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Blowey Introduction The prescription of a safe and effective dose of a medication for a child receiving dialysis can be a complicated task as both renal failure and dialysis can modify the absorption, distribution, metabolism, elimination, and action of a drug A safe and effective dosing regimen is one that delivers the appropriate drug in the optimal manner, producing the desired pharmacological response while minimizing the undesirable effects Achieving the goal of successful drug therapy requires a clear understanding of the therapeutic goal coupled with an appreciation of the factors governing drug disposition and action Failure to clearly identify the therapeutic goal or to account for the changes in drug disposition or B L Blowey Department of Pharmacy, Children’s Hospital of Philadelphia, Philadelphia, PA, USA J S Leeder Department of Pediatrics, Children’s Mercy Research Institute, Children’s Mercy Hospital, Kansas City, MO, USA e-mail: sleeder@cmh.edu D L Blowey (*) Department of Pediatrics, CMH Integrated Care Solutions, Children’s Mercy Hospital, Kansas City, MO, USA e-mail: dblowey@cmpcn.org effectiveness associated with renal failure and the performance of dialysis can culminate in drug toxicity or inadequate treatment Basic Concepts of Drug Disposition The desired and undesired effects of a drug generally correlate with the concentration of free (unbound) drug at the site of action Factors that determine drug concentration at the site of action are the rate and extent of absorption, distribution, biotransformation (i.e., metabolism), and elimination The characteristics of these processes are unique for each drug, and individual variations are influenced by genetic, environmental, physiological, and developmental factors [1] Absorption Under most circumstances, a drug must reach the systemic circulation in order to exert a biological effect Drug administered orally, intramuscularly, rectally, subcutaneously, topically, or directly into the peritoneum must cross membranes to gain access to the systemic circulation As a prerequisite to absorption, a drug must be released from the dosage form (e.g., tablet, capsule, transcutaneous patch) and be present at the site of absorption in an aqueous solution Most drugs © Springer Nature Switzerland AG 2021 B A Warady et al (eds.), Pediatric Dialysis, https://doi.org/10.1007/978-3-030-66861-7_36 683 B L Blowey et al 684 are either weak acids or weak bases that in an aqueous solution exist as either an ionized (charged) or nonionized (uncharged) moiety The most common mechanism of drug absorption is passive diffusion of the nonionized drug moiety Less common mechanisms of drug absorption include convective transport, active transport, facilitated transport, ion-pair transport, and endocytosis The extent to which a drug is nonionized is determined by the drug’s pKa (i.e., dissociation constant) and the pH at the site of absorption (e.g., stomach, small bowel, skin, peritoneal cavity) For example, the oral absorption of ketoconazole is enhanced by the stomach’s acidic environment that promotes the formation of the more readily absorbed nonionized drug compound [2] In this example, the coadministration of drugs that reduce gastric acid (e.g., proton pump inhibitors, antacids) may shift the equilibrium in favor of the poorly absorbed ionized form of ketoconazole resulting in decreased ketoconazole absorption with the potential for subtherapeutic serum concentrations [3] Distribution Following the absorption or direct infusion of a drug into the systemic circulation, drug distributes or equilibrates with tissue reservoirs The extent of drug partitioning among tissues depends on the drug’s pKa, the degree of binding to plasma proteins and tissue constituents, tissue blood flow, and the partitioning of drug to fat The relationship between the plasma drug concentration that theoretically exists at time zero (C0) and the fraction of the administered dose reaching the systemic circulation defines the volume of distribution (Vd): Vd = Dose ´ fraction absorbed Drug plasma concentration ( C0 ) The volume of distribution, generally expressed as liters or liters/kg, is a hypothetical value with no true anatomical correlate that relates the plasma drug concentration to the total amount of drug in the body and serves as a guide in determining whether a drug is distributed primarily within the systemic circulation or extravascular sites (e.g., fat, muscle) A