In:
Clinical Pharmacology & Therapeutics, Wiley, Vol. 109, No. 5 ( 2021-05), p. 1304-1313
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0009-9236
,
1532-6535
Language:
English
Publisher:
Wiley
Publication Date:
2021
detail.hit.zdb_id:
2040184-X
SSG:
15,3
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