Nonlinear pharmacokinetics of rituximab in non‐Hodgkin lymphomas: A pilot study

Abstract

Aims Rituximab is an anti‐CD20 monoclonal antibody approved in non‐Hodgkin lymphoma (NHL). This study aimed to assess the relationship between antigen mass and nonlinear pharmacokinetics of rituximab in NHL patients. Methods In a retrospective cohort of 25 NHL patients treated with rituximab, antigen mass was assessed at baseline by measuring metabolic tumour volume (MTV) by positron emission tomography. Rituximab pharmacokinetics was described using a semimechanistic 2‐compartment model including a latent target antigen. Rituximab target‐mediated elimination was described as irreversible binding between rituximab and it target. Histology (follicular or diffuse large B‐cell lymphomas), initial MTV and body weight were tested as covariates on pharmacokinetic parameters. Results The model allowed a satisfactory description of rituximab serum concentrations. Target‐mediated elimination was maximum at the beginning of treatment and became negligible towards the end of follow‐up. The second‐order elimination of rituximab due to target binding and complex elimination increased with baseline MTV. Central volume of distribution increased with body weight (P = .022) and baseline MTV (P = .005). Conclusions This study quantified for the first time the target‐mediated elimination of rituximab in NHL patients and confirmed rituximab retention by antigen mass.

Total Tumor Uptake and Absorbed Dose of 177Lu-Lilotomab Satetraxetan in a First in Human Trial for Relapsed Non-Hodgkin Lymphoma - Are We Hitting the Target?

“…Recent PK studies have reported that tumor burden in uences availability of two different CD20 mAbs, rituximab and obinutuzumab, in NHL patients. It was proposed that the standard dose given may not reach su cient therapeutic levels of mAbs in cases with high tumor burden [23,1,25]. Reduction of tRLU or tTAD with increasing tumor burden were not demonstrated in our study.…”

“…Patient weight and BSA are parameters which may affect biodistribution of pharmaceuticals as proposed by PK studies [22][23][24][25]. Our analysis did not show any correlations between neither patient weight nor BSA versus tTAD dosage (p = .34 and p = .50 respectively), and activity concentration in tumor (tRLU dosage /volume) (p = .59 and p = .66, respectively).…”

“…3 )[1] and Ternant et al (600cm3 )[25] might explain why we did not observe such effects. Unfortunately, Ternant et al used different methodology to assess tMTV; thus, a direct comparison with our study is not possible.…”

Population Pharmacokinetics of Rituximab in Pediatric Patients With Frequent-Relapsing or Steroid-Dependent Nephrotic Syndrome

“…To the best of our knowledge, this is the first population PK model for rituximab in pediatric patients with FRNS/SDNS. Thirteen PK models of rituximab have been reported in different disease populations: in patients with NHL ( Regazzi et al, 2005 ; Blasco et al, 2009 ; Müller et al, 2012 ; Gota et al, 2016 ; Tout et al, 2017a ; Rozman et al, 2017 ; Candelaria et al, 2018 ; Ternant et al, 2019 ), in patients with chronic lymphocytic leukemia (CLL) ( Li et al, 2012 ; Tout et al, 2017b ), in patients with rheumatoid arthritis ( Ng et al, 2005 ; Lioger et al, 2017 ) and in patients under plasmapherisis ( Puisset et al, 2013 ). Among these studies, rituximab PK was described as a two-compartment model ( Ng et al, 2005 ; Regazzi et al, 2005 ; Blasco et al, 2009 ; Li et al, 2012 ; Müller et al, 2012 ; Puisset et al, 2013 ; Gota et al, 2016 ; Tout et al, 2017a ; Tout et al, 2017b ; Lioger et al, 2017 ; Rozman et al, 2017 ; Candelaria et al, 2018 ; Ternant et al, 2019 ).…”

The impact of disease‐drug interactions on drug development and clinical practice

“…Pharmacokinetic disease‐drug interactions are more common for biologic drugs. Examples include target‐mediated drug disposition (TMDD) that is quantitatively modulated by exposure of the biological target correlated to disease load 3 …”