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Effects of Protein and Calorie Restriction on the Metabolism and Toxicity Profile of Irinotecan in Cancer Patients
Author(s) -
Man Femke M.,
Eerden Ruben A.G.,
Doorn Gerdien M.,
Oomende Hoop Esther,
Koolen Stijn L.W.,
Olieman Joanne F.,
Bruijn Peter,
Veraart Joris N.,
Halteren Henk K.,
Sandberg Yorick,
Moelker Adriaan,
IJzermans Jan N.M.,
Lolkema Martijn P.,
Gelder Teun,
Dollé Martijn E.T.,
Bruin Ron W.F.,
Mathijssen Ron H.J.
Publication year - 2021
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2094
Subject(s) - irinotecan , medicine , pharmacokinetics , neutropenia , gastroenterology , tolerability , toxicity , sn 38 , area under the curve , crossover study , pharmacology , cancer , adverse effect , colorectal cancer , pathology , placebo , alternative medicine
Preclinical data suggests that protein and calorie restriction (PCR) might improve treatment tolerability without impairing antitumor efficacy. Therefore, we have studied the influence of PCR on irinotecan pharmacokinetics and toxicity. In this crossover trial, patients with liver metastases of solid tumors were included and randomized to treatment with irinotecan preceded by 5 days of PCR (~ 30% caloric and ~ 70% protein restriction) during the first cycle and a second cycle preceded by a normal diet or vice versa . Pharmacokinetic blood sampling and biopsies of both healthy liver and liver metastases were performed. The primary end point was the relative difference in geometric means for the active metabolite SN‐38 concentration in healthy liver analyzed by a linear mixed model. No significant differences were seen in irinotecan (+ 16.8%, P = 0.22) and SN‐38 (+ 9.8%, P = 0.48) concentrations between PCR and normal diet in healthy liver, as well as in liver metastases (irinotecan: −38.8%, P = 0.05 and SN‐38: −13.8%, P = 0.50). PCR increased irinotecan plasma area under the curve from zero to 24 hours (AUC 0–24h ) with 7.1% ( P = 0.04) compared with normal diet, whereas the SN‐38 plasma AUC 0–24h increased with 50.3% ( P < 0.001). Grade ≥ 3 toxicity was not increased during PCR vs. normal diet ( P = 0.69). No difference was seen in neutropenia grade ≥ 3 (47% vs. 32% P = 0.38), diarrhea grade ≥ 3 (5% vs. 21% P = 0.25), and febrile neutropenia (5% vs. 16% P = 0.50) during PCR vs. normal diet. In conclusion, plasma SN‐38 exposure increased dramatically after PCR, whereas toxicity did not change. PCR did not alter the irinotecan and SN‐38 exposure in healthy liver and liver metastases. PCR might therefore potentially improve the therapeutic window in patients treated with irinotecan.