Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib

Abstract

Purpose 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. Conclusion 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.

Kinome and Transcriptome Profiling Reveal Broad and Distinct Activities of Erlotinib, Sunitinib, and Sorafenib in the Mouse Heart and Suggest Cardiotoxicity From Combined Signal Transducer and Activator of Transcription and Epidermal Growth Factor Receptor Inhibition

“…We treated female 14‐to‐16‐week‐old FVB mice daily with vehicle or 1 of 3 kinase inhibitors (erlotinib 50 mg/kg per day, sorafenib 30 mg/kg per day, or sunitinib 40 mg/kg per day) for 14 days in the UNC Lineberger Animal Models core. We chose these doses because they yield plasma drug concentrations similar to the therapeutic range in human studies and have limited systemic toxicities in published mouse experiments . On Day 9, 4 mice were euthanized for failure to thrive: 2 from the erlotinib group and 1 each from the sorafenib and sunitinib groups.…”

“…We chose these doses because they yield plasma drug concentrations similar to the therapeutic range in human studies and have limited systemic toxicities in published mouse experiments. [17][18][19][20][21][22][23][24] On Day 9, 4 mice were euthanized for failure to thrive: 2 from the erlotinib group and 1 each from the sorafenib and sunitinib groups. These mice were included in our analyses.…”

Non-Targeted Metabolomics Analysis of the Effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Heart, Muscle, Liver and Serum Metabolism In Vivo

“…Erlotinib is also orally delivered and given daily (150 mg) 1–2 h after meals, resulting in C max of ~1500 ng/mL, with a half-life of ~16 h [ 16 ]. In this study, we chose to treat mice with 50 mg/kg erlotinib daily, as this dosing achieves plasma concentrations within the therapeutic range for humans [ 17 ].…”

TKI combination therapy: strategy to enhance dasatinib uptake by inhibiting Pgp‐ and BCRP‐mediated efflux

“…Enhanced efflux of TKIs by over‐expression of Pgp and BCRP in cancer cells has been implicated to be an important resistance mechanism and is responsible for the poor chemotherapeutic response . Accumulating evidence continues to show that numerous TKIs are dual substrates of Pgp and BCRP and in addition, many of them have also been found to be inhibitors of Pgp and BCRP .…”

“…Because of the dual roles of TKIs on Pgp and BCRP, when different TKIs are used in combination, we anticipate that TKIs may not only exert anticancer effects but also act as chemosensitizers to reverse efflux transporter‐mediated resistance against a co‐administered TKI, thus improving the overall treatment outcome synergistically. Currently, investigations on efflux transporter‐mediated TKI–TKI interaction are fairly limited . To fill the literature gap, our study objective was to investigate the transporter‐mediated interaction of various TKIs against dasatinib, the chosen model substrate TKI, to come up with potential, promising combinations of TKIs that will help to overcome or reverse MDR and to enhance intracellular targeted TKI concentrations.…”