687 Drug elimination during dialysis occurs by both diffusion and convection The contribution of each process to the dialysis clearance of a drug varies among the different dialysis modalities Diffusi[.]
36 Drug Administration and Pharmacogenomics in Children Receiving Acute or Chronic Renal… Drug elimination during dialysis occurs by both diffusion and convection The contribution of each process to the dialysis clearance of a drug varies among the different dialysis modalities Diffusion is the movement of drug across a dialyzer membrane or peritoneal membrane from a higher to lower drug concentration While drug usually moves from the blood compartment to the dialysis fluid, drug can be absorbed from the dialysis fluid into the systemic circulation when the drug concentration of the dialysis fluid exceeds the serum concentration This is the mechanism by which potentially therapeutic serum drug concentrations are achieved with intraperitoneal dosing Convection is the movement of drug across the dialyzer membrane or peritoneal membrane that occurs when drug is “trapped” within the flow of ultrafiltrate Dialysis removes only free drug from the body as drug bound to plasma proteins and other cellular constituents result in drug complexes that are too big and not cross the dialyzer membrane or peritoneal membrane The efficiency of drug removal (e.g., amount of drug removed per unit time) is greatest for hemodialysis, followed by continuous renal replacement therapies (CRRT), and least by peritoneal dialysis Although drug removal by CRRT and peritoneal dialysis is less efficient than hemodialysis, the total drug removal may be equivalent to hemodialysis as CRRT and peritoneal dialysis are usually performed for a longer duration of time upon the size of the drug, protein binding, and dialyzer properties The blood flow rate, dialyzer surface area, and membrane characteristics are dialyzer factors that impact drug elimination During hemodialysis, the dialysis flow rate is rapid (e.g., 600 ml/min) and does not limit drug diffusion as the concentration gradient between blood within the dialyzer capillaries and dialysis fluid is continuously refreshed A dialyzer with a larger surface area and a more porous membrane will increase drug clearance [15] As technology has advanced, the newer synthetic membranes can be manufactured with larger pore size (e.g., high flux) that may allow for greater clearance of larger molecules than with the traditional membranes Published drug clearance data should be viewed with caution as the reported clearance values may not be representative of the newer more porous membranes used in current practice For example, vancomycin is a relatively large drug, and earlier reports suggested that vancomycin removal by hemodialysis was minimal With the use of high-flux dialyzers (e.g., more porous membranes), the removal of vancomycin during dialysis is much greater than previously noted [16] Dialysis drug clearance (Cld) can be calculated by measuring the prefilter (arterial (Ca)) and postfilter (venous (Cv)) serum drug concentration and the rate of blood flow through the filter (Qb): Hemodialysis In hemodialysis, blood flows through a parallel series of synthetic capillaries contained in a plastic shell (dialyzer), while dialysis fluid flows in the opposite direction outside the blood-filled capillaries As blood flows along the length of the capillaries, unbound solutes (e.g., drugs) diffuse across the membrane from the blood into the dialysis fluid Depending on the need for fluid removal, ultrafiltration and convective drug removal occur, but diffusion is the most important factor influencing solute loss The elimination of a drug during hemodialysis is dependent 687 é ( C - Cv ) ù Cl d = ê a ú ´ Qb ë Ca û (36.4) Equation 36.4 can be corrected for protein binding and hematocrit when appropriate [1] The equation can be further adapted to account for drug removal that occurs with ultrafiltration by measuring the ultrafiltration rate (Quf): éỉ Cv ù é ( C - Cv ) ù Cl d = a ỳ Qb + ờỗ ữ Quf ú êëè Ca ø úû ë Ca û (36.5) The drug clearance by hemodialysis is considered significant when the dialysis procedure accounts for more than 25% of systemic drug clearance However, drug clearance of less than 25% may be clinically relevant when a drug has a B L Blowey et al 688 very narrow therapeutic index – the differences between concentrations associated with effect and those with toxicity ontinuous Renal Replacement C Therapies The term “continuous renal replacement therapies” (CRRT) incorporates continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CCVHDF) Drug removal during CRRT is governed by the ultrafiltration and dialysis fluid flow rates as well as the same factors identified in hemodialysis, namely, drug size, protein binding, access blood flow, and dialyzer characteristics During hemofiltration (e.g., CVVH), countercurrent dialysis fluid is not present, and fluid and solute (e.g., drug) removal occur consequent to convection (i.e., solute movement associated with fluid Sieving coefficient = Ultrafiltrate drug concentration ( Ca + C v ) / A sieving coefficient of suggests that the solute is filtered without hindrance through the dialyzer, whereas a sieving coefficient of suggests there is no ultrafiltration of the drug Most drugs are small enough that if not bound to plasma protein or cellular constituents, they are easily filtered Saturation coefficient = Cl CRRT = Si ( or Sa ) ´ ( Qd + Quf ) (36.8) The drug clearance by CRRT is considered to be significant when the dialysis procedure accounts for more than 25% of systemic drug clearance Similar to hemodialysis, when a drug has a very narrow therapeutic window, a (36.6) When countercurrent dialysis fluid is present (i.e., CVVHD, CVVHDF), the relationship between the drug concentration in the combined dialysate and ultrafiltrate and the average drug concentration in plasma is termed the saturation coefficient (Sa): Ultrafiltrate + dialysate drug concentration ( Ca + C v ) / Drug clearance during CRRT (ClCRRT) can be calculated by measuring the sieving (Si) or saturation (Sa) coefficient and the dialysis (Qd) and ultrafiltration (Quf) flow rates: movement) In order to optimize solute removal, large volumes of ultrafiltration are prescribed, and the patient is provided with a large amount of replacement fluids to offset the hemofiltration losses During continuous hemodialysis (e.g., CVVHD), countercurrent dialysis fluid is present, and most of the drug removal occurs by diffusion During hemodiafiltration (CVVHDF), solutes are cleared by both convection and diffusion, but diffusion is the predominant process, and the dialysis fluid flow rate is the factor limiting solute (e.g., drug) removal such that increasing the dialysis fluid flow rate can enhance drug clearance [17] Typical replacement fluid and dialysis flow rates during CRRT are 2000 mL/h/1.73 m2 During isolated hemofiltration, the relationship between drug concentration in the ultrafiltrate and the average drug concentration in the plasma calculated from the arterial (Ca) and venous (Cv) concentrations is termed the sieving coefficient: (36.7) drug clearance less than 25% may be clinically relevant Peritoneal Dialysis In peritoneal dialysis, the peritoneal membrane serves as a highly vascularized semipermeable membrane separating blood and dialysis fluid Fresh dialysis fluid is placed into the peritoneal cavity for a predetermined length of time, ranging anywhere from 30 min to 6 h, during which 36 Drug Administration and Pharmacogenomics in Children Receiving Acute or Chronic Renal… drug moves across the peritoneal membrane in both directions by way of diffusion and convection Factors influencing peritoneal drug clearance are characteristics of the peritoneal membrane (transport capacity), dialysis exchange volume (e.g., amount of peritoneal surface area exposed to dialysate), ultrafiltration rate, drug size, and protein binding Drug clearance by peritoneal dialysis is more difficult to measure because peritoneal blood flow Cl pd = rates cannot be easily determined Drug clearance by peritoneal dialysis can be estimated by measuring the amount of drug present in the dialysate along with an estimate of the average serum concentration during the dialysis procedure A middialysis plasma drug level is used to estimate the average serum drug concentration (Eq. 36.9), or alternatively multiple blood samples can be obtained and an area under the curve (measure of exposure) calculated (Eq. 36.10): Volume of dialysate ´ drug concentration Mid - dialysis Ca ´ time Cl pd = Volume of dialysate ´ drug concentration AUC0 - t Peritonitis, a common infectious complication of children receiving peritoneal dialysis, is often due to Gram-positive organisms but may also be a result of Gram-negative or fungal infections In the presence of cloudy dialysis fluid, the empiric administration of intraperitoneal antibiotics is recommended after the appropriate laboratory studies and cultures are completed [18, 19] Treatment is initiated with an intraperitoneal loading dose that dwells for 3–6 h and is followed by continuous or intermittent maintenance therapy to complete a 14–21-day treatment course During continuous intraperitoneal maintenance therapy, antibiotic is present in the dialysis fluid of each exchange and ensures that the antibiotic concentration in the dialysis fluid exceeds the minimal inhibitory concentration (MIC) for the infective organisms throughout the treatment course During intermittent maintenance dosing, serum antibiotic concentrations are maintained by placing a higher dose of antibiotic in the dialysis fluid for a single exchange each day or, in the case of vancomycin and