Population pharmacokinetic model for once‐daily intravenous busulfan in pediatric subjects describing time‐associated clearance

Abstract

This study aimed to characterize the population pharmacokinetics (PK) of busulfan focusing on how busulfan clearance (CL) changes over time during once‐daily administration and assess different methods for measuring busulfan exposure and the ability to achieve target cumulative exposure under different dosing adjustment scenarios in pediatric stem cell transplantation recipients. Daily serial blood sampling was performed and concentration‐time data were analyzed using a nonlinear mixed‐effects approach. The developed PK model was used to assess achievement of target exposure under six dose‐adjustment scenarios based on simulations performed in RStudio (RxODE package)®. A total of 2491 busulfan plasma concentration–time measurements were collected from 95 patients characterizing 379 dosing days. A two‐compartment model with time‐associated CL best described the data with a typical CL of 14.5 L/h for an adult male with 62 kg normal fat mass (NFM; equivalent to 70 kg total body weight), typical volume of distribution central compartment (V1) of 40.6 L/59 kg NFM (equivalent to 70 kg total body weight), and typical volume of distribution peripheral compartment of 3.57 L/62 kg NFM. Model interindividual variability in CL and V1 was 14.7% and 34.9%, respectively, and interoccasional variability in CL was 6.6%. Patient size described by NFM, a maturation component, and time since start of treatment significantly influenced CL. Simulations demonstrated that using model‐based exposure estimates with each dose, and either a proportional dose‐adjustment calculation or model‐based calculated individual CL estimates to support dose adjustments, increased proportion of subjects attaining cumulative exposure within 5% of target compared with using noncompartmental analysis (100% vs. 0%). A time‐associated reduction in CL during once‐daily busulfan treatment was described.

Population Pharmacokinetic Modeling for Twice-Daily Intravenous Busulfan in a Large Cohort of Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation—A 10-Year Single-Center Experience

“…However, CL and k were not reduced in all patients over time, as concluded from the variance of the random effects for d k and the comparison of the individual non-parametric k or CL. Our finding that CL was reduced in most (but not all) patients after one day of treatment is consistent with other large PK studies in pediatric patients, which demonstrated that CL on the first day was 8% to 15% higher [ 18 , 23 , 24 , 52 , 54 , 57 ] than subsequent days. This contrasts with PK studies in adult patients, where usually minimal inter-occasion variability of busulfan CL was observed [ 47 , 48 , 58 , 59 ].…”

“…Including a function for the age-dependent maturation of k improved our model. The reduction in k and thus CL in patients < 1 year of age is in agreement with previous findings [ 18 , 23 , 24 , 25 , 54 ] and implies a maturation of the elimination mechanisms [ 55 ], which needs to be taken into account. Several approaches have been published to describe the maturation of busulfan CL [ 18 , 25 , 52 ].…”

“…By replacing the elimination rate constant k in the population PK model with a dynamic parameter, we were able to account for a change in k and CL with time. In our model, we used an exponential function to describe the change in k with time, while other studies used a step function [ 23 , 24 ], e.g., from the first to subsequent days, or a saturation function [ 54 ]. The half-life of the change in k in our analysis was 13.4 h, resulting in a constant CL 2–3 days after the start of busulfan therapy, which is in agreement with the reduction after the first day described in other studies [ 23 , 24 ].…”

Maximum a posteriori Bayesian methods out-perform non-compartmental analysis for busulfan precision dosing

“…NCA does not consider time-dependent changes in patient PK, and as a result, tended to overdose patients on day 2 of our simulated trial. PopPK-based methods can account for this decrease in clearance over time, potentially leading to more appropriate dose selection [ 22 ]. The models used for simulation and estimation differed in how they modeled this time-dependent clearance, resulting in slight under- dosing on day 2 in the MAP arm of our simulated trial, and pinpointing a need for accurate description of time-dependent changes in clearance.…”