large volume of distribution implies that the majority of drug present in the body resides outside the vascular space, whereas a small volume of distribution suggests that most of the drug is present within the vascular compartment For example, digoxin binds more strongly to tissue sites outside the vascular space (e.g., muscle) and consequently has a large volume of distribution (16 L/kg) At the other extreme, phenytoin has a small volume of distribution (0.7 L/kg) because it is highly bound to albumin (90–95% protein binding) and is contained within the vascular and extracellular fluid compartments Disease-related changes in tissue or protein binding or changes in the volume of a compartment (e.g., extracellular fluid volume expansion with edema) can alter the disposition and biological effect of a drug [4] In some clinical situations, immediate therapeutic drug concentrations are desired, and a loading dose is prescribed to saturate the sites of distribution A simple rearrangement of Eq. 36.1 shows that the Vd determines the size of the loading dose: Loading dose ( mg / kg ) = desired concentration ( mg / L ) ´ Vd ( L / kg ) Biotransformation/Elimination The total amount of drug eliminated from the body consists of the amount eliminated by the kidneys plus the amount eliminated by biotransformation (i.e., metabolism) and other pathways (36.1) (36.2) of elimination such as lung, skin, gastrointestinal, and dialysis-related losses The rate of drug elimination, or drug clearance, does not indicate how much drug is being removed from the body but, rather, the volume of blood or plasma that would need to be completely freed of drug per unit of 36 Drug Administration and Pharmacogenomics in Children Receiving Acute or Chronic Renal… time to account for the amount eliminated Drug clearance is additive such that the total (systemic) drug clearance is equal to the sum of the clearances by each individual pathway: Clsystemic = Cl renal + Cl hepatic + Cl dialysis + Cl other (36.3) The processes responsible for drug elimination and metabolism usually require that the drug be present within the systemic circulation Drug partitioned outside the vascular space must return to the vascular space (redistribute) in order to be excreted or metabolized Therefore, while dialysis may effectively clear drug that is present in the plasma, the fraction of the total drug removed from the body by dialysis may be small when the majority of the drug resides outside the vascular space (e.g., large Vd) Biotransformation is the enzymatic conversion of a drug to a new chemical moiety The new drug product (i.e., drug metabolite) is usually an inactive compound that is more easily eliminated from the body In some cases, metabolites may be generated that have significant pharmacological activity [5, 6], toxic properties [7], and be eliminated differently than the parent drug Most tissues, including the kidney, possess the ability to biotransform drugs Quantitatively, the liver and gastrointestinal tract are the most important organs of drug metabolism Although there are many different types of enzymes capable of carrying out drug biotransformation, the cytochromes P450 (CYP) are the most important in the metabolism of therapeutic drugs There is great interindividual variability in the biological activity of CYPs because of genetic, environmental, physiological, and developmental factors [8, 9] The kidney is the most important organ for drug and drug metabolite elimination Other pathways of drug excretion include biliary, salivary, mammary, sweat, lungs, and intestinal Renal drug excretion occurs through the combined processes of glomerular filtration, tubular secretion, and tubular reabsorption Unless limited by size or charge, drug and drug metabolites not bound to plasma proteins are freely filtered through the glomeruli at a rate equal to the glomerular filtration rate (GFR) The active renal 685 tubular secretion of drug and drug metabolites in the proximal tubule can contribute substantially to renal drug elimination Other drugs or endogenous substrates that employ the same nonspecific transport system may inhibit the renal tubular uptake and secretion of drugs A clinically relevant example of competitive inhibition of tubular secretion is the coadministration of probenecid and cidofovir [10, 11] Probenecid inhibits the renal tubular uptake of cidofovir and protects the kidney from cidofovir nephrotoxicity Reabsorption is the passive diffusion of the nonionized