Principles of Drug Dosing in Renal Impairment

Bethany Tellor

Jennifer Hagopian

Introduction

One of the most significant drug-related errors in patients with renal impairment is inappropriate medication dosing leading to toxicity or ineffective therapy.¹
Drugs with renally eliminated active metabolites require special dosing consideration as the consequences of accumulation can be particularly dangerous.
High degrees of precision are required when dosing medications with a narrow therapeutic index (e.g., aminoglycosides, digoxin) that rely on renal elimination.
Deciding on the appropriate dosing strategy of medications in patients with chronic kidney disease (CKD) or acute kidney injury (AKI) requires an understanding of the basic principles of pharmacokinetics, including absorption, protein binding, metabolism, and elimination.
Renal impairment affects glomerular blood flow and filtration, tubular secretion, reabsorption, renal bioactivation, and metabolism.
Nonrenal drug clearance, through mechanisms that are poorly understood, may also be impaired by kidney injury.¹
Dosing for medications that undergo renal elimination is based primarily on an estimate of glomerular filtration rate (GFR). The Modification of Diet in Renal Disease (MDRD) study and Cockcroft–Gault equations provide useful estimates of GFR in adults. Patient-specific dosages calculated using these equations should be conducted in the presence of stable renal function and in patients not on renal replacement therapy (RRT).
Patients who are treated with different forms of dialysis may require supplemental dosing. The ability of dialysis to remove drugs is influenced by a variety of factors discussed elsewhere in this chapter.
Drugs that can further impair renal function in high-risk patients (heart failure [HF], liver disease, hypoperfusion) should be used with caution or avoided altogether in preference for safer alternatives.
Nephrotoxic medications have been linked to >20% episodes of AKI. Clinicians must recognize commonly used agents in order to ensure safety of medication administration in the setting of renal dysfunction.
Table 24-1 lists common medications that are potentially nephrotoxic.

General Dosing and Pharmacokinetic Principles

In general, renal insufficiency makes it difficult to predict whether a medication dose will produce an adequate, supratherapeutic, or subtherapeutic effect.²

Loading doses are often used to rapidly achieve a therapeutic drug concentration; they depend on the urgency with which a pharmacologic effect is needed against the half-life of the drug.

The time needed to reach 90% of the plateau drug concentration is 3.3 times the half-life. If this time is too long relative to the clinical urgency of the situation, a loading dose is needed.

TABLE 24-1 MECHANISMS OF NEPHROTOXICITY AND ALTERNATIVES TO SOME COMMON DRUGS

Drug	Mechanism	Alternatives/Comments
ACE inhibitors	Intraglomerular hemodynamic alteration	β-Blockers, calcium channel blockers
Acetaminophen	Chronic interstitial nephropathy	Avoid doses >4 g/day chronically
Acyclovir (intravenous)	Acute tubular injury	Hydration, oral administration, dose adjustment
Aminoglycosides	Acute tubular injury	Monitor serum concentration, alternative antibiotic
Amphotericin	Acute tubular injury	Saline loading, lipid formulation
β-Lactam antibiotics	Interstitial nephritis	Alternative antibiotic
Carboplatin	Tubular injury	Hydration, alternative chemotherapy agents
Ciprofloxacin	Interstitial nephritis	Alternative antibiotic
Cisplatin	Tubular injury	Hydration, alternative chemotherapy agents
Cyclosporine	Chronic interstitial nephritis, intraglomerular hemodynamic alteration	Monitor serum concentrations, belatacept
Foscarnet	Tubular injury, crystal nephropathy	Dose adjustment, ganciclovir
Hydralazine	ANCA-associated vasculitis	Alternative antihypertensive
Lithium	Interstitial disease, hypercalcemia, CKD	Monitor serum concentrations, alternative mood stabilizer
Loop diuretics	Interstitial nephritis	Non–sulfa-containing diuretics
Methotrexate	Tubular injury	Adjust dosage, urinary alkalinization, allopurinol
NSAIDs	Chronic interstitial nephropathy, intraglomerular hemodynamic alteration	Acetaminophen, opiate analgesic
Phenytoin	Interstitial nephritis	Alternative anticonvulsant
Phenobarbital	Interstitial nephritis	Alternative anticonvulsant
Proton pump inhibitors	Interstitial nephritis, CKD	H₂ blockers
Sulfonamides	Tubular obstruction, interstitial nephritis	Non–sulfa-containing antibiotic
Tacrolimus	Interstitial nephritis, intraglomerular hemodynamic alteration	Monitor serum concentrations, belatacept
Vancomycin	Tubular and interstitial injuries	Monitor serum concentrations, alternative antibiotic
ACE, angiotensin-converting enzyme; CKD, chronic kidney disease.

