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. 2023 Nov 23;24(23):16677.
doi: 10.3390/ijms242316677.

No Interference of H9 Extract on Trastuzumab Pharmacokinetics in Their Combinations

Seung Yon Han  1 , Jeong-Eun Yu  1 , Byoung Hoon You  1 , Seo-Yeon Kim  1 , Mingoo Bae  1 , Hee-Sung Chae  1   2 , Young-Won Chin  3 , Soo-Hwa Hong  4 , Ju-Hee Lee  5 , Seung Hyun Jung  5 , Young Hee Choi  1
Affiliations

No Interference of H9 Extract on Trastuzumab Pharmacokinetics in Their Combinations

Seung Yon Han et al. Int J Mol Sci. .

Abstract

Trastuzumab is used to treat breast cancer patients overexpressing human epidermal growth factor receptor 2, but resistance and toxicity limit its uses, leading to attention to trastuzumab combinations. Recently, the synergistic effect of trastuzumab and H9 extract (H9) combination against breast cancer has been reported. Because drug exposure determines its efficacy and toxicity, the question of whether H9 changes trastuzumab exposure in the body has been raised. Therefore, this study aimed to characterize trastuzumab pharmacokinetics and elucidate the effect of H9 on trastuzumab pharmacokinetics at a combination dose that shows synergism in mice. As a result, trastuzumab showed linear pharmacokinetics after its intravenous administration from 1 to 10 mg/kg. In the combination of trastuzumab and H9, single and 2-week treatments of oral H9 (500 mg/kg) did not influence trastuzumab pharmacokinetics. In the multiple-combination treatments of trastuzumab and H9 showing their synergistic effect (3 weeks of trastuzumab with 2 weeks of H9), the pharmacokinetic profile of trastuzumab was comparable to that of 3 weeks of trastuzumab alone. In tissue distribution, the tissue to plasma ratios of trastuzumab below 1.0 indicated its limited distributions within the tissues, and these patterns were unaffected by H9. These results suggest that the systemic and local exposures of trastuzumab are unchanged by single and multiple-combination treatments of H9.

Keywords: H9 extract; combination; dosage regimen; pharmacokinetic interaction; trastuzumab.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Dosage design scheme of trastuzumab and H9 according to the experimental groups of this study: (a) 1 and 10 mg/kg with single treatment of trastuzumab with or without H9, (b) 1 mg/kg with single treatment of trastuzumab with or without multiple treatment of H9, (c) 1 mg/kg with multiple treatment of trastuzumab with or without multiple treatment of H9.
Figure 2
Figure 2
Mean (±SD) plasma concentrations of trastuzumab after intravenous administration of trastuzumab at a dose of 1 mg/kg with (○; n = 6) and without (●; n = 7) 500 mg/kg of oral H9 in mice. Corresponding values in trastuzumab at a dose of 10 mg/kg with (△; n = 6) and without (▲; n = 6) 500 mg/kg of oral H9 in mice. Error bars represent standard deviations.
Figure 3
Figure 3
Mean (± SD) plasma concentrations of trastuzumab after its intravenous administration at a dose of 1 mg/kg with (○; n = 6) and without (●; n = 6) 2-week pretreatment of 500 mg/kg of oral H9 in mice. Error bars represent SD.
Figure 4
Figure 4
Mean (±SD) plasma concentrations of trastuzumab after its intravenous administration at a dose of 1 mg/kg with and without 500 mg/kg of oral H9 in multiple TM1 (○; n = 5) and multiple H9+TM1 mice (●; n = 6), respectively. Trastuzumab (1 mg/kg) was intravenously administered twice weekly for 3 weeks, and H9 (500 mg/kg) was orally administered once daily for 2 weeks in multiple H9+TM1 mice, whereas multiple TM1 mice were pretreated with the same dose and frequency of trastuzumab without 500 mg/kg of oral H9, respectively.
Figure 5
Figure 5
(a) Mean concentrations (μg/mL for plasma and μg/g tissue) and (b) T/P ratios of trastuzumab in plasma and tissues after intravenous administration of trastuzumab at a dose of 1 mg/kg with (○; n = 5) and without (●; n = 5) 500 mg/kg of oral H9 to mice. Error bars represent SD.
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