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Cancer Chemother Pharmacol. 2019 Jul;84(1):175-185. doi: 10.1007/s00280-019-03852-z. Epub 2019 May 17.

Pharmacokinetics of trastuzumab emtansine (T-DM1) as a single agent or in combination with pertuzumab in HER2-positive breast cancer patients with recurrent or locally advanced metastatic breast cancer.

Author information

1
Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. lu.dan@gene.com.
2
Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
3
Metrum Research Group, 2 Tunxis Rd # 112, Tariffville, CT, USA.
4
F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland.

Abstract

PURPOSE:

The phase III MARIANNE study investigated single-agent trastuzumab emtansine (T-DM1) and combination T-DM1 plus pertuzumab as the first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Pharmacokinetic properties of T-DM1 and pertuzumab in these patients and the potential for drug-drug interactions (DDIs) were assessed.

METHODS:

Pharmacokinetic samples of T-DM1-related analytes (T-DM1 conjugate, total trastuzumab, DM1) and pertuzumab were analyzed. Observed pharmacokinetic data were summarized for all analytes. Historical population pharmacokinetic models for T-DM1 conjugate and pertuzumab in HER2-positive MBC were used to derive empirical Bayes estimates of pharmacokinetic parameters.

RESULTS:

In MARIANNE (N = 375), mean ± standard deviation population pharmacokinetic model-predicted Cycle 1 Cmax for T-DM1 conjugate was 74.4 ± 10.1 µg/mL, Cycle 1 Ctrough was 1.34 ± 0.802 µg/mL, and area under the concentration-time curve from time zero to infinity after first dose (AUCinf) was 338 ± 69.5 µg*day/mL. These values were similar to other T-DM1 studies. Pharmacokinetics of T-DM1 conjugate and other analytes (total trastuzumab, DM1) were similar with or without pertuzumab. In the pertuzumab plus T-DM1 arm, mean model-predicted Cycle 1 pertuzumab Cmax, Ctrough, and AUCinf were 276 ± 50.0 µg/mL, 64.8 ± 17.9 μg/mL, and 4470 ± 1360 µg*day/mL, respectively. These values were similar to other pertuzumab studies.

CONCLUSIONS:

Based on the population pharmacokinetic analysis of T-DM1 conjugate and pertuzumab, pharmacokinetics are similar across different lines of treatment and stages of disease including previously untreated MBC patients, and no DDIs were identified for combined use of T-DM1 and pertuzumab.

KEYWORDS:

HER2; MARIANNE; Pharmacokinetics; Previously untreated metastatic breast cancer; Trastuzumab emtansine (T-DM1)

PMID:
31102024
DOI:
10.1007/s00280-019-03852-z

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