Physiologic determinants affecting loading doses, such as an increase in total body water (e.g., edema, ascites), may warrant a higher than normal loading dose to account for change in volume of distribution (V_d), whereas dehydration may require a loading dose reduction.
The loading dose is a function of the V_d and the initial target blood concentration.

Loading dose = V_d × C_p

V_d = volume of distribution in L/kg

C_p = desired plasma concentration in mg/L

Maintenance doses are used to achieve steady-state concentrations.
- Dose reduction, increasing the interval, or both can be used to avoid the accumulation of renally eliminated drugs or their metabolites.
- The best dosing option to employ depends on the properties of the medication and the disease state being treated.
- Regimens with closer dosing frequencies and small individual doses result in less fluctuations between peak and trough concentrations. This may be particularly helpful for medications that need to be maintained within a narrow concentration range for optimal efficacy (e.g., anticonvulsants, antiarrhythmics).
Pharmacokinetics refers to the action of drugs in the body over time, and is used to understand drug handling as a means to optimize efficacy and minimize toxicity. As noted in Table 24-2, it involves four parameters of drug activity: absorption, distribution, metabolism, and clearance.¹
It is important to identify how the pharmacokinetic profile of medications can be altered in patients with renal impairment (Table 24-2).
Accumulation of renally excreted active metabolites may occur (Table 24-3).

Dosage Adjustments of Commonly Used Drugs

Anticoagulants

Vitamin K Antagonists

Warfarin metabolism and elimination is not significantly altered in renal insufficiency, however CKD is a known risk factor associated with warfarin-related hemorrhage. This is likely due to platelet dysfunction and concomitant drug interactions.
Reduced doses should be used in patients with significant renal impairment.

Heparins

Unfractionated heparin (IV, SC) is primarily metabolized in the liver and endothelium; however, there is limited evidence to ensure safety of this agent in GFRs <30 mL/min.
Low–molecular-weight heparins (e.g., enoxaparin, dalteparin) administrated SC have predictable pharmacokinetic profiles and dosing curves that justify the use of these agents without routine coagulation monitoring. However, they primarily undergo renal clearance and require dose adjustment in renal insufficiency.
Anti-Xa monitoring has been recommended for GFRs <30 mL/min.
Use in dialysis is contraindicated and not Food and Drug Administration (FDA) approved.

Anti-Xa Inhibitors

Fondaparinux (SC) is primarily excreted in the urine as unchanged drug. Use with caution for GFRs <50 mL/min. Do not use if GFR <30 mL/min.
Rivaroxaban, apixaban, and edoxaban are three of the new direct oral anticoagulant agents (DOACs).³

Rivaroxaban and apixaban are renally eliminated and require dose adjustments. Use is not recommended for GFRs <30 mL/min. Neither agent is dialyzable but recent

pharmacokinetic studies suggest a dose reduction may be used safely. However, clinical efficacy and long-term safety data are lacking in this patient population. Extreme caution is advised.

