693 Table 36 4 (continued) Drug Adjustment for renal failure Supplement for dialysis CommentsHemodialysis Peritoneal dialysis CRRT Sieving coefficient* Famciclovir [93, 94] Yes No ? ? Dose after hemod[.]
36 Drug Administration and Pharmacogenomics in Children Receiving Acute or Chronic Renal… 693 Table 36.4 (continued) Yes Yes Supplement for dialysis Peritoneal Hemodialysis dialysis No ? Yes No Sieving CRRT coefficient* Comments ? Dose after hemodialysis Yes 0.8 Yes Yes Yes Yes ? ? ? Yes 0.8 Nephrotoxicity Dose after hemodialysis Yes Yes Yes Yes 0.8 TDM Yes Yes No Yes Seizures No No No No Ketoconazole [115] Loracarbef [116] Meropenem [117–120] Metronidazole [32, 42, 50, 121, 122] Oxacillin [123] Penicillin G [32] Pentamidine [124, 125] Piperacillin [126–129] Piperacillin/tazo [130, 131] Rifampin [32, 111] Ticarcillin [45, 132, 133] Tobramycin [134–136] Valacyclovir [137] No Yes Yes No Yes Yes No ? ? No ? Yes 0.9 Yes No No No 0.9 No Yes No No Yes No No No No No Yes No 0.02 Yes Yes No Yes 0.8 Yes Yes No ? No Yes No Yes No Yes No Yes Yes Yes Yes Yes TDM Yes No No No Valganciclovir [138, 139] Vancomycin [32, 42, 140, 141] Anticonvulsants Carbamazepine [142, 143] Gabapentin [144] Lamotrigine [145, 146] Levetiracetam [147–153] Phenobarbital [32, 154] Phenytoin [32, 155] (Fosphenytoin) Yes ? ? ? Yes No No No Dose after hemodialysis neurotoxicity Not recommended in dialysis TDM Yes No No No TDM Yes Yes No No No ? No ? Dose after hemodialysis Yes Yes ? No Yes Yes Yes Yes 0.8 No ? No ? 0.4 Drug Famciclovir [93, 94] Fluconazole [42, 95–97] Foscarnet [98, 99] Ganciclovir [100–104] Gentamicin [105–107] Imipenem/cilastatin [50, 108–110] Isoniazid [111–114] Adjustment for renal failure TDM dose after hemodialysis Dose after hemodialysis 0.7 0.7 ↓ Protein binding TDM – free levels (continued) B L Blowey et al 694 Table 36.4 (continued) Drug Valproic acid [4, 156–159] Adjustment for renal failure No Cardiovascular agents Aliskiren [160] No Amlodipine No [161–163] Atenolol [164–167] Yes Captopril [168–172] Yes Clonidine [173, No 174] Digoxin [13, Yes 175–178] Enalapril [179, 180] Yes Esmolol [181, 182] No Fosinopril [183, Yes 184] Labetalol [185, 186] No Lisinopril [172] Yes Minoxidil [32, 187] No Nifedipine No [188–190] Nadolol [191] Yes No Metoprolol [32, 167] Prazosin [192] No Propranolol No [193–195] Immunosuppressive agents Daclizumab No Yes Azathioprine [32, 196] No Cyclosporine [197–199] No Mycophenolate [200–202] Prednisone [203] No Sirolimus No Tacrolimus [204, No 205] Miscellaneous Buspirone [206, Yes 207] Cetirizine [208, Yes 209] Diazepam [32] No Enoxaparin Yes [210–212] Supplement for dialysis Peritoneal Hemodialysis dialysis No No Sieving CRRT coefficient* Comments No ↓ Protein binding; HD/ CRRT may be useful in setting of overdose No No ? No ? ? Yes Yes No No No No ? Yes ? No No No Yes No No No No No Yes No No No Yes No No No No No No No Yes ? ? Yes Yes No ? ? ? No No No No ? No ? Yes ? ? ? ? No No No 0.6 TDM, nephrotoxicity No No No 0.02 TDM No ? No No ? No No ? No TDM TDM, nephrotoxicity No ? ? Active metabolites No ? ? No Yes ? ? ? Yes 0.8 ↓ Vd (adjust loading dose) Avoid K+ depletion Dose after hemodialysis 0.3–0.7 Active metabolites TDM 36 Drug Administration and Pharmacogenomics in Children Receiving Acute or Chronic Renal… 695 Table 36.4 (continued) Drug Famotidine [213–215] Fentanyl [32] Fluoxetine [216–218] Hydromorphone [219, 220] Imipramine [32, 221] Lansoprazole [222–224] Lithium [225–227] Loratadine [228] Meperidine [7] Methadone [32, 229, 230] Methylphenidate Midazolam [5, 231, 232] Montelukast Morphine [6, 32, 233, 234] Omeprazole [235, 236] Ondansetron Oxycodone [32] Paroxetine [237] Ranitidine [238–241] Sufentanil [229] Warfarin [32] Yes Supplement for dialysis Peritoneal Hemodialysis dialysis No No Sieving CRRT coefficient* Comments No 0.7 Active metabolites Yes No No No ? No ? No Yes No ? ? No No No ? No No ? ? Yes Yes Yes Yes No ? No ? ? ? ? ? Yes No ? ? No Yes ? ? ? ? ? ? No Yes ? No ? ? ? ? No No ? ? No Yes Yes Yes ? ? ? No ? ? ? No ? ? ? ? No No ? No ? No ? ? Adjustment for renal failure TDM Seizures, metabolites not recommended 0.04 Active metabolites Active metabolites 0.8 Dose after hemodialysis * Sieving coefficient may vary based on membrane and should be confirmed with membrane-specific data when