Pharmacokinetic drug-drug interaction of the novel anticancer agent E7070 and acenocoumarol.
E7070 is a novel sulfonamide anticancer agent that arrests cancer cells at the G1/S boundary of the cell cycle. Three patients receiving chronic therapy with the oral anticoagulant acenocoumarol experienced bleeding and/or a prolonged prothrombin time after treatment with E7070 at a dose of 700 mg/m2 given as a 1-h infusion. In vitro studies have shown that E7070 has the potential to inhibit several cytochrome P450 (CYP)-enzymes, including CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The major enzyme involved in the metabolism of acenocoumarol in man is CYP2C9. This study was performed to investigate the interaction between E7070 and acenocoumarol. Blood samples were obtained from two patients receiving daily oral maintenance treatment with acenocoumarol both prior to and following treatment with E7070. In addition, we incubated acenocoumarol enantiomers with pooled human microsomes with and without E7070 and measured the in vitro plasma protein binding of acenocoumarol after incubation with E7070. Pharmacokinetic parameters of acenocoumarol were calculated by noncompartmental analysis and revealed that in both patients the area under the concentration-time curve up to 24 h after the acenocoumarol administration was higher following E7070 (2.56 and 1.58 h*micromol/L) compared to the systemic exposure in the absence of E7070 (1.87 and 1.23 h*micromol/l). The formation of acenocoumarol metabolites was retarded by E7070 at already low concentrations (2.1 microM). The plasma protein binding of acenocoumarol was reduced at higher concentrations of E7070 (259 microM). These results indicate that E7070 may primarily interact with acenocoumarol by reducing its systemic clearance. Displacement of acenocoumarol's plasma protein binding by E7070 may also occur but to a minor extent. In the absence of careful monitoring this drug-drug interaction may result in hypoprothrombinemia and a hemorrhagic tendency.
van den Bongard
H J G Desirée
HJ
Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands. apdvb@slz.nl
Sparidans
Rolf W
RW
Critchley
David J P
DJ
Beijnen
Jos H
JH
Schellens
Jan H M
JH
D000074:Acenocoumarol / Q000097:blood / Q000493:pharmacokinetics*; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D016009:Chi-Square Distribution; D004347:Drug Interactions; D015507:Drugs, Investigational / Q000493:pharmacokinetics*; D006801:Humans; D016018:Least-Squares Analysis; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D011517:Prothrombin Time / Q000706:statistics & numerical data; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*
D000925:Anticoagulants; D000970:Antineoplastic Agents; D015507:Drugs, Investigational; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides; D000074:Acenocoumarol