drug mon- plasma concentration (Cmax) and the time when it occurs (Tmax), the itoring, and the frequency at which this occurs should be area under the concentration-time curve (represented as shaded area), increased in settings where the drug clearance (CL) is and the elimination t1/2 (determined using the blue lines). signiﬁcant reduced or where this ﬂuctuates, as in AKI. Clin J Am Soc Nephrol 13: 1085–1095, July, 2018 Pharmacokinetics and Drug Dosing—Principles, Lea-Henry et al. 1087 Cyclophosphamide maximize the likelihood that the desired drug concentration- Cyclophosphamide is used to treat various autoimmune time proﬁle is achieved. CL and volume of distribution (Vd) diseases and malignancies, and much of the effect of cyclo- are the primary pharmacokinetic parameters that determine phosphamide occurs through CYP450-mediated forma- the concentration-time proﬁle (drug exposure) and therefore, tion of active metabolites, which are eliminated by the the appropriate dosing regimen (more discussion is in part 2 kidney. Thus, active dose reductions are performed in ). Patients with kidney disease are particularly susceptible patients with impaired kidney function (e.g., plasma creat- to changes in both CL and Vd in both chronic and acute inine concentration.300 mmol/L ) in autoimmune conditions. Half-life (t1/2) is a widely used pharmacokinetic disease and oncology (13) to limit the accumulation of parameter, which depends on both CL and Vd, and therefore, cyclophosphamide and active metabolites (13,14). Cyclo- it is referred to as a secondary parameter (Equation 5). phosphamide bioactivation may increase in patients with GN compared with those with other types of kidney disease, which may prompt different approaches to dose Absolute Bioavailability Absolute bioavailability is the fraction of drug that reaches adjustment (15). Inadequate dose reductions of cyclophos- the systemic circulation after administration, and it is cal- phamide in CKD may contribute to the increased adverse culated by comparing the AUC of an administered dose events and death in patients with systemic vasculitis in the with the AUC achieved after rapid intravenous infusion ﬁrst 12 months of treatment (16). However, studies have (Equation 1). This is most commonly thought of in terms of also highlighted that low-dose cyclophosphamide reduces oral bioavailability, where an orally administered drug’s treatment efﬁcacy in, for example, the treatment of lupus bioavailability depends on the extent of gastrointestinal nephritis (17). Therefore, more research is required to absorption and hepatic ﬁrst-pass elimination: determine how to optimize cyclophosphamide therapy in patients with CKD, which ideally incorporates both phar- F5ðAUCpo 3 Div Þ=ðAUCiv 3 Dpo Þ; (1) macokinetic and pharmacodynamic measures of effect. where F is the absolute bioavailability, AUCpo is the AUC Metformin with oral dosing, AUCiv is the AUC with intravenous Metformin is the ﬁrst-line oral antihyperglycemic drug dosing, Dpo is the oral dose administered, and Div is the for type 2 diabetes mellitus. However, its use was formerly intravenous dose administered. considered to be contraindicated in patients with CKD due The principles can also be used to quantify the effect of to concerns around metformin-associated lactic acidosis. kidney disease on drug exposure. Several processes involved in Metformin-associated lactic acidosis is attributed to met- drug absorption and hepatic metabolism are affected by kidney formin accumulation in the context of impaired kidney disease (Table 1), but the signiﬁcance of these changes for a function, and it is characterized by severe lactic acidosis given drug is not well deﬁned. Indeed, the relative inﬂuence of (18,19). Regardless, preliminary studies have shown that bioavailability and/or CL on a change in the AUC cannot be metformin can be safely prescribed to patients with advanced readily differentiated in many instances. However, if an in- CKD after appropriate dose reduction (4,20), increasing the crease in AUC is mostly due to an increase in bioavailable dose, treatment options for these patients. then the Cmax and AUC would be expected to increase to a similar extent (Equation 2). For example, in Figure 5A, the effect Novel-acting/Direct-acting Oral Anticoagulants of a 50% decrease in CL is that the Cmax increased 20% and the The increasing use of NOACs/DOACs has presented AUC increased 100%, which is consistent with the relationship issues for patients with both acute kidney disease and CKD, shown in Equation 6 rather than an increase in bioavailable and NOACs/DOACs were previously contraindicated in dose (Equation 2). Clinical applications of this in patients with advanced CKD. There is variability in the extent to which CL kidney disease are discussed in part 2 of this series (23). of these drugs depends on kidney function, such that kidney disease has differing effects on drug exposure and the risk of Volume of Distribution (Vd) adverse events. For example, dabigatran pharmacokinetics