Potential interactions between HIV drugs, ritonavir and efavirenz and anticancer drug, nilotinib--a study in primary cultures of human hepatocytes that is applicable to HIV patients with cancer.
Nilotinib is used to treat chronic myeloid leukemia (CML), and is metabolized by CYP3A. With a black-box warning for QT prolongation, which is exposure dependent, controlling for drug interactions is clinically relevant. Treatments of HIV patients with CML are with HAART drugs, ritonavir and efavirenz, may cause complex drug interactions through CYP3A inhibition or induction. We evaluated the interactions of ritonavir or efavirenz on nilotinib using human hepatocytes and compared these interactions with those of ketoconazole or rifampin, classical CYP3A inhibitor and inducer, respectively. Hepatocytes were treated with vehicle, ritonavir (10 μM), ketoconazole (10 μM), efavirenz (10 μM), or rifampin (10 μM) for 5 days. On day 5, nilotinib (3 μM) was coincubated for an additional 24-48 hours. The concentrations of nilotinib were quantitated in collected samples (combined lysate and medium) by LC-MS. Apparent intrinsic clearance (CL(int,app)) of nilotinib was lowered 5.8- and 3.1-fold, respectively, by ritonavir and ketoconazole. Efavirenz and rifampin increased the CL(int,app) of nilotinib by 2.1- and 4.1-fold, respectively. The clinically recommended dose (300 mg twice daily) of nilotinib may have to be reduced substantially (150 mg once daily) or increased (400 mg thrice daily), respectively, to achieve desired drug exposure, when ritonavir or efavirenz is co-administered.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Venkateswaran C
VC
Pillai
Robert A
RA
Parise
Susan M
SM
Christner
Michelle A
MA
Rudek
Jan H
JH
Beumer
Raman
R
Venkataramanan
D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D003521:Cyclopropanes; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D000480:Alkynes; D019380:Anti-HIV Agents; D000904:Antibiotics, Antitubercular; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D011743:Pyrimidines; C498826:nilotinib; C098320:efavirenz; D019438:Ritonavir; D007654:Ketoconazole; D012293:Rifampin
HIV drugs; drug-drug interactions; human hepatocytes; nilotinib