Model-Informed Precision Dosing to Reduce Vincristine-Induced Peripheral Neuropathy in Pediatric Patients: A Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis

Abstract

Background Vincristine-induced peripheral neuropathy (VIPN) is a common adverse effect of vincristine, a drug often used in pediatric oncology. Previous studies demonstrated large inter- and intrapatient variability in vincristine pharmacokinetics (PK). Model-informed precision dosing (MIPD) can be applied to calculate patient exposure and individualize dosing using therapeutic drug monitoring (TDM) measurements. This study set out to investigate the PK/pharmacodynamic (PKPD) relationship of VIPN and determine the utility of MIPD to support clinical decisions regarding dose selection and individualization. Methods Data from 35 pediatric patients were utilized to quantify the relationship between vincristine dose, exposure and the development of VIPN. Measurements of vincristine exposure and VIPN (Common Terminology Criteria for Adverse Events [CTCAE]) were available at baseline and for each subsequent dosing occasions (1–5). A PK and PKPD analysis was performed to assess the inter- and intraindividual variability in vincristine exposure and VIPN over time. In silico trials were performed to portray the utility of vincristine MIPD in pediatric subpopulations with a certain age, weight and cytochrome P450 (CYP) 3A5 genotype distribution. Results A two-compartmental model with linear PK provided a good description of the vincristine exposure data. Clearance and distribution parameters were related to bodyweight through allometric scaling. A proportional odds model with Markovian elements described the incidence of Grades 0, 1 and ≥ 2 VIPN overdosing occasions. Vincristine area under the curve (AUC) was the most significant exposure metric related to the development of VIPN, where an AUC of 50 ng⋅h/mL was estimated to be related to an average VIPN probability of 40% over five dosing occasions. The incidence of Grade ≥ 2 VIPN reduced from 62.1 to 53.9% for MIPD-based dosing compared with body surface area (BSA)-based dosing in patients. Dose decreases occurred in 81.4% of patients with MIPD (vs. 86.4% for standard dosing) and dose increments were performed in 33.4% of patients (no dose increments allowed for standard dosing). Conclusions The PK and PKPD analysis supports the use of MIPD to guide clinical dose decisions and reduce the incidence of VIPN. The current work can be used to support decisions with respect to dose selection and dose individualization in children receiving vincristine. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01336-1.

Vincristine exposure in Kenyan children with cancer: CHAPATI feasibility study

“…Two recently published studies support individualized dosing through the development of a target area under the curve (AUC) in relation to exposures observed in children with cancer 24 and to the risk of VIPN. 25 The latter might not be applicable to Kenyan patients, as our findings suggest that the lower incidence of VIPN is the result of pharmacodynamics (PD) rather than PK. The use of a target AUC might not be sensible in Kenyan children until this is elucidated.…”

Pharmacogenetic Testing or Therapeutic Drug Monitoring: A Quantitative Framework

“…Vincristine: A two-compartmental vincristine model by Centanni et al was selected (Table 1 ) [ 24 ]. This model accounted for the 87% increased clearance of vincristine amongst the CYP3A5 high-expresser genotype versus the low-expresser genotype [ 25 ].…”

“…This outcome can be partly attributed to the fact that AUC calculation relied on three optimized sampling times, which may be too sparse for accurate trapezoidal calculations, particularly for drugs with multiple PK phases. This is problematic for both vincristine, which exhibits a rapid distribution (within 10 min), and 5-FU, which displays a short half-life (10–20 min), making precise measurement of exposure challenging [ 23 , 24 ]. Nonetheless, three samples are regarded as relatively high within the clinical context, as obtaining a larger number of blood samples is labor-intensive and difficult in routine practice [ 26 ].…”

“…Future efforts may explore combining pharmacogenetic biomarkers and TDM for more sophisticated dose adjustments [ 40 – 42 ]. However, integrating multiple biomarkers simultaneously may pose challenges in decision making, requiring methods like MIPD to consolidate diverse dosing recommendations, as proposed for vincristine [ 24 ], tamoxifen [ 43 ], and tacrolimus [ 44 ].…”