is Vd is an apparent (theoretical) volume rather than being a largely dependent on kidney CL and P-glycoprotein trans- true entity. It is the parameter relating the concentration of a porters, and very signiﬁcant increases in AUC can occur with drug in the plasma to the total amount of the drug in the progressive decline in kidney function (21), predisposing to body. It is quantiﬁed as liters per kilogram body weight, and adverse events. In comparison, there is less of a decrease in it is mostly determined by the distribution and binding of the the CL of apixaban from advanced kidney disease, and after drug to extravascular tissues compared with plasma pro- studies on the basis of core pharmacokinetic principles, an teins. Vd is also used to estimate the Cmax (Figure 1) after a appropriate dose reduction was determined and tested (5), single dose, and it inﬂuences the loading dose (equation 1 in providing guidance for its use in patients who are dialysis part 2 of this series in ref. 23) and t1/2 (Equation 5). dependent (22). However, data about interindividual vari- After a rapid bolus dose, the Cmax is predicted by ability are still limited for these drugs, and therefore, there Equation 2, where F is bioavailability (F51 after intrave- may be circumstances where therapeutic drug monitoring nous administration; discussed above and in Equation 1): may be beneﬁcial. Dose 3 F C max 5 : (2) Vd Pharmacokinetic Principles and Parameters Quantifying changes in pharmacokinetics allows the Vd is highly dependent on not only body mass but also, dosing regimen to be adjusted with some precision to body composition, notably the absolute and relative 1088 Clinical Journal of the American Society of Nephrology Table 1. Changes in pharmacokinetics in patients with CKD (15,36,46,47) Potential Alteration to Potential Change Anatomic Implications Process Example Drugs This Process in in Kinetics with Location for Dosing CKD CKD Regimen Absorption and bioavailability Passive: Multiple Enterocytes Decrease or Decreased or Increased or concentration- increase increased decreased dependent bioavailability dose absorption Enzymatic See below Enterocytes Decreased Increased Decrease in metabolism bioavailability dose (multiple; in particular, CYP3A4) Active: Calcineurin inhibitors, Enterocytes Decreased Increased Decrease in P-glycoprotein digoxin, bioavailability dose (ABCB1) methotrexate Distribution Passive: Multiple Systemic No change or No change or No change or concentration- increased increased increase in dependent initial dose diffusion Protein binding Multiple Systemic Decrease in Increase in free Potential protein (unbound) increase in concentration fraction, dose and or protein which can either binding increase increase or clearance and decrease in distribution frequency depending on change in Vd relative to CL Active See above Liver, brain, Unknown Decreased No change or transporters elsewhere activity: increase in (P-glycoprotein; increased Vd initial dose ABCB1) Drug Clearance Passive: Multiple, including Glomerulus Decreased Decreased Decrease glomerular methotrexate clearance maintenance ﬁltration dose or frequency of dosing Active: organic b-Lactam antibiotics, Brain, liver, Decreased Decreased Decrease anion methotrexate, kidneys, intestine clearance maintenance transporting atorvastatin, dose or polypeptide imatinib, frequency of rosuvastatin dosing Active: organic Metformin Liver, kidney, Decreased Decreased Decrease cation brain, lung, etc. clearance maintenance transporter dose or frequency of dosing Active: See above Liver, kidney Unknown Decreased Decrease P-glycoprotein (decreased in clearance maintenance (ABCB1) rats) dose or frequency of dosing Enzymatic: S-Warfarin, ﬂuoxetine, Liver Decreased or no Decreased Decrease CYP2C8/9a tamoxifen, glipizide change clearance maintenance dose or frequency of dosing Enzymatic: Citalopram, Liver Decreased or no Decreased Decrease CYP2C19a cyclophosphamide, change clearance maintenance warfarin, diazepam dose or frequency of dosing Clin J Am Soc Nephrol 13: 1085–1095, July, 2018 Pharmacokinetics and Drug Dosing—Principles, Lea-Henry et al. 1089 Table 1. (Continued) Potential Alteration to Potential Change Anatomic Implications Process Example Drugs This Process in in Kinetics with Location for Dosing CKD CKD Regimen Enzymatic: Carvedilol, Liver Decreased Decreased Decrease CYP2D6a metoprolol, clearance maintenance tramadol, dose or tamoxifen, frequency of codeine dosing Enzymatic: Atorvastatin, Liver, enterocytes, Decreased or no Decreased Decrease CYP3A4/5a verapamil, kidneys change clearance maintenance tacrolimus, (CYP3A5) dose or ﬂuconazole, frequency of cyclophosphamide, dosing carbamazepine, tolvaptan Enzymatic: Caffeine, theophylline, Liver Decreased or no Decreased Decrease CYP1Aa warfarin change clearance maintenance dose or frequency of dosing Enzymatic: Cyclophosphamide, Liver, kidney Increased or Increased or Increase or CYP2B6a bupropion, decreased decreased decrease methadone clearance maintenance dose or