By Prathap Shastri and Jaydeep Yadav
With an increase in awareness of differences in metabolism of pharmacokinetics of adults and children, the number of clinical trials in children to establish safety and efficacy have increased substantially. Pediatric patient population is relatively small and has special vulnerabilities. As per a recent survey by Momper et al, about 42% of recent pediatric clinical trials failed to establish standards. A total of 44 unique products failed the trails, with more than 80% of the products failing as a result of lack of efficacy, and the rest failing due to safety concerns.
Ten of the trials failed due to lack of efficacy as a result of inappropriate dosage levels. A range of dose was not tested, which limited the pediatric drug exposure to that which proved efficacious in adults. This further emphasizes that it is critical to test range of doses in pediatric population and build dose-response relationships. Eight of the trials failed due to the differences in disease process between pediatrics and adults. Examples include differences in immune tolerance, differences in platelet aggregation process, and differences in manifestations of herpes simplex virus. Other reasons for clinical trial failure included placebo response in pediatrics and improper study design (for example, lack of controls).
As rightly pointed out in some of the previous blog posts and several pieces of literature, the pharmacokinetics, disease progression, and body physiology between adults and children are significantly different. For instance, gastric pH, gastric emptying time, intestinal transit time, and integrity of intestinal mucosa all differ in children and do not linearly correlate with adult values. An allometric approach, which basically considers children the same as small adults, may not account for the complex development changes. In addition, characterizing the ontogeny of enzyme/transporter development is very critical to being able to predict drug clearance in pediatrics. One of the important changes is a developmental switch from CYP3A7 to CYP3A4 during the early post-natal period, which results in a low clearance in infants for drugs that are substrates to CYP3A4.
All the above factors further emphasize the need for more commitment in terms of funding and research efforts from the academic labs and pharmaceutical industry to streamline pediatric product development. The recent newsletter from the Drug Metabolism Focus Group revolves around the theme of metabolism and pharmacokinetics in pediatric population including technical and mini literature reviews and interviews of peers in the field. Of course, you will also find several interesting references on the topic!