Journal of Steroid Biochemistry & Molecular Biology 77 (2001) 39 – 47 Pharmacokinetics and metabolism of formestane in breast cancer patients Per Eystein Lønning a , Ju ¨ rgen Geisler a , Dag Clement Johannessen a , Hans-Peter Gschwind b, *, Felix Waldmeier b , Werner Schneider b , Bruno Galli c , Tammo Winkler d , Wolfgang Blum e , Hans-Peter Kriemler f , William Russell Miller g , Johann Werner Faigle h a Department of Oncology, Haukeland Hospital, Uniersity of Bergen, N-5021 Bergen, Norway b Preclinical Safety, Drug Metabolism & Pharmacokinetics, Noartis Pharma AG, CH-4002 Basel, Switzerland c Preclinical Safety, Pharma Analytical Deelopment, Noartis Pharma AG, CH-4002 Basel, Switzerland d Spectroscopy Department, Syngenta AG, CH-4002 Basel, Switzerland e Pharma Research, Core Technology Area, PSB, Noartis Pharma AG, CH-4002 Basel, Switzerland f Klingnaustrasse 23, CH-4058 Basel, Switzerland g Western General Hospital, Uniersity of Edinburgh, Paderewski Building, Edinburgh EH42XU, Scotland, UK h Rheinparkstrasse 8, CH-4127 Birsfelden, Switzerland Received 25 July 2000; accepted 28 November 2000 Abstract Formestane (Lentaron ® , 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) injection. To investigate the pharmacokinetics, bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose of 1 mg of 14 C-labelled formestane. The plasma kinetics after i.m. dosing confirmed a sustained release of formestane from the site of injection. Within 24–48 h of the first dose, the circulating drug reached a C max of 48.0 20.9 nmol/l (mean S.D.; N =7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3 1.8 nmol/l. The kinetic variables did not significantly change during prolonged treatment. Intramuscular doses appear to be fully bioavailable. Following i.v. injection of 14 C-formestane, the unchanged drug disappeared rapidly from plasma, the terminal elimination half-life being 18 2 min (N =3). Plasma clearance, CL was 4.2 1.3 l/(h kg) and the terminal distribution volume V z was 1.8 0.5 l/kg. The drug is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14 C-compounds in urine and faeces totals up to 98.9 0.8% of the i.v. dose after 168 h. The 14 C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3,4-dihydroxy-5-androstane-17-one and 3,4-dihydroxy-5-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Formestane; Clinical pharmacokinetics; Metabolism; Breast cancer; Excretory balance; Radiotracer www.elsevier.com/locate/jsbmb 1. Introduction Formestane (Lentaron ® ) is a synthetic steroid acting as a selective aromatase inhibitor in vitro and in vivo. It reduces the circulating oestrogen levels, and has shown anti-tumour activity in postmenopausal women with breast cancer [1–5]. Clinically, it is administered as a * Corresponding author. Tel.: +41-61-696-6629; fax: +41-61-696- 4317. E-mail address: hans-peter.gschwind@pharma.novartis.com (H.-P. Gschwind). 0960-0760/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0960-0760(01)00029-2