frequency of dosing Vd, volume of distribution; a The effect of CKD on the expression and activity of some cytochrome P450 isoenzymes is controversial and may instead reﬂect changes in transporter function as discussed in the text. Rowland Yeo et al. (45) found a reduction in cytochrome P450 activity across a range of isoenzymes. However, although some studies have identiﬁed progressive reductions in clearance by individual isoenzymes (for example, CYP2D6 ), others have found no difference in enzyme activity in advanced CKD for CYP3A4/5 (16,46) and CYP2C9 (47–50). Additional studies in human subjects are required to clarify the extent of any effect. amounts of body water and adipose tissue. In the clinical (for example, kidney replacement therapy or metabolism by circumstance where there is an increase in Vd (e.g., severe circulating esterases). The sum of CLH and CLother is nephrotic syndrome), this can require a proportional in- sometimes referred to as nonrenal CL. The relationship crease in the dose to achieve the same Cmax. Conversely, between different routes of CL is shown graphically in Figure changes in drug bioavailability may require a change in the 2, where the anticipated change in total CL is related to GFR. dose, and bioavailability can increase or decrease in kidney Although this is a convenient way to think about changes in disease, which is discussed later and in Table 1. Clinical pharmacokinetics in the setting of kidney dysfunction, it can applications of this are discussed in part 2 of this series (23). be an oversimpliﬁcation for some drugs, because changes in nonrenal drug CL occur at the same time, which is discussed Clearance in detail below and represented in Figure 3. CL is the volume of blood cleared of a drug in a period of Kidney Clearance. The traditional way to determine time usually measured in units of liters per hour or kidney CL is to measure the rate of excretion of the drug in milliliters per minute, and it is the parameter that most urine and changes in the drug plasma concentration at the closely describes drug elimination. CL determines the same time. Kidney CL is the net result of three different maintenance dose rate of a drug required to achieve a processes: ﬁltration at the glomerulus, active secretion in target plasma concentration (and therefore, effect) at the proximal tubule, and passive reabsorption along the steady state. kidney tubules: CL can be referred to by a particular organ (e.g., liver or kidney), a particular metabolic pathway, or the whole CLK 5ðFu 3 GFRÞ 1 CLsecretion 2 CLreabsorption ; (4) body. The total or systemic CL is the sum of the CL by individual organs, which incorporates both active (e.g., where Fu is the fraction of the total drug concentration that metabolism or active secretion) and passive (e.g., glomer- is unbound to plasma proteins (free), CLsecretion is due to ular ﬁltration) processes, as follows: active secretion in the kidney tubules, and CLreabsorption refers to reabsorption from the glomerular ﬁltrate back to CL 5 CLK 1 CLH 1 CLother ; (3) the circulation. Glomerular ﬁltration varies with kidney blood ﬂow, where CLK is kidney clearance, CLH is hepatic clearance, which can decrease when there is a reduced cardiac output and CLother accounts for other routes of drug elimination or volume depletion. However, for some drugs, active 1090 Clinical Journal of the American Society of Nephrology drug-drug interactions may decrease CL due to competi- tive binding and being a saturable process. The clinical implication of this for drugs that are substrates of drug transporters in the kidney is that greater dose reductions are required in patients with kidney tubulopathy compared with those with a similarly reduced GFR due solely to glomerulopathy (24). In the case of glomerulopathy, drug CL may be preserved relative to the reduced GFR by preservation of active tubular secretion of drugs and/or Figure 2. | Changes in total drug clearance with declining kidney metabolites (25,26). This is contrary to the intact nephron function relates to the extent of drug clearance by the kidney. Rep- hypothesis that assumes that drug CL has a linear relation- resentation on the basis of Equation 3 for drugs with three different pharmacokinetic profiles. Here, Drug A is 100% cleared by the kidney, ship to GFR, because reductions in kidney function are and therefore, it is predicted that a 50% decrease in GFR will correlate caused by a reduction in the number of intact (complete) with a 50% decrease in total clearance, prompting a 50% decrease in nephrons. Furthermore, drug transporter activity can be dose or doubling of the dosing interval to maintain the same mean plasma pH dependent (for example, the active secretion of met- concentration. Drugs from many classes can be represented: for ex- formin is reduced when the ﬁltrate in the tubular lumen is ample, antibiotics (A: b-lactams or aminoglycosides, B: macrolides, and alkaline [27,28], which has the potential to decrease kidney C: fluoroquinolones), anticoagulants (A: dabigatran, B: warfarin, and C: CL). This challenges the use of GFR as the sole criterion for rivaroxaban), and b-blockers (A: atenolol, B: metoprolol, and C: biso- estimating kidney CL of drugs. prolol). Unfortunately, this representation is an oversimplification, Finally, some drugs are reabsorbed from the glomerular because it does not consider changes to nonrenal clearance in kidney ﬁltrate in the tubules, and the extent of reabsorption can disease that occur with some drugs as discussed in the text. vary with urine pH and ﬂow (e.g., weak acids, such as salicylate or some herbicides), knowledge of which has secretion is signiﬁcant, and therefore, the kidney CL been used in the treatment of poisoning (29). The effect of exceeds GFR (for example, metformin, meropenem, amox- kidney disease on tubular reabsorption and the implica- ycillin, cefalexin, ampicillin, and piperacillin). The rela- tions on drug dosing are poorly deﬁned. tive contributions of the processes shown in Equation 4 Nonrenal Clearance. There can be an apparent increase are illustrated in Figure 4, and Table 1 summarizes the in nonrenal CL in patients with kidney disease, which more common drug transporters that contribute to this probably reﬂects increased opportunity for elimination by phenomenon. alternative CL mechanisms or possibly, upregulation in Furthermore, as GFR declines, the extent to which total other CL processes. For example, lower proportions of the kidney CL of a drug depends on active secretion can dose of meropenem and piperacillin are eliminated in urine increase. Active transporters are also important, because in patients with CKD compared with that predicted from data in healthy subjects (30,31), which is not consistent with Equation 3 or Figure 2. However, for some drugs, nonrenal CL is decreased in the context of kidney disease, although most of these data are in the setting of CKD rather than AKI. The proposed mechanism for decreased nonrenal CL is inhibition of enzymes and transporters by circulating uremic toxins, which can be reversed (corrected) with their removal by hemodialysis (32). Here, the t1/2 decreases (rectiﬁes) when affected drugs are administered immediately after hemo- dialysis (33). This is supported by in vitro studies (34–36), with some exceptions (37), and therefore, other mecha- nisms may also contribute, such as changes in protein expression (36,38). Of note, inhibition of drug transporters Figure 3. | Drug clearance by metabolism can also decrease with may decrease nonrenal drug CL due to either decreased declining kidney function. Drawn from data presented by Rowland Yeo secretion (e.g., P-glycoprotein, organic anion transporting et al. (45), the analyses are of clearance data in clinical studies after polypeptide, or organic cation transporter) or uptake into correcting for differences in protein binding and blood to plasma par- hepatocytes (e.g., organic anion transporting polypeptide titioning. The drugs were chosen as a probe of different CYP450s (the- or organic cation transporter). The extent to which kidney ophylline for 1A2, rosiglitazone for 2C8, bosentan for 2C9, omeprazole disease decreases the CL of selected drugs that are for 2C19, bufuralol for 2D6, and midazolam for 3A4). Although these substrates of the cytochrome P450 isoenzyme system is data are illustrative, the effect on expression and activity of some cyto- shown in Figure 3 and Table 1, potentially reﬂecting chrome P450 isoenzymes is controversial. For example, some studies have identified progressive reductions in clearance by CYP2D6 (46), changes in both enzyme and transporter activity. whereas others have found no difference in enzyme activity in advanced Another factor to consider when interpreting nonrenal CKD for CYP3A4/5 (16,46) and CYP2C9 (47). Instead, the changes in drug CL data is the decrease in protein binding that occurs metabolic clearances noted in CKD may also relate to changes in in CKD and the limited data describing changes in free expression or function of drug transporters (for example, those on the (unbound compared with total) drug CL. For example, hepatocyte cell membrane). Additional studies in human subjects are research describing the effect of CKD on benzodiazepine required to further clarify the extent of any effect. hepatic CL noted a decrease in CL of the free fraction in Clin J Am Soc Nephrol 13: 1085–1095, July, 2018 Pharmacokinetics and Drug Dosing—Principles, Lea-Henry et al. 1091 Figure 4. | Total kidney clearance is dependent on the contributions of each of glomerular filtration, secretion in the proximal tubule, and reabsorption in the distal tubule. OATP, organic anion transporting polypeptide; OCT, organic cation transporter. 