Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib.
OBJECTIVE
Prevalence of non-AIDS-defining cancers (NADCs) has increased in the era of potent antiretroviral treatments. Incidence rates of NADCs now exceed AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by interactions between antiretrovirals and chemotherapy mostly via inhibition or induction of CYP3A4. Erlotinib is used to treat non-small cell lung and pancreatic cancer and is primarily metabolized by CYP3A4 into multiple products including the active metabolite (OSI-420). Preclinical in vivo assessment was performed to gain a better understanding of CYP3A4-mediated interactions between antiretrovirals and erlotinib.


METHODS
Erlotinib (50 mg/kg p.o.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. QDx4), efavirenz (25 mg/kg p.o. QDx4), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). Blood samples were collected to characterize exposure (AUC).


RESULTS
Administration of erlotinib with CYP3A4 inducers (dexamethasone) and inhibitors (ketoconazole and ritonavir) resulted in significant alterations in erlotinib exposure. Ketoconazole and ritonavir resulted in a 1.7- and 3.0-fold increase in erlotinib AUC, respectively, while dexamethasone results in a 0.6-fold decrease in erlotinib AUC. The CYP3A4 inducer efavirenz did not have a significant effect on erlotinib exposure.


CONCLUSIONS
CYP3A4 inducers and inhibitors altered the exposure of erlotinib. Until a definitive clinical trial is performed, erlotinib should be used with caution in patients on a ritonavir-containing antiretroviral regimen, while standard doses may be appropriate for patients on an efavirenz-containing antiretroviral regimen.
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.|INOVA Comprehensive Cancer and Research Institute, Virginia Commonwealth University, INOVA Campus, Falls Church, VA, USA.
John F
JF
Deeken
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Jan H
JH
Beumer
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, Bunting-Blaustein Cancer Research Bldg. Room 1M52, Baltimore, MD, 21231-1000, USA.
Nicole M
NM
Anders
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, Bunting-Blaustein Cancer Research Bldg. Room 1M52, Baltimore, MD, 21231-1000, USA.
Teresia
T
Wanjiku
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Milan
M
Rusnak
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, Bunting-Blaustein Cancer Research Bldg. Room 1M52, Baltimore, MD, 21231-1000, USA. mrudek2@jhmi.edu.
Michelle A
MA
Rudek
D000284:Administration, Oral; D000480:Alkynes; D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000008:administration & dosage / Q000494:pharmacology; D001682:Biological Availability; D001711:Biotransformation / Q000187:drug effects; D003521:Cyclopropanes; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage / Q000494:pharmacology*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008815:Mice, Inbred Strains; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000097:blood; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*
D000480:Alkynes; D044966:Anti-Retroviral Agents; D000970:Antineoplastic Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; C487471:OSI-420; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D003907:Dexamethasone; D000069347:Erlotinib Hydrochloride; C098320:efavirenz; D019438:Ritonavir; D007654:Ketoconazole
AIDS; Drug interaction; Efavirenz; Erlotinib; Ritonavir