Phase I Enzyme Pathways
The development of phase I enzymes such as cytochrome P450 (CYP450) enzymes changes significantly in the first few weeks and months of life, and even more dramatically in the preterm infant. To study these changes, researchers administer a drug such as caffeine or theophylline and measure the elimination half-life of the metabolites. Values are compared to known adult values to determine the pediatric variation in metabolism. Metabolism varies based on the specific CYP450 enzyme that is being studied, with some enzymes reaching adult activity levels earlier than others. Many of the CYP450 enzymes have higher-than-adult levels of activity in early childhood and reach adult levels at puberty.4,5 The complexity of metabolism is increased with multiple drug therapy because some drugs may induce (increase the activity) or inhibit (slows metabolism through the pathway) the CYP450 enzymes, causing significantly altered metabolism and leading to altered therapy outcomes.6
The CYP450 enzymes that have significant impact on pediatric prescribing are CYP1A2 and CYP3A4, although further research may expand this list. CYP1A2 has very low activity at birth and in the first 2 to 4 weeks of life. It reaches adult levels at age 4 months and exceeds adult levels of activity at age 1 year to 2 years. The activity level of CYP1A2 remains high until puberty, when it drops back to adult levels. Many pediatric medications are metabolized via the CYP1A2 enzymes, including erythromycin, phenobarbital, phenytoin, carbamazepine (Tegretol), clarithromycin (Biaxin), cimetidine (Tagamet), theophylline and caffeine. Foods such as cruciferous vegetables (cabbage, brussels sprouts, broccoli and cauliflower) and charbroiled foods are CYP1A2 inducers. Grapefruit juice is a known CYP1A2 inhibitor. Cigarette smoke is known to induce CYP1A2. Cystic fibrosis (CF) is also known to affect CYP1A2 activity.
Apply this knowledge clinically by altering dosing for the neonate (for example, lengthen time between dosing of theophylline in the neonate), by monitoring therapeutic drug levels closely as children go through puberty, understanding that CF patients may not metabolize some drugs predictably, and educating about food-drug interactions if appropriate.
The most abundant CYP isoform in the body is CYP3A4. In children, it has very low activity at birth, reaching 30% to 40% of adult levels at 1 month of age and full adult levels at age 6 months. CYP3A4 exceeds adult activity levels at 1 to 4 years of age and then drops back to adult levels during puberty.4 More than 20 commonly prescribed pediatric medications are metabolized via the CYP3A4 pathway, including: carbamazepine, prednisone, oral contraceptives, macrolide antibiotics (clarithromycin, erythromycin), nonsteroidal anti-inflammatory medications (ibuprofen), second-generation antihistamines (cetirizine [Zyrtec], fexofenadine [Allegra], loratadine [Claritin]), cyclosporine and even acetaminophen, which is used extensively in children. Oxcarbazepine (Trileptal) requires higher milligrams-per-kilogram dosing in younger children than older children and adults.7 CYP3A4 activity has a significant impact on the metabolism of cyclosporine in young children. Monitor blood levels closely. Seizure medications administered concomitantly with CYP3A4 inducers or inhibitors may require dosage adjustments to maintain therapeutic blood levels. Carbamazepine levels are decreased by CYP3A4 inducers such as felbamate (Felbatol), phenobarbital, phenytoin, rifampin and theophylline, and levels are increased when administered with CYP3A4 inhibitors such as cimetidine, macrolides (clarithromycin, erythromycin), danazol (Danocrine), fluoxetine (Prozac), ketoconazole (Nizoral), loratadine, valproate (Depacon) and grapefruit juice. Oxcarbazepine (Trileptal) increases phenobarbital levels by 14% and decreases carbamazepine levels by 15% when coadministered.8
Many pediatric neurologists provide patients on seizure medications with a list of drugs that should be avoided. When prescribing for a patient on seizure medications, prudent practice would be to investigate possible drug interactions before prescribing.8 Be aware of the differences in CYP3A4 activity when prescribing more than one medication that is metabolized via this pathway and during developmental changes such as puberty. Monitoring therapeutic blood levels during periods of developmental variation (infancy and puberty) will ensure patient safety by avoiding consequences of subtherapeutic or toxic levels of medications.