drug from the filtrate back into the renal tubular cell Basic urine (e.g., urine pH >7.5) favors the ionized form of acidic drugs and limits reabsorption This concept is used clinically when urine alkalinization is used to enhance the elimination of salicylates in overdose situations [12] lteration of Drug Disposition A in Renal Failure and Dialysis For many drugs and drug metabolites, the kidney is the primary pathway of elimination, and any reduction in renal function will decrease the kidney’s ability to eliminate drug from the body Although a reduced capacity to eliminate drug stands out as the most important change in drug disposition associated with renal failure, clinically significant alterations may occur in other determinants of drug disposition including drug absorption, distribution, and metabolism [4, 13, 14] (Table 36.1) The impact of renal failure on drug disposition is largely determined by the relative contribution of renal drug clearance to systemic drug clearance (Eq. 36.3) When renal drug clearance accounts for more than 25% of systemic drug clearance, it is likely that drug will accumulate to higher and potentially toxic serum drug concentrations with renal failure unless the dosing regimen is modified (Fig. 36.1) In contrast, modification of the dosing regimen is generally not required for drugs that are predominately eliminated by extrarenal pathways unless there B L Blowey et al 686 Table 36.1 Possible changes in drug disposition associated with renal failure PK parameter Absorption Effect ↓ Distribution ↑ Metabolism ↓ Excretion ↑ ↓ 16 14.1 mcg/mL 14 Serum gentamicin concentration (mcg/mL) Fig 36.1 Serum concentration – time profile for a child receiving intravenous gentamicin (2.5 mg/kg IV every 8 h) The solid line depicts the profile in a child with normal renal function The dashed line depicts the gentamicin accumulation that occurs when dosing adjustments are not made in a child with a GFR measuring 15 mL/ min/1.73 m2 Proposed mechanism Edema of GI tract, uremic nausea/vomiting, delayed gastric emptying Drug interaction – phosphate binders, H2 blockers Altered GI pH Increased unbound drug fraction Hypoalbuminemia (nephrosis, malnutrition) Uremic changes in albumin structure; expansion of extracellular, intracellular, and/or total body water spaces Inhibition of CYP 450 metabolism (liver, intestine, kidney) Drug interaction Direct inhibition by “uremic” milieu Induced CYP 450 metabolism Decreased GFR Decreased tubular secretion Increased tubular reabsorption 12 10 7.4 mcg/mL 6.5 mcg/mL 0.5 mcg/mL 0 10 are clinically significant changes in drug absorption, distribution, or metabolism (Table 36.1) Importantly, even though the disposition of the parent drug may be unchanged in renal failure, drugs undergoing extensive biotransformation may have pharmacologically active metabolites that are eliminated by the kidney and accumulate in renal failure [5–7] An example is the enhanced central nervous system toxicity of the opioid analgesic meperidine in individuals with renal failure While meperidine biotransformation proceeds unaltered in renal failure, the active and central nervous system toxic metabolite normeperidine is eliminated by the kidneys and accu- 20 30 Time (hours) 40 50 60 mulates with repeated dosing with an increased risk of seizures in patients with renal failure [7] The impact of dialysis on drug disposition is determined largely by the extent of drug removal by the dialysis procedure During dialysis, systemic drug clearance encompasses renal, hepatic, and other intrinsic clearance pathways plus the additional clearance provided by dialysis (Eq. 36.3) In general, drug removal is considered clinically significant when more than 25% of the administered dose is removed by dialysis Failure to recognize the extent of drug removal and provide supplemental dosing can result in underdosing and therapeutic compromise ... environment that promotes the formation of the more readily absorbed nonionized drug compound [2] In this example, the coadministration of drugs that reduce gastric acid (e.g., proton pump inhibitors,... drug in the body and serves as a guide in determining whether a drug is distributed primarily within the systemic circulation or extravascular sites (e.g., fat, muscle) A large volume of distribution... vascular space, whereas a small volume of distribution suggests that most of the drug is present within the vascular compartment For example, digoxin binds more strongly to tissue sites outside the