Abstract P1-12-15: Intermittent dosing of aromatase inhibitors (AI) to improve tolerance in post-menopausal women
Authors: Launay-Vacher Vincent , Salmon Rémy , Rey Jean-Baptiste 
Published: May 2015

Clinical rationale: A significant proportion of post-menopausal, patients treated with AI reports side-effects, especially bone pain. In such patients, the difficulties to treat pain and to clearly identify its causes may lead to treatment discontinuation. Individual cases reported an improvement in AI tolerance when dosage is reduced. The aim of this work was thus to analyse pharmacological data in order to validate this concept ie. ensuring that intermittent dosing would not result in a possibly deleterious under-dosing of AI.

Pharmacological rationale: Ageing is associated with physiological modifications that may impair drug pharmacokinetics (PKs). The elimination can be altered, with decreased drug clearance (CL), resulting in an increased exposure to the drug, reflected by increased AUCs. Drugs benefit-risk balance can thus be modified. The major sources of PKs alterations in the elderly are hepatic and/or renal impairments (HI/RI).

It has been shown that AI PKs are altered in the elderly and/or in case of HI or RI. Exemestane AUC is increased 3-fold in the elderly and in case of RI [1,2]. Letrozole AUC can double in case of HI [3] and a 42%-increase has been reported in the elderly [4]. The renal CL of anastrozole is reduced by 50% in RI, resulting in a 10% decrease in total body CL. In HI, total body CL is 30% lower as compared to normal [5].

These data demonstrate that elderly patients may be overexposed to AI when treated with the usual dosage, resulting in safety issues occurring in some patients. As a result, a dosage adjustment approach could help prevent over-exposure and reduce side-effects incidence/severity.

Proof-of-Concept studies: The reported increases in AI exposure being around 50%, an intermittent dosing schedule of 1 administration every other day could result in a similar drug exposure as compared to the usual daily schedule. AI elimination half-lives in the absence of any alteration also are consistent with this dosing schedule (24, 48, and 50 hours for exemestane, letrozole, and anastrozole, respectively). In order not to impair plasma concentrations, such a schedule is preferably suggested as compared to a half-dose daily schedule. Prospective studies are needed, in which the PKs, efficacy, and safety of this intermittent dosing schedule should be conducted.

References:

[1] Aromasin® FDA Labeling Information; 2013 labeling revision; http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020753s014lbl.pdf; accessed 04/29/2014

[2] Jannuzzo MG, et al. Cancer Chemother Pharmacol. 2004; 53(6): 475-81.

[3] Femara® FDA Labeling Information; 2014 labeling revision; http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020726s027lbl.pdf; accessed 04/29/2014

[4] Pfister CU, et al. Effect of age and single versus multiple dose pharmacokinetics of

letrozole (Femara) in breast cancer patients. Biopharm Drug Dispos. 2001; 22(5): 191-7.

[5] Arimidex® FDA Labeling Information; 2013 labeling revision; http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020541s027lbl.pdf; accessed 04/29/2014.

Citation Format: Vincent Launay-Vacher, Rémy Salmon, Jean-Baptiste Rey. Intermittent dosing of aromatase inhibitors (AI) to improve tolerance in post-menopausal women [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-15.