Trial Simulation: An Innovative Approach to Assess Pediatric Drug Dosing

Trial Simulation: An Innovative Approach to Assess Pediatric Drug Dosing

As a pediatric nephrologist, I help care for some very sick kids. And because our young patients are so ill, it’s a challenge to recruit them into clinical studies. Of course, we want to provide our patients with the best care; getting the dose right on their medications is a big part of that. However, variability in both demographic (age, weight) and clinical factors like receiving continuous renal replacement therapy (CRRT) can alter drug pharmacokinetics (PK). In silico approaches like computer-assisted trial design can help us to assess which dosing regimens are most likely to achieve target attainment while minimizing the risk to pediatric patients. In this blog, I’ll discuss the clinical situation that led us to use Certara’s Trial Simulator to model dosing of an antibiotic in children with acute kidney injury who are receiving CRRT.

Sepsis: Still a major cause of pediatric mortality

Sepsis is a prevalent cause of acute kidney injury in children which may require the need for CRRT. You can think of CRRT as a continuous form of dialysis. The outcomes in this population show critically ill children who are receiving CRRT have mortality rates exceeding 40%.1 Inadequate treatment with antibiotic therapy is predictive of patient mortality.2 So it’s critical to adequately dose potentially life-saving antibiotics in this population. Meropenem is a potent, broad spectrum antibiotic that is frequently prescribed in this population.

Meropenem PK

Let’s briefly review the pharmacokinetic properties of meropenem. It is primarily excreted by the kidneys3 and is characterized by time-dependent bactericidal activity. Thus, meropenem’s efficacy is determined by the percentage of time during the dosing interval that the concentration of free drug in the serum exceeds the minimum inhibitory concentration (MIC) for the targeted bacterial agent. And the MIC is the minimum amount of drug necessary to prevent bacterial growth on a petri dish.

The characteristics of meropenem render it significantly removed by CRRT. It has a small volume of distribution, insignificant protein binding, and has a small molecular size.

Principles of CRRT

To understand how we incorporated CRRT into the model, I’ll explain how it works at a high level. The CRRT machine is hooked up at the patient’s bedside. It contains a filter to clean the blood. Then a patient would typically have a catheter inserted at an internal jugular vein. Their blood would flow through an access line and then circulate through the filter and then return to the patient through a return line. Blood is cleaned by additional fluid that runs through the machine, mixes with the blood, and is then removed. This process clears the patient of toxins that build up in kidney failure. The total dose of CRRT is typically represented by the total amount of fluid that is collected by the machine, expressed in mL/hr.

PK in patients receiving CRRT

Understanding the pharmacokinetics of medications in critically ill children is challenging for multiple reasons. First, pediatric patients with sepsis can have alterations in their PK compared to healthy children. For example, they can have an increased volume of distribution. That can be due to capillary leak associated with the inflammation itself or to receiving excessive amounts of resuscitative fluids. Also, they can have acute kidney injury which can affect the clearance of renally cleared drugs. And this population has documented interindividual variation in PK parameters. In addition, CRRT itself affects drug clearance. It removes drugs smaller than a certain size including meropenem. The main CRRT dosing prescription parameter that affects drug clearance is the total effluent volume.

In summary, CRRT dosing and prescription differences can affect drug pharmacokinetics. These alterations in PK can then influence the optimal dose to give to these pediatric patients.


References

[1] Sutherland SM, et al. (2010). Fluid overload and mortality in children receiving continuous renal replacement therapy: The prospective pediatric continuous renal replacement therapy registry. American Journal of Kidney Diseases, 55(2), 316–325.

[2] Garnacho-Montero J, et al. (2003). Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Critical Care Medicine, 31(12), 2742–2751.

[3] Hurst M & Lamb HM. (2000). Meropenem: A review of its use in patients in intensive care. Drugs, 59(3), 653–680.


To learn how we used trial simulation to evaluate the probability of target attainment for various meropenem dosing regimens in a range of age groups and fluid overload levels in children receiving CRRT, please watch this webinar. Let me know what you think in the comments section!

Edward Nehus

About the Author

Dr. Edward Nehus is a Pediatric Nephrologist in the Division of Nephrology at the Cincinnati Children’s Hospital Medical Center and an Assistant Professor at the University of Cincinnati, Department of Pediatrics. Edward conducted and published a cross-sectional study which investigated the association of serum resistin with cardiovascular risk factors in children with chronic kidney disease. In addition, he recently published a study evaluating the outcomes steroid-avoidance protocols in pediatric kidney transplant recipients. He continues to be the primary investigator for ongoing studies that explore pharmacokinetic alterations in critically ill children receiving continuous renal replacement therapy. (Photo courtesy of Cincinnati Children's Hospital Medical Center: www.cincinnatichildrens.org)