Phase II Enzymes
The phase II enzymes are responsible for the synthesis of water-soluble compounds. While information about phase II enzymes lags behind information about phase I enzymes, we do know that most phase II enzymes reach adult levels by age 3 years to 4 years and that there are ethnic variations in phase II enzyme activity. Activity levels of thiopurine methyltransferase (TPMT) did not reach adult activity levels in a small study (N = 309) of Korean children until subjects reached age 7 years to 9 years. Whether this translates to other ethnic groups is unknown at this time. Common pediatric medications metabolized by phase II enzymes are acetaminophen, morphine, propofol and caffeine. Monitor medications metabolized via phase II enzymes for effectiveness based on developmental age and understand that ethnic variations may be present. Clearly, more knowledge about phase II enzyme activity in children is needed.
Pharmacogenetics, the study of how people respond differently to medicines due to their genetic inheritance, is a growing body of knowledge that will significantly influence prescribing. In pediatric patients, polymorphism of some drug-metabolizing enzymes may impact prescribing. In CF patients, CYP2C9 demonstrates altered activity, leading to altered ibuprofen clearance and altered plasma concentration of phenytoin.4 Some patients (up to 7% of the white population and 7.25% of African Americans) are labeled poor metabolizers of CYP2D6.4,9 Patients who have altered CYP2D6 activity have altered plasma clearance of tramadol (Ultram, Ultracet) and dextromethorphan (found in PediaCare, Robitussin and many other products). CYP2D6 is active in the metabolism of more than 40 other medications, including many psychopharmacologic drugs. Patients who are poor CYP2D6 metabolizers experience a stronger analgesic effect and more adverse effects from tramadol, a centrally-acting analgesic.
Pharmacogenetics is thought to be a factor in asthma management. Developing a marker to identify patients at risk for progression of disease and to assist in medication selection would significantly impact asthma management.10 As our knowledge base in this area increases, there may come a time when genetic testing is a standard part of a workup before prescribing certain medications for pediatric patients.
In spite of our growing knowledge base about pediatric pharmacology, some basic issues require resolution before we can move on. Pediatric formulations for many medications are lacking. There is also a lack of designated research teams to perform comprehensive pharmacology studies. Institutional review board (IRB) approval of drug studies in children is tricky, and drug studies in children are problematic.
Lack of pediatric formulations. Many medications are effective in adults but not used in children due to lack of pediatric-friendly formulations. Little funding is available for the development of liquid-stable forms of drugs. The FDAMA incentive encourages pediatric formulations of new medications, but there is little financial incentive for older medications. The biggest obstacle is that data about the stability of drugs in liquid form is scarce. Stability is affected by many things, such as storage temperature, type of container and vehicle (sugar can affect the stability of some medications). Until pediatric-friendly formulations are developed and researched, fewer medications will be available for pediatric use.
Pediatric pharmacology research units. To facilitate the study of pediatric pharmacology, the National Institute of Child Health and Human Development (NICHD) has established pediatric pharmacology research units (PPRUs). The mission of the PPRU network is to facilitate and promote pediatric labeling of new drugs or drugs already on the market.11 The PPRUs study the pharmacokinetics and pharmacodynamics of drugs in a collaboration involving pediatric clinical pharmacologists, pediatric academic researchers and industry. Ideally, a PPRU would be associated with every medical school in the United States. But only 13 PPRUs were in the network as this article went to press (Table 3).
Pediatric drug studies. While it is widely acknowledged that studies need to be performed in children before medications are prescribed for them, many ethical concerns are raised by such research. Institutional review boards, knowing that children cannot legally consent to study participation, place the burden of consent on parents. This is to protect children, but it also makes obtaining pediatric drug research approval more difficult. Another issue with pediatric drug trials is that the majority of children are healthy. Finding an adequate number of ill children to study is difficult, except in the case of common pediatric medications such as antibiotics, antipyretics and drugs to treat asthma. Finding adequate numbers of hypertensive pediatric patients or children with high cholesterol to study common adult medications is challenging, but the PPRU network does help with this. One area of debate is whether healthy children should be used in non-therapeutic clinical pharmacology research to study the pharmacokinetics of medications in children.12 This debate will continue, as will the need for drug studies in children.
We are entering an era of expanding pediatric pharmacology knowledge. As more medications are studied, we can become more informed about the safety and efficacy of the drugs we are prescribing for children. We must keep current with this growing body of knowledge and adjust our prescribing accordingly.
Teri Moser Woo is a pediatric nurse practitioner at Kaiser Pediatric Urgent Care in Portland, Ore. She is a member of the nurse practitioner faculty at the University of Portland School of Nursing in Portland and a doctoral student at the University of Colorado Health Science Center.