Pharmacokinetic Characterization of Amrubicin Cardiac Safety in an Ex Vivo Human Myocardial Strip Model. I. Amrubicin Accumulates to a Lower Level than Doxorubicin or Epirubicin

Abstract

Antitumor anthracyclines such as doxorubicin and epirubicin are known to cause cardiotoxicity that correlates with anthracycline accumulation in the heart. The anthracycline amrubicin [(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-␤-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-napthacenedione hydrochloride] has not shown cardiotoxicity in laboratory animals or patients in approved or investigational settings; therefore, we conducted preclinical work to characterize whether amrubicin attained lower levels than doxorubicin or epirubicin in the heart. Anthracyclines were evaluated in ex vivo human myocardial strips incubated in plasma to which anthracycline concentrations of 3 or 10 M were added. Four-hour incubations were performed to characterize myocardial anthracycline accumulation derived from anthracycline uptake in equilibrium with anthracycline clearance. Short-term incubations followed by multiple washouts were performed to obtain independent measurements of anthracycline uptake or clearance. In comparison with doxorubicin or epirubicin, amrubicin attained very low levels in the soluble and membrane fractions of human myocardial strips. This occurred at both 3 and 10 M anthracycline concentrations and was caused primarily by a highly favorable clearance of amrubicin. Amrubicin clearance was facilitated by formation and elimination of sizeable levels of 9-deaminoamrubicin and 9-deaminoamrubicinol. Amrubicin clearance was not mediated by P glycoprotein or other drug efflux pumps, as judged from the lack of effect of verapamil on the partitioning of amrubicin and its deaminated metabolites across myocardial strips and plasma. Limited accumulation of amrubicin in an ex vivo human myocardial strip model may therefore correlate with the improved cardiac tolerability observed with the use of amrubicin in preclinical or clinical settings.

The Novel Anthracenedione, Pixantrone, Lacks Redox Activity and Inhibits Doxorubicinol Formation in Human Myocardium: Insight to Explain the Cardiac Safety of Pixantrone in Doxorubicin-Treated Patients

“…DOX accumulation was determined by the net levels of DOX retention in the strips at the end of the 4-hour incubations. In the DOX loading/washout (s) experiments, uptake was determined as [(DOX accumulation) 1 (DOX efflux in plasma)]; DOX clearance was determined as [100 Â (efflux/uptake)] (Salvatorelli et al, 2012b). Similar procedures were adopted in ad hoc experiments with single-agent anthracenedione.…”

“…The calcium channel blocker verapamil was used to inhibit P-glycoprotein and MRP1 (Vellonen et al, 2004). To avoid confounding effects due to calcium channel blockade, verapamil was used at a concentration level (1 mM) that was high enough to inhibit DOX extrusion by MDR proteins (Salvatorelli et al, 2012b) but was lower than verapamil plasma levels associated with calcium channel blockade and cardiovascular effects in clinical studies of tumor resistance reversal (Motzer et al, 1995;Warner et al, 1998). In the strips sequentially exposed to DOX loading/multiple washouts and PIX, 1 mM verapamil increased the accumulation of DOX but not of PIX (Fig.…”

Pharmacokinetic Characterization of Amrubicin Cardiac Safety in an Ex Vivo Human Myocardial Strip Model. II. Amrubicin Shows Metabolic Advantages over Doxorubicin and Epirubicin

“…Doxorubicin exhibited these characteristics (Xu et al, 2011;Salvatorelli et al, 2012). Amrubicin attained much lower levels in the membrane and was considerably less polar than doxorubicin ; therefore, amrubicin had more chances to produce H 2 O 2 through a canonical redox cycling mechanism.…”

“…In conclusion, the pharmacokinetic and biotransformation characteristics of amrubicin, as described here and in Salvatorelli et al (2012), provide mechanistic explanations supporting the lack of cardiotoxicity in preclinical models and clinical trials. Amrubicin seems to offer safety advantages over older anthracycline analogs and is worthy of further study in malignant clinical indications where cumulative dose restrictions may limit efficacy.…”

Amrubicin as second- or third-line treatment for women with metastatic HER2-negative breast cancer: a Sarah Cannon Research Institute phase 1/2 trial

“…The active metabolite, amrubicinol, has been shown to be 5-54 times more potent than amrubicin and as potent as doxorubicin [9]. Preclinical studies found very low levels of amrubicin accumulation in human myocardial strips when compared to doxorubicin or epirubicin, suggesting a lower potential for cardiotoxicity [10]. To date, no classic anthracycline-induced cardiomyopathy has been observed with amrubicin.…”