Evaluation for pharmacokinetic exposure of cytotoxic anticancer drugs in elderly patients receiving (R-)CHOP therapy

Junichi Nakagawa,Yu Chen,Kensuke Saito,Kazuhiro Hosoi,Takenori Niioka,Takenori Takahata,Rui Hyodo,Kayo Ueno,Kota Sasaki,Atsushi Sato,Kengo Hasui,Kazufumi Terui

doi:10.1038/s41598-020-80706-2

Junichi Nakagawa, Yu Chen + Show 10 more

Open Access

https://doi.org/10.1038/s41598-020-80706-2

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Abstract

(R-)miniCHOP therapy, which delivers approximately half-doses of the (R-)CHOP regimen, has shown efficacy and safety in patients who are more than 80 years old. This study aimed to compare the area under the plasma concentration–time curves (AUCs) of vincristine (VCR), doxorubicin (DXR), and cyclophosphamide (CPA) between (R-)CHOP and (R-)miniCHOP regimens. The AUCs were compared between patients aged 65–79 years receiving (R-)CHOP therapy and those aged 80 years and older receiving (R-)miniCHOP therapy. Age was not an independent variable for predicting the dose-adjusted AUCs (AUC/Ds) of cytotoxic anticancer drugs. The median AUCs of DXR and CPA were significantly smaller in the (R-)miniCHOP group than in the (R-)CHOP group (168.7 vs. 257.9 ng h/mL, P = 0.003, and 219.9 vs. 301.7 µg h/mL, P = 0.020, respectively). The median AUCs of VCR showed the same trend but the difference was not significant (24.83 vs. 34.85 ng h/mL, P = 0.135). It is possible that the AUCs of VCR, DXR, and CPA in patients aged 80 years and older receiving (R-)miniCHOP therapy may be lower than those in patients 65–79 years old receiving (R-)CHOP therapy.

Highlights

Diffuse large B-cell lymphoma (DLBCL) accounts for more than 30% of all non-Hodgkin’s lymphoma (NHL) cases in Japan[1], and its incidence continues to increase[2]
The minimum effective and toxic concentrations for each cytotoxic anticancer drug are not clear. It is unclear whether a dose adjustment based on body surface area (BSA) or age can be used uniformly to establish the pharmacokinetic exposure of these cytotoxic anticancer drugs
Very few clinical studies have focused on the pharmacokinetics of cytotoxic anticancer drugs in elderly patients receiving CHOP therapy

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL) accounts for more than 30% of all non-Hodgkin’s lymphoma (NHL) cases in Japan[1], and its incidence continues to increase[2]. CHOP therapy, a multidrug combination chemotherapy with vincristine (VCR), doxorubicin (DXR), cyclophosphamide (CPA), and prednisolone (PSL), is the standard chemotherapy for the treatment of various subtypes of NHL, including DLBCL. Low relative or intended dose intensity (DI) reduces the efficacy of CHOP therapy and maintaining high treatment intensity is important for successful treatment of D LBCL6–9 These DIs may be associated with the pharmacokinetic exposure of cytotoxic anticancer drugs in CHOP therapy[7,9]. The relationship between dose and blood concentration levels of cytotoxic anticancer drugs in elderly patients receiving CHOP therapy is not sufficiently clear. We first investigated the factors that contribute to the effects of individual patient characteristics on the pharmacokinetics of VCR, DXR, and CPA in elderly patients aged 65 years or older. We compared the AUCs of VCR, DXR, and CPA between elderly patients aged 80 years and older receiving (R-)miniCHOP therapy and those aged 65–79 years old receiving (R-)CHOP therapy

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