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

Abstract

Purpose Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. Methods A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. Results While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. Conclusion Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.

Vincristine Disposition and Neurotoxicity Are Unchanged in Humanized CYP3A5 Mice

“…A potential connection of ABCB1mediated efflux and vincristine toxicity is supported by the previous finding that variants in the ABCB1 gene are correlated with VIPN in some populations (Pozzi et al, 2021). Interestingly, studies involving physiology-based pharmacokinetic modeling of vincristine (Pilla Reddy et al, 2021) and the use of knockout mice (Wang et al, 2010) have suggested that pharmacological inhibition or genetic deficiency of ABCB1 is associated with negligible increases in the plasma concentrations of vincristine. Although further validation studies are required under ABCB1deficient conditions and to determine the potential for drug-drug-gene interactions (Malki and Pearson, 2020), this collective prior work implies that modulation of ABCB1 in target cells within the peripheral nervous system can affect the cellular retention of vincristine and downstream toxic events without altering systemic clearance (Stage et al, 2021).…”

Vinblastine pharmacokinetics in mouse, dog, and human in the context of a physiologically based model incorporating tissue‐specific drug binding, transport, and metabolism

“…An example of such an approach is the recently published PBPK model for vincristine and its application to predict potential drug–drug interactions with Bruton tyrosine kinase inhibitors being added to R‐CHOP protocols for lymphoma. 25 ABCB1 activity is of particular concern in veterinary medicine as the frequency and variability of canines presenting the ABCB1‐1Δ 61 mutation necessitates further understanding of its implications in the context of VBL treatment. Although VBL PK levels in all other tissues are not significantly different between the wild‐type and Mdr1a/b(−/−) mouse data, the presence of a known mutation in a clinical setting can have implications on achieved VBL plasma concentrations.…”

“…This model provides the quantitative framework to test and validate potential drug–drug interactions and extrapolate to individual physiological conditions such as diminished liver or renal function. An example of such an approach is the recently published PBPK model for vincristine and its application to predict potential drug–drug interactions with Bruton tyrosine kinase inhibitors being added to R‐CHOP protocols for lymphoma 25 . ABCB1 activity is of particular concern in veterinary medicine as the frequency and variability of canines presenting the ABCB1‐1Δ 61 mutation necessitates further understanding of its implications in the context of VBL treatment.…”

“…Previous human PBPK models have been published for vincristine with incorporation of tubulin as a key driver of drug disposition. 24 , 25 These previous models, however, utilized a relative tubulin expression value for all relevant tissues. To our knowledge, the presented model is the first PBPK model of VBL, and the first vinca alkaloid model to incorporate variability in organ tubulin expression and provide an interspecies scaled model from mouse to canine and human.…”

“…Previous human PBPK models have been published for vincristine with incorporation of tubulin as a key driver of drug disposition 24,25 . These previous models, however, utilized a relative tubulin expression value for all relevant tissues.…”