Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition

Abstract

Vincristine is a cytotoxic chemotherapeutic agent used as first‐line therapy for pediatric acute lymphocytic leukemia. It is cleared by hepatic oxidative metabolism by CYP3A4 and CYP3A5 and via hepatic (biliary) efflux mediated by P‐glycoprotein (P‐gp) transporter. Bottom‐up physiologically based pharmacokinetic (PBPK) models were developed to predict vincristine disposition in pediatric and adult populations. The models incorporated physicochemical properties, metabolism by CYP3A4/5, efflux by P‐gp, and intracellular binding to β‐tubulin. The adult and pediatric PBPK models predicted pharmacokinetics (PK) within twofold of the observed PK parameters (area under the curve, terminal half‐life, volume of distribution, and clearance). Simulating a higher hypothetical (4.9‐fold) pediatric expression of β‐tubulin relative to adult improved predictions of vincristine PKs. To our knowledge, this is the first time that intracellular binding has been incorporated into a pediatric PBPK model. Utilizing this PBPK modeling approach, safe and effective doses of vincristine could be predicted.

Impact of Hepatic CYP3A4 Ontogeny Functions on Drug–Drug Interaction Risk in Pediatric Physiologically‐Based Pharmacokinetic/Pharmacodynamic Modeling: Critical Literature Review and Ivabradine Case Study

“…In vitro-derived hepatic ontogeny functions using diverse reference drugs (e.g., midazolam and sildenafil) showed an increase in CYP3A4 abundance and/or activity over age. 16,[34][35][36][37][38] Although several studies using in vivo data were in agreement with these in vitro-derived functions, recently reported maturation functions showed a different profile. 22 Upreti and Wahlstrom 22 indicated an increase in hepatic CYP3A4 fraction of the adult value up to 2 years old.…”

“…All CYP3A4‐reported ontogeny relationships are plotted in Figure . In vitro –derived hepatic ontogeny functions using diverse reference drugs (e.g., midazolam and sildenafil) showed an increase in CYP3A4 abundance and/or activity over age 16,34–38 . Although several studies using in vivo data were in agreement with these in vitro –derived functions, recently reported maturation functions showed a different profile 22 .…”

Vincristine-Induced Peripheral Neuropathy in Childhood Acute Lymphoblastic Leukemia: Genetic Variation as a Potential Risk Factor

“…These pharmacokinetic manifestations limit the clinical efficacy of VCR due to its high binding capacity to normal tissue and limited tumor tissue exposure ( Said and Tsimberidou, 2014 ). VCR is primarily metabolized in the liver by the CYP3A subtype, specifically CYP3A4 and CYP3A5 enzymes ( Lee et al, 2019 ). M1 is the major metabolite.…”

“…M2 and M4 are the two minor metabolites of VCR ( Pozzi et al, 2021 ). In the human body, most VCR is excreted through bile and feces, and less through the kidneys ( Bender et al, 1977 ; Lee et al, 2019 ). VCR is excreted as an unchanged parent drug along with metabolites ( Jackson et al, 1978 ) ( Figure 1 ).…”

Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors

“…Based on these overall results, there is no reason to anticipate an increased risk of VIPN in patients treated with acalabrutinib and R-CHOP. Further studies examining the effects of vincristine binding to tubulin [48] and on vincristine distribution and DDI will be explored to more fully elucidate factors increasing the risk of VIPN. Additionally, the two ongoing studies assessing acalabrutinib in combination with R-CHOP regimens (NCT03571308, NCT04002947) will provide further information regarding the safety profile of therapies combining acalabrutinib and vincristine.…”