TABLE 24-2 EFFECT OF RENAL DISEASE ON VARIOUS PHASES OF PHARMACOKINETICS

Phases	Characteristics	Effects of Renal Disease	Examples of Medications
Absorption	Bioavailability refers to the fraction of medication that reaches the systemic circulation after oral ingestion. Several factors and physiologic processes influence intestinal absorption and bioavailability.	Patients with CKD and AKI exhibit changes in the gastrointestinal tract that affect bioavailability. Gastroparesis: Patients with CKD often suffer from gastroparesis. This results in delayed gastric emptying and prolongs the time to maximum drug concentrations, which can be important when rapid onset of action is desired. Gastric alkalinization: Common use of medications such as phosphate binders, antacids, H₂-receptor antagonists, and proton pump inhibitors in patients with CKD reduces the absorption of many medications requiring an acidic environment. Cationic chelation: Ingestion of common cation-containing antacids (e.g., calcium, magnesium, aluminum hydroxide, sodium polystyrene sulfonate) in patients with renal dysfunction decreases the absorption of many coadministered medications because of chelation.	Examples of medications affected by gastric alkalinization: Furosemide Ferrous sulfate Examples of drugs affected by chelation: Quinolones Warfarin Levothyroxine Tetracycline
Distribution	Drug distribution or volume of distribution (V_d) is the total amount of drug present in the body, divided by the plasma concentration, expressed in liters. The V_d determines peak concentrations. Plasma protein binding, tissue binding, active transport, and body composition affect the V_d. Albumin and other plasma proteins bind most drugs to varying degrees. Plasma drug concentrations are representative of both bound and unbound drug, but only free drug is capable of crossing cellular membranes and exerting pharmacologic effects.	Several drugs have shown changes in V_d in patients with renal dysfunction and this may mandate a change in a loading dose of a medication. Hypoalbuminemia due to the nephrotic syndrome often leads to an increase in the free drug fraction of medications that are highly bound to albumin. An increase in α-1-acid glycoprotein (an acute phase protein) associated with renal dysfunction will lead to increase in protein binding of medications bound to nonalbumin proteins. In addition, accumulation of metabolites and endogenous substances increase competition for binding sites.	Digoxin: V_d that is one-half that in a patient with normal renal function. β-Lactams: They have increased V_d and may need higher dosing in in renal dysfunction. Examples of acidic drugs that are usually protein bound, and have higher free drug levels with decreased albumin: Penicillins Cephalosporins Phenytoin Furosemide Salicylates Examples of alkaline drugs affected by increased protein binding in CKD: Propranolol Morphine Vancomycin
Metabolism	The majority of drugs in the clinical setting undergo first-order kinetics (i.e., drug concentrations decline logarithmically over time) and rates are proportional to the total body concentration of the drug present. Biotransformation at numerous sites in the body happens through phase reactions. Phase I reactions include hydrolysis, reduction, and oxidation (cytochrome P450 reactions). These serve to increase drug hydrophilicity to prepare for excretion or further phase II metabolism. Phase II reactions or conjugation reactions include glucuronidation, sulfation, glutathione conjugation, acetylation, and methylation.	Hepatic metabolism of medications is inhibited in both CKD and AKI. Renal dysfunction significantly slows both phase I and phase II reactions. Renal dysfunction reduces P-glycoprotein activity, resulting in increased bioavailability of some medications. Changes to oxidation reactions result in reduced activity of several of the CYP450 isoenzymes (2C9, 2C19, 2D6, 3A4). All phase II reactions are slowed in renal dysfunction.	Examples of medications with narrow therapeutic index affected by decreased P-glycoprotein activity: Cyclosporine Tacrolimus Examples of drugs affected by decreased phase II actions: Acetylation: dapsone, hydralazine, isoniazid, procainamide Glucuronidation: acetaminophen, morphine, lorazepam, naproxen Sulfation: acetaminophen, minoxidil, dopamine, albuterol Methylation: dobutamine, dopamine, 6-mercaptopurine
Elimination	Elimination is reported as a half-life (T½), or the time needed to reduce medication plasma concentrations by 50%. T½ is influenced by both V_d and clearance and can reflect a change in either or both of these parameters. T½ and clearance of a drug are different. Approximately 5 T½s are required to eliminate 97% of drug from the body. This parameter is especially useful for estimation of the time required to achieve steady state (approximately 4–5 T½s), and to estimate appropriate drug dosing intervals.	The rate of renal elimination is dependent on GFR, renal tubular secretion, and reabsorption. Reduced GFR results in prolonged free drug elimination T½. Medication-specific characteristics (e.g., molecular weight, protein binding) determine glomerular filtration with filtration rate dependent on free fraction. Drugs that are highly protein bound are not filtered, but actively secreted into the proximal convoluted tubule through a saturable process. In the distal portion of the nephron substantial passive reabsorption occurs and this is affected by urine concentrating activities, pH, lipophilicity, and protein binding. Reduced GFR will decrease secretion by active transport.	Examples of drugs affected by reduced active secretion: Ampicillin Furosemide Penicillin G Trimethoprim Examples of drugs affected by reduced passive absorption: Aspirin Lithium
CKD, chronic kidney disease; AKI, acute kidney injury; V_d, volume of distribution; CYP450, cytochrome P450; GFR, glomerular filtration rate.

TABLE 24-3 COMMON MEDICATIONS WITH ACTIVE METABOLITES

Drug	Metabolite	Cumulative Toxicity
Acetaminophen	N-acetyl-p-benzoquinoneimine	Hepatotoxicity, tubular acute necrosis
Allopurinol	Oxypurinol	Bone marrow suppression
Glyburide	4-trans-hydroxyglibenclamide (M1) 3-cis-hydroxyglibenclamide (M2)	Hypoglycemia
Meperidine	Normeperidine	Seizures
Primidone	Phenobarbital	Oversedation, coma
Procainamide	N-acetyl-procainamide	Arrhythmia, hypotension, respiratory failure
Nitroprusside	Thiocyanate	Lactic hallucinations, coma, acidosis, tinnitus
Morphine	6-Morphine glucuronide	Oversedation, coma
Tramadol	O-desmethyltramadol	Respiratory depression, seizures, increased serotonin

Edoxaban requires dose adjustments in renal insufficiency. Use is not recommended for GFRs <15 mL/min and is not dialyzable. In patients with nonvalvular atrial fibrillation, use is not recommended if GFR >95 mL/min as an increased risk of ischemic stroke compared to warfarin has been noted.