available The determinants of drug disposition and action in children with renal failure and those children receiving dialysis are frequently altered such that changes in the dosing regimen are necessary to avoid toxicity or inadequate treatment In view of the many factors that can alter both the disposition and action of a given drug, it is important to individualize drug therapy for the known alterations associated with age, kidney failure, and dialysis uture Considerations: Pediatric F Pharmacogenetics The application of pharmacogenetic principles to the optimal use of medications in children requires an understanding that the consequences of genetic variation in genes involved in drug disposition and response are superimposed upon variability associated with the processes of growth and development Changes in end-organ 696 function, such as ontogeny of renal function early in life as well as renal failure and drug removal by dialysis, represent additional factors that must be considered in the pharmacotherapeutic decision-making process Nevertheless, there are two factors that should be considered when determining if genetic variation (pharmacogenetics) is likely to be clinically relevant for a particular medication in a given patient First, pharmacogenetic variation is most relevant when the pathway subject to genetic variation is quantitatively important to the overall clearance of the drug from the body There are no specific guidelines as to what constitutes “quantitatively important,” but pharmacokinetic differences between “poor metabolizers” who have two nonfunctional copies of the gene and “extensive metabolizers,” who have two functional copies of the gene, begin to manifest when the polymorphic pathway accounts for at least 50% of the overall clearance Traditionally, genetic variation has been considered to be increasingly important as the therapeutic index – the difference between concentrations associated with effect and those associated with toxicity – decreases; warfarin is one example of a narrow therapeutic index medication where genetic information is becoming a very useful adjunct to initial dose selection More recently, however, there is an increasing appreciation for pharmacogenetic variation to impact the use of broad therapeutic index drugs, with the primary concern being lack of efficacy, rather than increased risk of toxicity Efforts to assess the relative contributions of ontogeny and genetic variation to overall interindividual variability in drug disposition and response have largely focused on genes involved in hepatic drug biotransformation For example, cytochrome P450 2D6 (CYP2D6) is one of the best-studied, clinically relevant pharmacogenetic polymorphisms [21] The CYP2D6 gene locus is highly polymorphic with more than 140 allelic variants with corresponding activity phenotypes ranging from poor metabolizer phenotypes (no functional activity) at one end of the activity spectrum to intermediate, extensive, and ultrarapid metabolizer phenotypes at the other end of the spectrum From a pediatric perspective, B L Blowey et al CYP2D6 is not expressed to an appreciable degree in fetal liver, but functional activity appears relatively soon after birth [8] Thus, for pharmacogenetics to be integrated into pediatric drug therapy, knowledge of ontogeny is essential as the functional consequences of genetic variability will not become fully apparent until the genes are fully expressed In the case of CYP2D6, a longitudinal phenotyping study was conducted in children over the first year of life using a test dose of the over-the-counter cough suppressant dextromethorphan as a measure of CYP2D6 activity Measured CYP2D6 activity based on urinary metabolite ratios (phenotype) was concordant with genotype at 2 weeks of age and throughout the following 12 months [22] Thus, in vivo phenotyping data indicate that genetic variation in CYP2D6 is expected to be a more important determinant of variability in drug disposition than developmental considerations The relevance of pharmacogenetics to drug administration in renal failure relates more to ancillary drug therapy than the renally eliminated medications whose clearance is prolonged by renal failure or altered during dialysis For example, CYP2D6 is important for elimination