The challenges and complexities of pediatric drug development are well recognized. Pharmacometric modeling and simulation (M&S) leverages prior knowledge to support pediatric drug dosing, trial design and regulatory writing for submissions. As the benefits of pharmacometrics for drug development and regulatory decision-making become increasingly well documented, the FDA has challenged the industry to more rigorously apply modeling and simulation to double the success rate of pediatric trials. To highlight the power of this approach, I’ll present a journal article on using population pharmacokinetics (PopPK) and Bayesian methods to develop an optimal sampling strategy to estimate drug exposure.
Organ transplant recipients take immunosuppressants to ensure graft survival
Liver transplantation is a surgical treatment for patients with liver cancer or end-stage liver failure whose disease cannot be managed medically. A wide variety of conditions can lead to whole or “cut-down” liver transplants in children, including biliary atresia, tryosinaemia, North American Indian childhood cirrhosis, and other conditions. After receiving a liver transplant, patients must take immunosuppressive drugs to prevent their immune systems from rejecting the graft.
Dose optimization of tacrolimus is essential to the success of pediatric liver transplants
Tacrolimus is widely used as an immunosuppressant for both adult and pediatric solid organ transplant recipients. Its PK properties have mainly been studied in adults. Tacrolimus has a narrow therapeutic index and significant inter- and intra-individual PK variability. In addition, it has highly variable oral bioavailability due to extensive pre-systemic metabolism by CYP3A and uptake by P-glycoprotein transporters.
To ensure graft survival, it is essential to optimize the dose of tacrolimus for individual patients. The standard of care has been therapeutic drug monitoring wherein trough concentration (Ctrough) has been used to guide tacrolimus dosing. There is an urgent need for alternative strategies for estimating tacrolimus exposure as the relationship between Ctrough and organ rejection is controversial.
One alternative would be to use Area Under the Concentration-Time Curve (AUC) as a basis for clinical monitoring. However, AUC-based monitoring requires measuring many concentration-time points over the dosing interval. This is both expensive and time consuming, not to mention impractical and ethically questionable in a pediatric population.
Using PopPK models to develop an optimal sampling strategy
We determined that the best solution was an optimal sampling strategy (OSS) using maximum a posteriori Bayesian estimators (MAP-BE). This method can predict individual PK parameters, including AUC, using a limited number of samples, which can be taken on a flexible schedule. To establish an OSS using MAP-BE, we developed a PopPK model for tacrolimus in pediatric liver transplant patients using rich sampling.
We analyzed 12-hour intensive PK profiles performed on pediatric liver transplant patients in a retrospective study. While other PopPK studies on this population found that tacrolimus PK followed a one-compartment model, we found that a two-compartment model with first-order absorption and elimination best fit the concentration-time profiles of tacrolimus at steady state. We leveraged the PopPK approach to develop an OSS, which allowed estimation of tacrolimus PK parameters and AUC using a more feasible sampling schedule (three or four time points within four hours).
Despite the high between-subject variability in PK and patient demographics, the combination of PopPK and Bayesian estimation appears to provide an accurate method for predicting tacrolimus exposure in pediatric liver transplant patients. This OSS will support designing prospective clinical trials aimed at determining the drug’s therapeutic window in this population. Ultimately, defining optimal pediatric drug dosing guidelines for tacrolimus will be a major step in preventing graft rejection while minimizing toxicity. Getting the dose right will help pediatric patients return to the important work of just being little kids again.
This research was performed with my colleague, Dr. Samer Mouksassi. I encourage you to read our British Journal of Clinical Pharmacology article, “Population Pharmacokinetics and Bayesian Estimation of Tacrolimus Exposure in Pediatric Liver Transplant Recipients.”
All information presented derive from public source materials.
Ready to learn more about how M&S supports pediatric drug development?
My colleague, Dr. JF Marier, recorded a short webinar that highlights the major challenges associated with pediatric drug development. He also discussed an approach that helps sponsors identify an optimal drug dose that balances safety and efficacy while minimizing the exposure of children to experimental therapeutics. Please listen to the recording and let me know what you think in the comments section!