Coadministration of lapatinib increases exposure to docetaxel but not doxorubicin in the small intestine of mice.
Combination therapy is increasingly being utilized for the treatment of metastatic breast cancer. However, coadministration of drugs, particularly agents that are substrates for or inhibitors of p-glycoprotein, can result in increased tissue toxicity. Unfortunately, determination of levels of chemotherapeutics in human tissues is challenging, and plasma drug concentrations are not always indicative of tissue toxicokinetics or toxicodynamics, especially when tissue penetration is altered. The aim of the present work was to determine whether concomitant administration of compounds currently being combined in clinical trials for metastatic breast cancer treatment alters plasma and tissue pharmacokinetics in mice if both agents are p-glycoprotein substrates and/or inhibitors. Accordingly, we investigated the pharmacokinetic interactions of the classic cytotoxics and p-glycoprotein substrates docetaxel and doxorubicin when administered concurrently with the targeted agent and p-glycoprotein inhibitor lapatinib. Our time-course plasma and tissue distribution studies showed that coadministration of lapatinib with doxorubicin did not appreciably alter the pharmacokinetics of this anthracycline in the plasma or six tissues evaluated in mice, presumably because, at doses relevant to human exposure, lapatinib inhibition of p-glycoprotein did not significantly alter doxorubicin transport out of these tissue compartments. However, combining lapatinib with docetaxel significantly increased intestinal exposure to this chemotherapeutic, which has clinical implications for enhancing gastrointestinal toxicity. The significant lapatinib-docetaxel interaction is likely CYP3A4-mediated, suggesting that caution should be exercised when this combination is administered, particularly to patients with compromised CYP3A activity, and recipients should be monitored closely for enhanced toxicity, particularly for adverse effects on the intestine.
Department of Clinical Sciences, Animal Cancer Center, Colorado State University, Fort Collins, USA. susanhudachek@gmail.com
Susan F
SF
Hudachek
Daniel L
DL
Gustafson
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D000077143:Docetaxel; D004317:Doxorubicin / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D000077341:Lapatinib; D049990:Membrane Transport Modulators / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D008815:Mice, Inbred Strains; D009362:Neoplasm Metastasis / Q000188:drug therapy; D011799:Quinazolines / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D043823:Taxoids / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000187:drug effects; D059005:Topoisomerase II Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D050257:Tubulin Modulators / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D049990:Membrane Transport Modulators; D011799:Quinazolines; D043823:Taxoids; D059005:Topoisomerase II Inhibitors; D050257:Tubulin Modulators; D000077341:Lapatinib; D000077143:Docetaxel; D004317:Doxorubicin; D051544:Cytochrome P-450 CYP3A