Pharamacokinetic modeling for boronophenylalanine-fructose mediated neutron capture therapy:10B concentration predictions and dosimetric consequences

Abstract

A two-compartment open model has been developed for predicting 10B concentrations in blood following intravenous infusion of the L-p-boronophenylalanine-fructose complex in humans and derived from pharmacokinetic studies of 24 patients in Phase I clinical trials of boron neutron capture therapy. The 10B concentration profile in blood exhibits a characteristic rise during the infusion to a peak of approximately 32 microg/g (for infusion of 350 mg/kg over 90 min) followed by a biexponential disposition profile with harmonic mean half-lives of 0.32 +/- 0.08 and 8.2 +/- 2.7 h, most likely due to redistribution and primarily renal elimination, respectively. The mean model rate constants k12, k21, and k10 are (mean +/- SD) 0.0227 +/- 0.0064 min(-1), 0.0099 +/- 0.0027 min(-1), 0.0052 +/- 0.0016 min(-1), respectively, and the central compartment volume of distribution V1 is 0.235 +/- 0.042 L/kg. In anticipation of the initiation of clinical trials using an intense neutron beam with concomitantly short irradiations, the ability of this model to predict, in advance, the average blood 10B concentration during brief irradiations was simulated in a retrospective analysis of the pharmacokinetic data from these patients. The prediction error for blood boron concentration and its effect on simulated dose delivered for each irradiation field are reported for three different prediction strategies. In this simulation, error in delivered dose (or, equivalently, neutron fluence) for a given single irradiation field resulting from error in predicted blood 10B concentration was limited to less than 10%. In practice, lower dose errors can be achieved by delivering each field in two fractions (on two separate days) and by adjusting the second fraction's dose to offset error in the first.

Uptake of two 10B‐compounds in liver metastases of colorectal adenocarcinoma for extracorporeal irradiation with boron neutron capture therapy (EORTC Trial 11001)

“…The pharmacokinetic data gained by analysis of the 10 B-concentration in blood after infusion of BPA was modeled according to the 2-compartment model published by Kiger et al 31 , which fits the data well. The 10 B-concentration in blood reached a maximum at the end of the BPA-infusion and dropped gradually, but considerably faster as compared to BSH.…”

Boron neutron capture therapy of skin melanomas at the RA-6 reactor: A procedural approach to beam set up and performance evaluation for upcoming clinical trials

“…5,31,32 The mean value of 10 B concentration in blood was estimated from pharmacokinetic profiles measured at Harvard-MIT. 33 The Harvard-MIT data relate to 10 patients who had received infusions of nominally 350 mg/kg BPA-F over 90 min. Mean blood 10 B value reported 60 min after the end of infusion was 15 g/g.…”

“…A pharmacokinetic model will be used to predict the 10 B concentration profile in blood during the irradiation session. 33 The blood 10 B analysis will be performed by inductively coupled plasma-atomic emission spectroscopy. 36 As with conventional radiation therapy, immobilization will be important in assuring the planned dose is actually delivered to the tumor.…”

EORTC trial 11001: distribution of two 10B‐compounds in patients with squamous cell carcinoma of head and neck, a translational research/phase 1 trial

“…The pharmacokinetic of 10 B in blood as delivered by BPA was modelled with the measured data according to a two-compartment model [7] (Fig. 1A).…”