Drug Safety and AEs in Children
As the saying goes, children are not small adults. Children differ markedly from adults in terms of biology and physiology. In particular, how they handle drugs is quite different. Thus the approach of pharmacovigilance to SAEs and AEs in children needs to be somewhat different from that in adults.
An additional complexity lies in the fact that there are differences between and amongst neonates, young babies, older babies and adolescents – all of whom are “children”. Premature infants may have even more marked differences compared to full term babies. In fact, one really needs to sub-categorize “children” for purposes of into the categories noted above. The exact age range for each can vary. This is not always done in research and publications. As noted, this is a very complex situation.
Differences in Pharmacology
There are certainly many differences in pharmacology seen in these groups of children. An excellent and detailed review can be found at: Factors and Mechanisms for Pharmaokinetic Differences between Pediatric Population and Adults Pharmaceutics 2011 Mar;3(1) 53-72.
Briefly, some of these differences are noted here. In “ADME” (absorption, distribution, metabolism and excretion) here are some key points:
Oral administration of drugs: The stomach pH at birth is neutral (pH 7) and falls to acid levels by day 1 but returns to neutrality by day 10 then drops slowly to adult pH levels by age 3 years. Because of these differences, some drugs (e.g. ampicillin and erythromycin) are more readily absorbed in neonates. Other drugs such as phenytoin are less readily absorbed in the babies than in adults. Gastric emptying is slower in babies to age 6-8 months. Intestinal transit time and absorption is also different in young babies and infants. Some drugs (including delayed release products) may have less complete absorption. Fat digestion is impaired in neonates due to immaturity of the pancreas and biliary secretion. This can lead to malabsorption of fats and fat-soluble vitamins (e.g. D & K). Immaturity of the intestinal mucosa may lead to abnormal protein digestion and abnormal bacterial colonization.
Intramuscular absorption may also be abnormal and unreliable due to lower blood flow to muscles in babies.
Once the drug is absorbed, it is circulated around the body. The factors that determine where the drug is distributed differ in children, particularly in neonates, compared to adults.
There is increased distribution to the brain and nervous system in neonates as the blood brain barrier is not yet fully functional. Plasma protein binding is also different in children and infants as the amount of binding protein may be lower. In babies the percent of total body water is higher and body fat is lower than in older children and adults. So water soluble drugs such as gentamicin, propofol and others will have a higher distribution than in adults and fat soluble ones such as diazepam, a lower volume of distribution.
Most drug metabolism occurs in the liver with initial oxidation, reduction and hydrolysis of the drug followed by conjugation with other molecules to make the final product water soluble for excretion in the urine.
The initial reactions often occur via the cytochrome p450 system which consists of several families of isoenzymes. These enzymes are usually much lower in young children’s livers and reach adult levels only at about 10 years of age. Other enzymes may be higher in children than adults. For example, caffeine metabolism is much lower in children under 2 years of age and these children require smaller doses of caffeine for an effect. However children over 2 years of age may develop higher enzyme levels decreasing to adult levels at age 15. Thus these children would require lower caffeine doses. The groups of p450 enzymes differ from each other in children and one must look at the specific drug and metabolic pathway to determine whether drug doses should be raised, lowered or left unchanged. A very complex situation.
Similarly, the water solubilization mechanism following the initial metabolism in the liver may also differ in children such that different amounts or even different metabolites may be produced in children compared to adults.
Excretion of drugs is primarily by the kidney and this depends on the glomerular filtration rate, tubular secretion and re-absorption which depend on renal blood flow. Renal blood flow to the kidney at birth is low reaching adult values only at 2 years of age. However, perhaps paradoxically, some drugs are more rapidly eliminated by children than adults and higher doses are needed to achieve therapeutic levels. The situation is complex and the reasons for this may differ from drug to drug.