1092 Clinical Journal of the American Society of Nephrology only two of nine studies, whereas in some studies, there organ that has a signiﬁcant role in the total drug CL (for was an increase in CL (32). example, determining kidney function by estimating GFR Despite these complexities, a common method to esti- for a drug that is predominantly cleared by the kidney). mate the change in total drug CL between speciﬁc patient Subsequently, using Equation 3, one can estimate the populations is to quantify the change in the function of the percentage change in drug CL in those with kidney Figure 5. | A change in either volume of distribution or clearance has differing effects on the concentration-time profile. Graphs are drawn to scalefor ready comparison. (A) A doubling involume ofdistribution(Vd) and a halvingofclearance have the same effect onthe elimination t1/2, but they incur substantially different concentration-time profiles. Halving clearance leads to a doubling of the area under the concentration-time curve (Equation 6). The doubling in Vd leads to a reduction in maximum plasma concentration (Equation 2) but no change in the area under the concentration-time curve, despite the change in the concentration-time profile. (B) In patientswith altered kinetics, continuous dosing will lead to drug accumulation if the regimen is not adjusted. Onset of toxicity will occur earlier from a decrease in clearance. (C) In patients with altered kinetics, increasing the dosing interval will prevent drug accumulation. Here, because the t1/2 was doubled in both cases, the dosing interval was also doubled. Although the trough concentrations are similar after the decrease in dosing frequency, the maximum plasma concentration and average concentration are lower when Vd is doubled, which may decrease the effectiveness of this regimen compared with in a patient with normal kinetics. Clin J Am Soc Nephrol 13: 1085–1095, July, 2018 Pharmacokinetics and Drug Dosing—Principles, Lea-Henry et al. 1093 impairment relative to healthy subjects. Drug CL relative Area Under the Curve (AUC) to kidney function can be found in some textbooks and For a given dose, the AUC is proportional to the decrease reviews (for example, ref. 39 for antibiotics). Where in CL. This relationship between AUC and CL is expressed possible, it is preferable to understand how total CL by Equation 6: changes with decreasing kidney function or consider the change in t1/2, because this incorporates both CL and Vd Dose AUC 5 : (6) (Equation 5). Another factor that may limit the precision Clearance with which GFR reliably estimates drug CL includes the Changes in drug CL as the result of kidney disease can, interindividual variability in pharmacokinetics. The clin- therefore, increase the AUC and overall drug exposure for a ical applications of the changes in CL are discussed further given dose, which in turn, increases the risk of adverse drug in part 2 of this series (23). reactions. Numerically, this can be quantiﬁed using the equation AUC2 Elimination t1/2 DAUC 5 ; (7) The elimination t1/2 is the time required for the plasma AUC1 concentration to decrease by 50% (Figure 1). t1/2 is determined where AUC1 is the initial or baseline AUC (e.g., with normal in an individual by measuring the rate of decrease in serial (a kidney function or before an intervention) and AUC2 is the minimum of three where possible) plasma drug concentra- observed AUC after the change (e.g., with kidney disease or tions. Plasma sampling can occur soon after an intravenous after the intervention). For example, a 50% decrease in CL dose or in the case of orally administered drugs, after will double the AUC (DAUC52, 100% increase, or twofold completion of absorption (after Cmax or Tmax) (Figure 1). increase), which is shown graphically in Figure 5A. t1/2 is a major determinant of the duration of action after a single dose, the time required to reach steady-state plasma concentrations (obtained approximately 4–5 t1/2 after drug initiation) with multiple doses, and the dosing When Should the Usual Dosing Regimen Be Adjusted? The minimum change in kidney function that frequency. It is important to recognize that the time to reach necessitates a change in dosing is not well deﬁned. A steady-state concentration will be delayed for drugs with long-standing rule of thumb is that dose adjustment is not relatively prolonged half-lives. required if a pharmacokinetic parameter changes by ,30% t1/2 incorporates both Vd and CL: (42), but this threshold is conservative. An FDA draft 0:693 3 Vd document recommends that detailed pharmacokinetic t1=2 5 : (5) studies should be performed if kidney disease has a “sub- CL stantial effect” on pharmacokinetics (for example, the drug t1/2 is prolonged in proportion to an increase in Vd or a exposure expressed as the AUC [Figure 1], increases by at decrease in CL. For example, the t1/2 will double after least 50%–100%) or less effect if the drug has a narrow either a 50% decrease in CL or doubling of Vd (Figure 5A). therapeutic range compared with in healthy subjects (2). Failure to dose adjust in the case of impaired kidney CL When comparing the same dose, an increase in AUC is will lead to drug accumulation and risk of toxicity (Figure usually proportional to the decrease in CL (Equations 6 and 5B), especially for chronic drug