teicoplanin, a single exchange every 5–7 days During the subsequent antibioticfree exchanges, antibiotic diffuses from the serum back into the dialysis fluid and accumulates to therapeutic intraperitoneal concentrations The movement of drug into the peritoneum is dependent on the ratio of the drug in the serum to the dialysate concentration and the time allowed for drug diffusion (e.g., dwell time) The prolonged 689 (36.9) (36.10) dwell time employed during continuous ambulatory peritoneal dialysis (CAPD) is usually sufficient to achieve a therapeutic intraperitoneal concentration if the serum drug concentration is adequate During continuous cycling peritoneal dialysis (CCPD), the dwell times may be too short to allow for adequate movement of drug into the peritoneum resulting in subtherapeutic peritoneal drug concentrations Whether therapeutic peritoneal antibiotic concentrations are required for the treatment of peritonitis is not known, and intermittent vancomycin and teicoplanin therapy has been used successfully in children receiving peritoneal dialysis [20] Guidelines for the intraperitoneal dosing of common antibiotics are provided in Table 36.2 The intraperitoneal administration of a drug is a convenient and acceptable route of administering medications for systemic effect but may not be appropriate for all drugs or all clinical circumstances It is of great importance to recognize that in the treatment of serious infections outside the peritoneal cavity, intraperitoneal administration is not superior to intravenous therapy as the bioavailability of the intravenous form is always 100%, whereas the bioavailability of intraperitoneal administration may not be consistently predictable In situations where intraperitoneal administration is required, therapeutic drug monitoring will help ensure that there has been adequate drug absorption B L Blowey et al 690 Table 36.2 Intraperitoneal dosing recommendations for children with peritonitis [18] Drug Ampicillin Cefazolin Cefepime Ceftazidime Clindamycin Gentamicin 500 500 500 300 Continuous therapy dosage (mg/L) 125 125 125 125 150 Teicoplanin Tobramycin 400 20 Vancomycin 1000 25 Loading dose (mg/L) osing Strategies in Children D with Renal Failure Given that there is little information on drug disposition in children with renal failure and children receiving dialysis, an individualized systematic approach (Table 36.3), using the available adult and pediatric data on drug disposition in renal failure, is required to design a drug administration regimen that maximizes the effectiveness of therapy while minimizing the potential for adverse effects The design of a successful therapeutic regimen begins with an estimate of the child’s residual renal function and an estimate of the relative contribution of renal elimination to the total drug elimination obtained from the literature While children receiving dialysis by definition have very poor renal function, it is inappropriate to assume that there is no renal elimination as many children maintain a significant amount of residual renal function Failure to account for the continued renal elimination of drug may result in insufficient drug dosing and therapeutic failure Additionally, patients receiving CRRT who require supraphysi- Intermittent therapy dosage 20 mg/kg QD 15 mg/kg QD 20 mg/kg QD Anuric: 0.6 mg/kg QD Non-anuric: 0.75 mg/kg QD 15 mg/kg Q 5–7 D Anuric: 0.6 mg/kg QD Non-anuric: 0.75 mg/kg QD 30 mg/kg with further doses based on TDM Table 36.3 Guidelines for drug dosing in children with renal failure Estimate residual renal function Determine percentage of drug eliminated by the kidneys Determine if there are any active/toxic metabolites and route of elimination Calculate the dosage adjustment factor (Q), or review published dosing recommendations Adjust dose size or dosing interval If patient is receiving dialysis, evaluate if supplemental dosing is required Monitor response Therapeutic drug monitoring (when available) ologic rates of clearance (i.e., >2000 ml/h/1.73 m2) may need closer patient-specific therapeutic monitoring to avoid insufficient drug dosing and therapeutic failure If one assumes that drug protein binding, distribution, and metabolism are not altered to a clinically significant degree in renal failure, an assumption that is likely true for most drugs, then a dosing adjustment factor (Q) can be estimated using the following equation: ( ( é ỉ Child¢s Cl cr mL / min/ 1.73m Q = - ê Fractional renal elimination ỗ ỗ Normal Cl cr mL / min/ 1.73m ê è ë An appropriate dose amount or dosing interval for a child with reduced kidney function is generated by applying the dosing adjustment factor to either the normal dose amount or normal dosing ) ư÷ùú ) ÷øúû (36.11) interval The dosage adjustment factor estimates the changes in elimination associated with renal failure but does not account for