of many drugs used to manage other conditions in children with renal failure These medications include selective serotonin reuptake inhibitors, fluoxetine and paroxetine; the selective norepinephrine reuptake inhibitors, atomoxetine and venlafaxine; tricyclic antidepressants, amitriptyline, nortriptyline, and desipramine; antipsychotics, haloperidol, aripiprazole, and risperidone; analgesics, codeine, oxycodone, and tramadol; antihistamines, chlorpheniramine and diphenhydramine; and drugs such as metoclopramide, ondansetron, and promethazine Genetic variation is also important for other CYPs as well, and two of the most important clinically are CYP2C9 and CYP2C19 Examples of CYP2C9 substrates include phenytoin, warfarin, glipizide, several NSAIDs, and angiotensin receptor blockers, such as losartan, valsartan, and irbesartan Clinically important CYP2C19 substrates include proton pump inhibitors (omeprazole, esomeprazole, pantoprazole, lansoprazole), clopidogrel, and escitalopram In most situations, individuals with 36 Drug Administration and Pharmacogenomics in Children Receiving Acute or Chronic Renal… two nonfunctional copies of the CYP2C9 or CYP2C19 genes are at increased risk for concentration- dependent side effects Proton pump inhibitors are an exception as “poor metabolism” is associated with higher systemic exposure of the drugs and thus improved clinical response Much less is known about the roles of ontogeny and genetic variation in transporter genes involved in drug elimination by the kidney and how this function is altered in chronic kidney disease As an example, organic cation transporters (OCTs) in the SLC22A subfamily are primarily expressed on the basolateral membrane of polarized epithelia and mediate the renal secretion of small organic cations OCT1 (also known as SLC22A1) is expressed at the apical side of proximal and distal renal tubules, whereas OCT2 (SLC22A2) is predominantly expressed on the basolateral surface of proximal renal tubules In adults, allelic variation in OCT1 and OCT2 is associated with increased renal clearance of metformin On the other hand, no studies addressing the genetic variation of OCT1 and OCT2 have been conducted in children, but developmental factors appear to be operative For example, neonates possess very limited ability to eliminate organic cations, but this function increases rapidly during the first few months of life; when standardized for body weight or surface area, it tends to exceed adult levels during the toddler stage Most importantly, the application of pharmacogenetics to aid in optimizing drug therapy in children is rapidly gaining momentum but has not yet reached the stage of routine incorporation into clinical decision-making, especially in specialized conditions like chronic renal failure Although a number of clinical guidelines have been released by the Clinical Pharmacogenetics Implementation Consortium (CPIC) to provide information regarding dosing of medications in the presence of a test result for a given patient, few of those published to date have specific information for children; an exception is the recently released guideline for CYP2D6 and atomoxetine in children and adolescents with attentiondeficit/hyperactivity disorder (ADHD) [23] 697 Nevertheless, pediatric experience across many subspecialty areas continues to accumulate, and a potential role for pharmacogenetics should be anticipated in situations where a medication is associated with a narrow therapeutic index, and when there is considerable variability in the response to a medication, whether lack of efficacy or toxicity References Blowey DL. 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[32, 167] Prazosin [192] No Propranolol No [193–195] Immunosuppressive agents Daclizumab No Yes Azathioprine [32, 196] No Cyclosporine [197–199] No Mycophenolate [200–202] Prednisone [203] No Sirolimus... [32] Fluoxetine [216–218] Hydromorphone [219, 220] Imipramine [32, 221] Lansoprazole [222–224] Lithium [225–227] Loratadine [228] Meperidine [7] Methadone [32, 229, 230] Methylphenidate Midazolam... ontogeny and genetic variation in transporter genes involved in drug elimination by the kidney and how this function is altered in chronic kidney disease As an example, organic cation transporters (OCTs)