Current Approaches and Challenges
Pediatric clinical trials are becoming more prevalent and are now typically mandatory within clinical development plans. The important challenge in pediatric studies is in selecting a safe and effective dose or dose range.
System Pharmacology and Pharmacometrics (PK) provide for development of model-based approaches to describe and understand important age-related factors influencing drug disposition and response in pediatric patients.
The application of Modeling and Simulation provide for better estimates of pediatric doses.
The Extrapolation of Efficacy findings from adults to the pediatric population has streamlined the development process especially for studies in older children.
According to the literature, the weight-corrected doses for drugs eliminated by renal excretion or metabolism involving CYP2C19, CYP2D6, N-acetyltransferase 2, or uridine diphosphate glucuronosyltransferases are similar in children and adults.
Unmet Need: Focus on developmental changes in infants as well as further developing a paradigm for conducting PK/efficacy studies in infants, and children remain important unmet needs. PK of drugs in children may differ from adults for several reasons: variability due to age, gender, body composition, functionality of liver and kidneys and maturation of enzymatic systems throughout the life span from neonates to adults are all potential sources of pharmacokinetic differences.
There are other challenges that arise during pediatric clinical trials which may not be apparent during clinical trials in adults such as recruitment difficulties, lower limits on blood collection volumes, the lack of surrogate markers which predict clinical outcome and the difficulty of dose selection in a rapidly changing population.
Additional Considerations
Children’s growth can be investigated using readily observable demographic factors such as weight and age.
Size is the primary covariate and can be referenced to a 70-kg person with allometry using a scale to the ¾ power coefficient for clearance and 1 for volume. The use of these coefficients is supported by fractal geometric concepts and observations from diverse areas in biology. Lean body mass might be expected to do better than total body weight when there are wide variations in fat affecting body composition.
Sigmoid Emax model best describes the gradual maturation of clearance in early life leading to a mature adult clearance. Assuming similar exposure–response relationships between adult and children, efficacy in children is warranted if the same exposure can be achieved in either population.
Case Studies
- Small molecule (desloratadine; Gupta et al. Br J Clin Pharmacol, 64, 174-184, 2007
- Large molecule (peginterferon alfa-2b; Xu, Gupta, et al. Eur J Clin Pharmacol, 69, 2045-2054, 2013
Desloratadine Dose Selection:
We combined data from the pediatric study with adult data for population pharmacokinetic analysis to determine doses of desloratadine suitable for administration to children aged ≥ 6 months-≤ 2 years in clinical and efficacy studies.
Single doses of 0.625 mg (1.25 ml) and 1.25 mg (2.5 ml) desloratadinesyrup were well tolerated in this age group. Because the study was designed to collect only a minimal number of blood samples, a population pharmacokinetic modelling approach was used.
Results of the pharmacokinetic analysis indicate :
- desloratadine apparent clearance rates were slower in the pediatric group studied than in adults, and that the 0.625 mg dose appeared to be suboptimal for both children aged ≥ 6 months-<1 year and for those aged ≥ 1 year- ≤ 2 years, particularly with respect to Cmax.
- Variability between subjects in the model parameters was moderate, but was consistent with estimates of pharmacokinetic variables obtained with noncompartmental analysis. No systematic bias was observed in parameter estimation.
- On the basis of the results of this analysis, to ensure similar desloratadine exposure to that seen in adults, the age appropriate doses for children aged ≥ 6 months-<1 year and for those aged ≥ 1 year- ≤2 years were established as 1.0 mg and 1.25 mg, respectively.
- Desloratadine is extensively metabolized in the liver to its active metabolite, 3-OH-desloratadine. It is known that some individuals, termed poor metabolizers, have a reduced ability to form the active metabolite. Exposure to desloratadine has previously been shown to be approximately six-fold greater in poor metabolizers than in the rest of the population, with a similar magnitude of reduction in the formation of 3-OH-desloratadine in adults and children given age-appropriate doses. Based on the observed AUC ratio of 3-OH-desloratadine relative to desloratadine, the proportion of poor metabolizers in this study population was approximately 7%. The poor metabolizers are African American. This is consistent with the findings of a large clinical study in older children and adults, which found an age-independent prevalence of this phenotype of 6%.
- Despite the difference in exposure to desloratadine in poor metabolizers, data from studies in patients as young as 2 years have shown it to be well tolerated. This was also the case in this study, with no differences in the safety profile of desloratadine between poor metabolizers and other subjects. These pediatric dose concentrations yielded systemic desloratadine exposures similar to those seen in adults.
Peginterferon alfa-2b dose selection:
The final population pharmacokinetic model of PEG-IFN alfa-2b was a one-compartment model with first-order absorption, first-order elimination, exponential inter-individual variability on apparent clearance, and with a combination additive and proportional residual error model. The body surface area normalized apparent clearance of PEG-IFN alfa-2b was similar across all age groups (3-17 years) and the mean estimated CL/F at age 19 was 1.38 L/hr, which is similar to the CL/F in adults of 1.29 L/hr to 1.54 L/hr. Populations in pediatric studies frequently cover a much wider relative range in body size than comparable studies in adults; the current pediatric data set confirms that size parameters—including body weight, height, BMI, and body surface area are highly correlated with other developmental or maturation-related parameters. Previous clinical trials have shown PEG-IFN alfa plus ribavirin to be an effective treatment option in children and adolescents. These studies have revealed that many of the predictors of sustained viral response (SVR) in adults are also applicable when treating children. Rates of SVR are lower among children with genotype 1 infection compared to genotype 2 or 3 (53% vs 93%, P = .0005), and within the genotype 1 population, baseline viral load <600,000 IU/mL is associated with increased rates of SVR compared to high baseline viral load. (72% vs 29%, P = 0.0006). Furthermore, rapid- and early virologic response are also strong predictors of SVR in the pediatric population with positive predictive values of 89% and 84%, respectively.
As with all studies of this type, several factors may limit interpretation of the data. The concentrations from sparse pharmacokinetic sampling may not contain enough information to estimate Ka accurately for each individual, and the estimated standard error of inter-individual variability for Ka was greater than for CL/F and V/F. In addition, there were 5 outliers with low CL/F whose observed concentration of PEG-IFN alfa-2b tended to increase after week 8, leading to lower CL/F values compared with other patients. To assess this further, an additional population pharmacokinetic analysis was performed, which included week 1-8 concentration data for all 107 patients. The final population pharmacokinetic one-compartment model suggests age-dependent increases in clearance and volume of distribution of PEG-IFN alfa-2b in pediatric patients with chronic hepatitis C. The body surface area normalized apparent clearance was similar across pediatric age groups, validating the use of a body size–adjusted dosing schedule in pediatric subjects.