any additional clearance by dialysis If appropriate, supplemen- 36 Drug Administration and Pharmacogenomics in Children Receiving Acute or Chronic Renal… tal drug doses or an increased dose amount may be required to replace the dialysis-related drug losses Whether a change is made in the dose amount or dosing interval depends on the therapeutic goal and relationships between drug concentrations and clinical response and toxicity As an example, the bactericidal aminoglycoside antibiotic gentamicin is primarily eliminated unchanged by the kidney (95% renal elimination), and if the dosing regimen is not modified, gentamicin accumulates to toxic blood levels in renal failure (Fig. 36.1) Using Eq. 36.11, the dosing adjustment factor (Q) for a 5-year-old child with a measured creatinine clearance of 12 ml/min/1.73 m2 is calculated to be 0.15: ( ( ) ÷ứú = 0.15 ) ÷øúû é ỉ 12 mL / min/ 1.73m Q = - ờ0.95 ỗ ç 120 mL / min/ 1.73m ê è ë A gentamicin dosing regimen modified for the reduced renal elimination is calculated by applying the dosage adjustment factor (Q) to either the dose amount or dosing interval When the dosage adjustment factor is applied to the dose amount (multiplied), the modified dose is calculated to be 0.375 mg/kg administered IV every 8 h (0.15 × 2.5 mg/kg/dose) When the dosage adjustment factor is applied to the dosing interval (divided), the modified regimen is calculated to be 2.5 mg/kg administered IV every 53 h (8 h ÷ 0.15) As displayed in Fig. 36.2, both adjustments produce similar mean gentamicin serum levels but very different gentamicin serum peak and trough concentrations Prolongation of the dosing interval (e.g., 2.5 mg/kg IV every (36.12) 53 h) results in gentamicin serum peak and trough concentrations that are similar to those observed with normal dosing In contrast, reduction of the dosage amount administered on a normal schedule (i.e., 0.375 mg/kg IV every 8 h) provides less variation between the serum peak and trough levels For gentamicin and other aminoglycoside antibiotics, therapeutic peak levels that exceed the MIC90 of the organism are desired, and a prolonged dosing interval regimen is the most appropriate For other drugs (e.g., antihypertensive agents), large swings in drug concentrations are undesired, and the method of reducing the dosage amount while maintaining the normal dosing interval will provide more consistent serum concentrations gentamicin serum concentration (mcg/mL) Fig 36.2 Serum concentration – time profile for a child with a GFR = 15 mL/ min/1.73 m2 The dashed line depicts the profile when the dosing interval is adjusted to 2.5 mg/kg IV every 53 h The solid line depicts the profile when the dosing interval is unchanged and the dosage amount is reduced (0.375 mg/kg IV every 8 h) 691 7.3 mcg/mL 3.6 mcg/mL 1.9 mcg/mL 0.5 mcg/mL 0 10 20 30 40 50 60 Time (hours) 70 80 90 100 B L Blowey et al 692 Once the prescribed drug dosing schedule has been adjusted for renal failure, a supplemental dose or dosing adjustment may be required for children receiving dialysis when more than 25% of drug is removed during the dialysis procedure Supplemental dosing is given to replace the amount of drug removed by dialysis and may be achieved as a partial or full dose administered after hemodialysis or an increase in the dosing amount or frequency in children receiving peritoneal dialysis or CRRT. When possible, routine maintenance drugs should be provided after hemodialysis Table 36.4 lists some common drugs and notes whether adjustments are needed for renal failure and if supplemental doses are suggested during dialysis Table 36.4 Dosing guidelines in renal failure and dialysis for common pediatric therapeutic agents Drug Antibiotic, antiviral, antifungal agents Acyclovir [24–30] Amantadine [31–33] Amikacin [34–39] Amoxicillin [40–42] Amoxicillin/ clavulanic acid [43–45] Amphotericin B [46, 47] Amphotericin B lipid complex [48, 49] Ampicillin [50–52] Azithromycin [32, 53] Cefaclor [54–56] Cefazolin [57–61] Cefepime [62–66] Cefixime [67, 68] Cefotaxime [50, 69, 70] Cefpodoxime [71–73] Cefprozil [74] Ceftazidime [42, 50, 75–77] Ceftriaxone [17, 50, 78, 79] Cefuroxime [50, 80–82] Cephalexin [32] Ciprofloxacin [32, 42, 83–85] Clindamycin [86] Co-trimoxazole [87–91] Erythromycin [32, 50, 92] Adjustment for renal failure Supplement for dialysis Peritoneal Hemodialysis dialysis Sieving CRRT coefficient* Comments Yes Yes Yes Yes Yes Yes No Yes Yes Yes No No Yes No ? No No Yes Yes ? 0.9 Neurotoxicity 0.9 0.7 (Clav) TDM No No No No 0.3 No No No No Yes No Yes No No No Yes No Yes Yes Yes Yes Yes Yes Yes Yes No Yes No Yes Yes No No ? Yes Yes No Yes Yes Yes No ? Yes Yes Yes Yes ? No ? Yes 0.9 No No No Yes 0.7 Yes Yes No Yes 0.9 Yes Yes Yes No No No ? No 0.9 No Yes No Yes No No No Yes Yes No No No Consider dosing BID in HD Dose after hemodialysis 0.7 Neurotoxicity Dose after hemodialysis