A limited sampling schedule to estimate individual pharmacokinetic parameters of fludarabine in hematopoietic cell transplant patients

Abstract

Purpose: Fludarabine monophosphate (fludarabine) is frequently administered to patients receiving a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplant (HCT) in an ambulatory care setting. These patients experience significant interpatient variability in clinical outcomes, potentially due to pharmacokinetic variability in 2-fluoroadenine (F-ara-A) plasma concentrations. To test such hypotheses, patient compliance with the blood sampling should be optimized by the development of a minimally intrusive limited sampling schedule (LSS) to characterize F-ara-A pharmacokinetics. To this end, we sought to create the first F-ara-A population pharmacokinetic model and subsequently a LSS.

Experimental design: A retrospective evaluation of F-ara-A pharmacokinetics was conducted after one or more doses of daily i.v. fludarabine in 42 adult HCT recipients. NONMEM software was used to estimate the population pharmacokinetic parameters and compute the area under the concentration-time curve.

Results: A two-compartment model best fits the data. A LSS was constructed using a simulation approach, seeking to minimize the scaled mean squared error for the area under the concentration-time curve for each simulated individual. The LSS times chosen were 0.583, 1.5, 6.5, and 24 hours after the start of the 30-minute fludarabine infusion.

Discussion: The pharmacokinetics of F-ara-A in an individual HCT patient can be accurately estimated by obtaining four blood samples (using the LSS) and maximum a posteriori Bayesian estimation.

Conclusion: These are essential tools for prospective pharmacodynamic studies seeking to determine if clinical outcomes are related to F-ara-A pharmacokinetics in patients receiving i.v. fludarabine in the ambulatory clinic.

Figure 1

Visual predictive check for F-ara-A plasma concentrations in HCT patients receiving IV fludarabine 30 mg/m²/day for 4 days.

Figure 2

Visual predictive check for F-ara-A plasma concentrations in HCT patients receiving IV fludarabine 50 mg/m²/day for 5 days with pharmacokinetic sampling after the first dose only.