Modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens.
Aurelia H.M. de Vries Schultink (1), Annelies H. Boekhout (1), J.G. Coen van Hasselt (2), Jan H.M. Schellens (1,3), Alwin D.R. Huitema (1,4)
(1) Antoni van Leeuwenhoek - Netherlands Cancer Institute, Amsterdam, (2) Leiden University, Netherlands (3) Pharmacoepidemiology & Clinical Pharmacology,, Utrecht University, Utrecht, (4) University Medical Center Utrecht, Utrecht.
Objectives: Trastuzumab is used to treat HER2-receptor positive breast cancer patients. Trastuzumab treatment is associated with cardiotoxicity, manifesting as a decline of the left-ventricular ejection fraction (LVEF) values [1]. Patients treated with trastuzumab are often pretreated with anthracyclines, which are also known to induce cardiotoxicity. Troponine-T (TnT) is a molecular marker suggested to allow earlier detection of drug-induced cardiotoxicity. In this analysis we aim to quantify the kinetics and exposure-response relationship of TnT and LVEF measurements, in patients receiving anthracycline and trastuzumab treatment.
Methods: Repeated measurements for cardiotoxicity biomarkers LVEF and TnT were available from a previously randomized clinical trial investigating protection for trastuzumab induced cardiotoxicity with candesartan [2] (n=206). Individual patient dosing records of anthracycline and trastuzumab were also available. The mean PK of trastuzumab was described using a previously published PK model [3]. A K-PD approach [4] was used for the anthracyclines (doxorubicin and epirubicin). We used a single effect-compartment model to associate drug exposure to the LVEF measurements and a turn-over model to associate anthracycline exposure to TnT concentrations.
Results: Anthracycline-induced cardiotoxicity translated into a peak increase of TnT, with a turnover time of 106 days (relative standard error (RSE) 8%). De linear slope effect of anthracycline on the Kin rate for TnT was significantly affected by the type of anthracycline administered, translating into a decrease in the slope parameter by 0.521 (RSE 17%) for epirubicine compared to doxorubicine. Trastuzumab-induced cardiotoxicity translated into a decrease of LVEF values, which recovered after treatment (recovery half-life of 57 days, RSE 22%). The maximum TnT concentrations during anthracycline treatment were related to the baseline LVEF values before start of trastuzumab.
Conclusions: A PK/PD model was developed, describing the relationship between trastuzumab exposure and LVEF and the relationship between anthracycline exposure and TnT. This analysis demonstrated, as previously reported, that the decline in LVEF recovers after treatment cessation. In addition, the maximum TnT concentrations during anthracycline pretreatment affected the baseline LVEF value before start of trastuzumab-treatment and can therefore possibly identify patients susceptible for cardiotoxicity.
References:
[1] Hasselt JGC, Boekhout AH, Beijnen, et al. Population pharmacokinetic-pharmacodynamic analysis of trastuzumab-associated cardiotoxicity. Clin Pharmacol Ther. 2011 90 (1): 126-132
[2] Boekhout AH, Gietema JA, Miljkovic Kerklaan B, et al. Angiotensin II-receptor inhibition with candesartan to prevent trastuzumab-related cardiotoxic effects in patients with early breast cancer. JAMA Oncology 2016 Aug 1;2(8):1030-7.
[3] Bruno R, Washington CB, Lu J-F, et al. Population pharmacokinetics of trastuzumab in patients with HER2+ metastatic breast cancer. Cancer Chemother. Pharmacol. 2005;56:361-9
[4] Jacqmin P, Snoeck E, van Schaick EA, et al. Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model. J Pharmacokinet Pharmacodyn. 2007 Feb;34(1):57-85