therapy. An example of this 7). Therefore, a decrease in kidney function is unlikely to be is the use of atenolol in patients with ESKD, in whom the clinically signiﬁcant if drug clearance decreases by less than t1/2 increases from 6 to 100 hours compared with in 50% (the “no effect boundary”). patients with preserved kidney function (40). A change The extent to which drugs (or their relevant metabolites) in either CL or Vd has a very different effect on the are excreted by the kidney are also important in determining concentration-time proﬁle (Figure 5, A and B), but in each whether dose adjustment is necessary in kidney disease. In case, the dosing interval should be doubled (Figure 5C). general, dose adjustment is unlikely to be required when However, Figure 5 is probably an oversimpliﬁcation, because ,30% of a dose is excreted by the kidneys (2). It is also both CL and Vd can change in acute and chronic clinical important to consider instances where dose adjustments for situations, such as sepsis, kidney disease, and liver disease. primarily hepatically metabolized drugs may be required, Finally, the t1/2 to consider is not only that of the parent because their pharmacologically active and/or toxic metab- drug, but also that of active or toxic metabolites. There are olites are primarily excreted by the kidney, which may many cases of poisoning occurring due to accumulation of increase the pharmacologic effect and/or risk of adverse metabolites that are eliminated by the kidney, such as events. For example, morphine is metabolized to morphine- morphine causing coma, meperidine (pethidine) causing 6-glucuronide (up to 360 times more potent than the parent seizures, allopurinol causing toxic epidermal necrolysis, drug ), which is cleared by the kidney and accumulates glyburide (glibenclamide) causing hypoglycemia, and cy- in kidney failure. Mycophenolate is metabolized to myco- clophosphamide causing immunosuppression. For exam- phenolic acid glucuronide (inactive), which is cleared by the ple, relative to patients with normal kidney function, active kidney, and it can accumulate in kidney impairment and cyclophosphamide metabolites had a signiﬁcantly pro- may contribute to the gastrointestinal intolerance of this longed t1/2 and accumulated in a patient with a creatinine medication seen in severe CKD (44). clearance of 18 ml/min, which contributed to prolonged Other considerations include the risk of drug accumulation bone marrow suppression (41) (discussed in Examples of and the clinical manifestations when this occurs. For exam- Drugs That Require Special Consideration When Prescrib- ple, dose adjustments are less necessary for a low-toxicity ing to Patients with Kidney Disease). drug being prescribed for a short course of treatment (e.g., an 1094 Clinical Journal of the American Society of Nephrology oral penicillin), where the risk of accumulation is mitigated 4. Duong JK, Roberts DM, Furlong TJ, Kumar SS, Greenfield JR, by the short duration of therapy (for example, several days). Kirkpatrick CM, Graham GG, Williams KM, Day RO: Metformin therapy in patients with chronic kidney disease. Diabetes Obes In contrast, dose adjustments are required for drugs with a Metab 14: 963–965, 2012 long treatment duration and a higher intrinsic toxicity (e.g., 5. Leil TA, Feng Y, Zhang L, Paccaly A, Mohan P, Pfister M: Quan- metformin, digoxin, lithium, or colchicine) (discussed in tification of apixaban’s therapeutic utility in prevention of venous Examples of Drugs That Require Special Consideration When thromboembolism: Selection of phase III trial dose. Clin Pharmacol Prescribing to Patients with Kidney Disease), particularly if Ther 88: 375–382, 2010 6. Blot S, Lipman J, Roberts DM, Roberts JA: The influence of acute they have a long elimination t1/2 (e.g.,.24 hours). kidney injury on antimicrobial dosing in critically ill patients: Are Therefore, dose adjustments may be required for selected dose reductions always necessary? Diagn Microbiol Infect Dis drugs with pharmacokinetics that change signiﬁcantly in 79: 77–84, 2014 kidney disease, particularly if there is a high risk of drug 7. Imani S, Buscher H, Marriott D, Gentili S, Sandaradura I: Too much accumulation and severe and/or irreversible toxicity. of a good thing: A retrospective study of b-lactam concentration- Methods for dose adjusting in patients with kidney disease toxicity relationships. J Antimicrob Chemother 72: 2891–2897, 2017 8. Oakley PW, Whyte IM, Carter GL: Lithium toxicity: An iatrogenic are discussed in detail in part 2 of this series (23). problem in susceptible individuals. Aust N Z J Psychiatry 35: 833–840, 2001 9. Baird-Gunning J, Lea-Henry T, Hoegberg LCG, Gosselin S, Conclusions Roberts DM: Lithium poisoning. J Intensive Care Med 32: Pharmacokinetic factors that inform the dosing of drugs 249–263, 2017 10. Roberts DM, Gallapatthy G, Dunuwille A, Chan BS: Pharmaco- are well described. However, limited data in patients with logical treatment of cardiac glycoside poisoning. Br J Clin kidney