So the bottom line on this is that ADME are different in children compared to adults and often in ways that differ from drug to drug and the age of the child making predictions without data difficult. Children are not adults and extrapolations of adult data into children of varying ages is fraught with difficulty. Data from trials and real-world clinical use in children is necessary. Again, for an excellent summary of ADME see the article referenced above.
Clinical Trials in Children
It is common knowledge that studying new (or even older) drugs in children is a very significant problem for society. This issue has been noted for over two decades and has resulted in legislation in the US and elsewhere to encourage clinical trials in children including Food and Drug Administration Modernization Act (1997), Best Pharmaceuticals for Children Act (2002), Pediatric Research Equity Act (2003), the Food and Drug Administration Amendments Act (2007), and the Food and Drug Administration Safety and Innovation Act (2012) and others.
Much has been written about this. A good summary can be found in an EU recommendations document developed by an ad hoc group in 2001-7.
This is a fairly long document and discusses and recommends actions in regard to ethical considerations, legalities, informed consent (by the family or others and/or by the child him/herself), emergency situations, ethics committees, clinical trial design, “pain, distress and fear minimization”, assessment of levels of risk and its monitoring, measures of benefit, lab tests (particularly volume of blood taken), healthy “volunteer” children in trials, replications, safety (see below), unnecessary replication of trials, insurance and money, inducements and compensation and more.
Adverse Events and Safety Reporting
Several issues arise in the area of DS and PV in children, both in trials and in the post-marketing setting.
In general, the legal and regulatory requirements for safety reporting in children are the same as for reporting in adults. In practice, one should be hypersensitive to possible AEs and SAEs in children as babies are not able to articulate or report problems. It is usually the external observer or caregiver who must notice a change in behavior, vital signs etc. Even young children who can speak may have trouble articulating problems. It may be necessary to look at target organ function (e.g. lab tests) to pick up AEs and SAEs.
There is a fairly large but not very informative literature on adverse events in children. See for example: Adverse Drug Reactions in Children – A Systemic Review. PLoS One 2012; 7(3):324061.
This publication is a review of the literature and concluded that the literature was extensive but did “not provide information about the drugs involved in ADRs or about which methods were used for detecting, or assessing the causality…of an ADR.” Most of the data came from hospitalizations of children rather than out-patient settings. ADR rates ranged from 0.33% to 11%. Many reports did not even list rates. Nonetheless, the authors concluded that their review “found that ADR incidence rates were generally higher in hospitalized children than ADR rates causing hospital admission or in an outpatient setting.” They also noted that “The types of drugs associated with ADRs differed substantially between studies” and that there was little data on how to avoid ADRs leading the authors to conclude that further “studies are clearly required to determine which ADRs are potentially avoidable.”
There are many articles articulating the need for PV in children but beyond the plea for more work and resources devoted to pediatric PV and DS, there is not much being done. See for example: Pharmacovigilance for children’s sake. Drug Safety 2014 Feb;37(2):91-8. doi: 10.1007/s40264-013-0133-8.
More recent work is pointing to the use of electronic health records for detecting and hopefully preventing or minimizing pediatric ADRs. See: Pharmacovigilance in children: detecting adverse drug reactions in routine electronic healthcare records. A systematic review. Br J Clin Pharmacol. 2015 Oct;80(4):844-54. doi: 10.1111/bcp.12645. Epub 2015 May 28.
Not too much to add beyond the fairly obvious call to pharmacovigilance and clinical trial personnel to pay particular attention to AEs, SAEs and even “possible” AEs in children. A very high level of suspicion and awareness should be maintained. Training of caregivers, parents and anyone else involved in the day to day affairs of the trial (or of non-trial out-patient drug treatment) must also be done.
Frankly, it seems the current pharmacology world, though imbued with good intentions, have not been able to crack this nut. Perhaps the pediatricians and caregivers in the community will have better ideas and out of the box thinking to make some further progress here.
Tags: clinical trials, drug safety, FDA, Pharmacovigilance