Population Pharmacokinetics of Vincristine Related to Infusion Duration and Peripheral Neuropathy in Pediatric Oncology Patients

Abstract

<jats:p>Vincristine (VCR) is frequently used in pediatric oncology and can be administered intravenously through push injections or 1 h infusions. The effects of administration duration on population pharmacokinetics (PK) are unknown. We described PK differences related to administration duration and the relation between PK and VCR-induced peripheral neuropathy (VIPN). PK was assessed in 1–5 occasions (1–8 samples in 24 h per occasion). Samples were analyzed using high-performance liquid chromatography/tandem mass spectrometry. Population PK of VCR and its relationship with administration duration was determined using a non-linear mixed effect. We estimated individual post-hoc parameters: area under the concentration time curve (AUC) and maximum concentration (Cmax) in the plasma and peripheral compartment. VIPN was assessed using Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score (ped-mTNS). Overall, 70 PK assessments in 35 children were evaluated. The population estimated that the intercompartmental clearance (IC-Cl), volume of the peripheral compartment (V2), and Cmax were significantly higher in the push group. Furthermore, higher IC-Cl was significantly correlated with VIPN development. Administration of VCR by push led to increased IC-Cl, V2, and Cmax, but were similar to AUC, compared to 1 h infusions. Administration of VCR by 1 h infusions led to similar or higher exposure of VCR without increasing VIPN.</jats:p>

Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology: A Randomized Controlled Trial Comparing Push Injections with One-Hour Infusions (The VINCA Trial)

“…Data on VCR PK and SNP’s were also collected as part of this trial, but analyses of these data was beyond the scope of this paper. Data of this trial regarding administration duration related to PK were published separately [ 42 ]. Potentially, infusion of VCR in one-hour could lead to an increased risk of extravasation, which is dangerous in VCR treatment.…”

The association between vincristine‐induced peripheral neuropathy and health‐related quality of life in children with cancer

“…For instance, it was demonstrated that certain genetic aberrations, like a single nucleotide polymorphism in centrosomal protein 72 (CEP72) influence the development of VIPN in children. 39 Following this, studies could be undertaken that use these genetic aberrations to dose modify VCR in certain populations requiring more or less. Another approach would be to study pharmacokinetics of VCR.…”

“…There is no established target VCR exposure yet, but reliable VCR PK data have been collected that could contribute to this. 13 , 40 When the target VCR exposure is known, VCR doses could be adapted accordingly. Finally, improving administration duration of VCR can optimize VCR treatment.…”

“…Finally, improving administration duration of VCR can optimize VCR treatment. 16 , 40 , 41 When one of these, or other, approaches are studied and used for the optimization of VCR treatment, ideally the effect of the intervention on HR‐QoL of children should also be studied.…”

Biomarkers of Chemotherapy-Induced Peripheral Neuropathy: Current Status and Future Directions

“…In a subsequent study assessing pharmacokinetics of vincristine in 74 pediatric patients, lower vincristine metabolite concentrations were associated with increased CIPN severity ( 45 ). Another study assessed vincristine pharmacokinetics in 35 patients receiving vincristine via push or 1 h infusions and found intercompartment clearance of vincristine was associated with an increased risk of CIPN, however other pharmacokinetic measures including maximum concentration were not associated with an increased CIPN risk ( 90 ).…”