disease, particularly for certain drugs, and marked Pharmacol 81: 488–495, 2016 interindividual variability complicate the development of 11. Chan BS, Isbister GK, O’Leary M, Chiew A, Buckley NA: Efficacy dosing guidelines. Furthermore, kidney disease can cause and effectiveness of anti-digoxin antibodies in chronic digoxin wide-ranging changes in pharmacokinetics through de- poisonings from the DORA study (ATOM-1). Clin Toxicol (Phila) 54: 488–494, 2016 rangement of not only kidney drug CL but also, nonrenal 12. de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, CL, Vd, and bioavailability. These considerations apply to Gross WL, Luqmani R, Pusey CD, Rasmussen N, Sinico RA, Tesar both the parent drug and any active or toxic metabolites. V, Vanhille P, Westman K, Savage CO; EUVAS (European Vas- Each requires a different approach to adjustment of the culitis Study Group): Pulse versus daily oral cyclophosphamide dosing regimen, and inappropriate adjustments, particu- for induction of remission in antineutrophil cytoplasmic antibody- larly with maintenance therapy, lead to drug concentra- associated vasculitis: A randomized trial. Ann Intern Med 150: 670–680, 2009 tions that are too low or too high, predispose patients to 13. Li YF, Fu S, Hu W, Liu JH, Finkel KW, Gershenson DM, Kavanagh harm due to therapeutic failure, or adverse drug reactions. JJ: Systemic anticancer therapy in gynecological cancer patients Drug dosing can be optimized on a case by case basis by with renal dysfunction. Int J Gynecol Cancer 17: 739–763, 2007 the use of rational dose design grounded in an understanding 14. Haubitz M, Bohnenstengel F, Brunkhorst R, Schwab M, Hofmann of basic pharmacokinetic concepts and therapeutic drug U, Busse D: Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney Int 61: monitoring, particularly for drugs that have a narrow 1495–1501, 2002 therapeutic index. This is a key component in the develop- 15. Joy MS: Impact of glomerular kidney diseases on the clearance of ment of personalized medical care for patients with kidney drugs. J Clin Pharmacol 52[Suppl]: 23S–34S, 2012 disease, and it is discussed further in part 2 of this series (23). 16. Little MA, Nightingale P, Verburgh CA, Hauser T, De Groot K, Savage C, Jayne D, Harper L; European Vasculitis Study (EUVAS) Group: Early mortality in systemic vasculitis: Relative contribu- Acknowledgments tion of adverse events and active vasculitis. Ann Rheum Dis 69: D.M.R. is a recipient of the Jacquot Research Establishment 1036–1043, 2010 Fellowship, Royal Australasian College of Physicians and the 17. Singh JA, Hossain A, Kotb A, Wells GA: Comparative effectiveness Clinician ‘Buy-Out’ Program, St. Vincent's Centre for Applied Medical of immunosuppressivedrugsand corticosteroidsforlupusnephritis: A Research. systematic review and network meta-analysis. Syst Rev 5: 155, 2016 18. Duong JK, Furlong TJ, Roberts DM, Graham GG, Greenfield JR, Williams KM, Day RO: The role of Metformin in Metformin- Disclosures Associated Lactic Acidosis (MALA): Case series and formulation None. of a model of pathogenesis. Drug Saf 36: 733–746, 2013 19. Juurlink DN, Roberts DM: The enigma of metformin-associated lactic acidosis. Clin Toxicol (Phila) 52: 85–87, 2014 References 20. Duong JK, Kroonen MYAM, Kumar SS, Heerspink HL, Kirkpatrick 1. Zhang Y, Zhang L, Abraham S, Apparaju S, Wu TC, Strong JM, CM, Graham GG, Williams KM, Day RO: A dosing algorithm for Xiao S, Atkinson AJ Jr, Thummel KE, Leeder JS, Lee C, Burckart GJ, metformin based on the relationships between exposure and renal Lesko LJ, Huang SM: Assessment of the impact of renal impairment clearance of metformin in patients with varying degrees of kidney on systemic exposure of new molecular entities: Evaluation of recent function. Eur J Clin Pharmacol 73: 981–990, 2017 21. Stangier J, Rathgen K, Stähle H, Mazur D: Influence of renal new drug applications. Clin Pharmacol Ther 85: 305–311, 2009 impairment on the pharmacokinetics and pharmacodynamics of 2. FDA: Pharmacokinetics in Patients with Impaired Renal Function— oral dabigatran etexilate: An open-label, parallel-group, single- Study Design, Data Analysis, and Impact on Dosing and Labeling, centre study. Clin Pharmacokinet 49: 259–268, 2010 2010. Available at: https://www.fda.gov/downloads/drugs/ 22. Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML: guidancecomplianceregulatoryinformation/guidances/ Apixaban pharmacokinetics at steady state in hemodialysis ucm204959.pdf. Accessed December 24, 2017 patients. J Am Soc Nephrol 28: 2241–2248, 2017 3. Khanal A, Castelino RL, Peterson GM, Jose MD: Dose adjustment 23. Roberts DM, Sevastos J, Carland JE, Stocker SL, Lea-Henry TN: guidelines for medications in patients with renal impairment: Clinical pharmacokinetics in kidney disease (part 2): Application How consistent are drug information sources? Intern Med J 44: to rational design of dosing regimens. Clin J Am Soc Nephrol 77–85, 2014 2018, in press Clin J Am Soc Nephrol 13: 1085–1095, July, 2018 Pharmacokinetics and Drug Dosing—Principles, Lea-Henry et al. 1095 24. Hori R, Okumura K, Kamiya A, Nihira H, Nakano H: Ampicillin 38. Yeung CK, Shen DD, Thummel KE, Himmelfarb J: Effects of and cephalexin in renal insufficiency. Clin Pharmacol Ther 34: chronic kidney disease and uremia on hepatic drug metabolism 792–798, 1983 and transport. Kidney Int 85: 522–528, 2014 25. Chapron A, Shen DD, Kestenbaum BR, Robinson-Cohen C, 39. Roberts DM: The relevance of drug clearance to antibiotic dosing Himmelfarb J, Yeung CK: Does secretory clearance follow glo- in critically ill patients. Curr Pharm Biotechnol 12: 2002–2014, merular filtration rate in chronic kidney diseases? Reconsidering 2011 the intact nephron hypothesis. Clin Transl Sci 10: 395–403, 2017 40. McAinsh J, Holmes BF, Smith S, Hood D, Warren D: Atenolol 26. Putt TL, Duffull SB, Schollum JB, Walker RJ: GFR may not ac- kinetics in renal failure. Clin Pharmacol Ther 28: 302–309, 1980 curately predict aspects of proximal tubule drug handling. Eur J 41. Bagley CM Jr, Bostick FW, DeVita VT Jr: Clinical pharmacology of Clin Pharmacol 70: 1221–1226, 2014 cyclophosphamide. Cancer Res 33: 226–233, 1973 27. König J, Zolk O, Singer K, Hoffmann C, Fromm MF: Double- 42. Levy G: Pharmacokinetics in renal disease. Am J Med 62: transfected MDCK cells expressing human OCT1/MATE1 or 461–465, 1977 43. Frances B, Gout R, Monsarrat B, Cros J, Zajac JM: Further evidence OCT2/MATE1: Determinants of uptake and transcellular trans- that morphine-6 beta-glucuronide is a more potent opioid agonist location of organic cations. Br J Pharmacol 163: 546–555, 2011 than morphine. J Pharmacol Exp Ther 262: 25–31, 1992 28. Müller F, König J, Glaeser H, Schmidt I, Zolk O, Fromm MF, Maas 44. MacPhee IA, Spreafico S, Bewick M, Davis C, Eastwood JB, R: Molecular mechanism of renal tubular secretion of the anti- Johnston A, Lee T, Holt DW: Pharmacokinetics of mycophenolate malarial drug chloroquine. Antimicrob Agents Chemother 55: mofetil in patients with end-stage renal failure. Kidney Int 57: 3091–3098, 2011 1164–1168, 2000 29. Roberts DM, Buckley NA: Pharmacokinetic considerations in 45. Rowland Yeo K, Aarabi M, Jamei M, Rostami-Hodjegan A: clinical toxicology: Clinical applications. Clin Pharmacokinet Modeling and predicting drug pharmacokinetics in patients with 46: 897–939, 2007 renal impairment. Expert Rev Clin Pharmacol 4: 261–274, 2011 30. Brogard JM, Jehl F, Blickle JF, Dorner M, Arnaud JP, Monteil H: Biliary 46. Yoshida K, Sun B, Zhang L, Zhao P, Abernethy DR, Nolin TD, pharmacokinetic profile of piperacillin: Experimental data and eval- Rostami-Hodjegan A, Zineh I, Huang SM: Systematic and uation in man. Int J Clin Pharmacol Ther Toxicol 28: 462–470, 1990 quantitative assessment of the effect of chronic kidney disease on 31. Ljungberg B, Nilsson-Ehle I: Pharmacokinetics of meropenem and CYP2D6 and CYP3A4/5. Clin Pharmacol Ther 100: 75–87, 2016 its metabolite in young and elderly healthy men. Antimicrob 47. Joy MS, Frye RF, Nolin TD, Roberts BV, La MK, Wang J, Brouwer Agents Chemother 36: 1437–1440, 1992 KL, Dooley MA, Falk RJ: In vivo alterations in drug metabolism and 32. Greenblatt DJ: Hepatic clearance of drugs in patients with renal transport pathways in patients with chronic kidney diseases. insufficiency. Clin Pharmacol Drug Dev 2: 295–297, 2013 Pharmacotherapy 34: 114–122, 2014 33. Nolin TD, Appiah K, Kendrick SA, Le P, McMonagle E, 48. Bergeron MG, Gennari FJ, Barza M, Weinstein L, Cortell S: Renal Himmelfarb J: Hemodialysis acutely improves hepatic CYP3A4 tubular transport of penicillin G and carbenicillin in the rat. J Infect metabolic activity. J Am Soc Nephrol 17: 2363–2367, 2006 Dis 132: 374–383, 1975 34. Nolin TD, Frye RF, Le P, Sadr H, Naud J, Leblond FA, Pichette V, 49. Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Himmelfarb J: ESRD impairs nonrenal clearance of fexofenadine Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, but not midazolam. J Am Soc Nephrol 20: 2269–2276, 2009 Timmins P, Williams KM: Clinical pharmacokinetics of metfor- 35. Volpe DA, Tobin GA, Tavakkoli F, Dowling TC, Light PD, Parker RJ: min. Clin Pharmacokinet 50: 81–98, 2011 50. Debruyne D, Ryckelynck JP: Clinical pharmacokinetics of flu- Effect of uremic serum and uremic toxins on drug metabolism in conazole. Clin Pharmacokinet 24: 10–27, 1993 human microsomes. Regul Toxicol Pharmacol 68: 297–303, 2014 36. Sun H, Frassetto L, Benet LZ: Effects of renal failure on drug transport and metabolism. Pharmacol Ther 109: 1–11, 2006 Published online ahead of print. Publication date available at www. 37. De Martin S, Orlando R, Bertoli M, Pegoraro P, Palatini P: cjasn.org. Differential effect of chronic renal failure on the pharmacokinetics of lidocaine in patients receiving and not receiving hemodialysis. See related article, “Introduction to Nephropharmacology for the Clin Pharmacol Ther 80: 597–606, 2006 Clinician: A New CJASN Series,” on pages 1083–1084.

Clinical Pharmacokinetics in Kidney Disease PDF

Document Details

Tags

Related

Summary

Full Transcript

Upgrade to continue