A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to the limited therapeutic benefit, TMZ also causes debilitating adverse events (AEs) that significantly impact the quality of life of GBM patients. Some of the most common AEs include hematologic (e.g., thrombocytopenia, neutropenia, anemia) and non-hematologic (e.g., nausea, vomiting, constipation, dizziness) toxicities. Recurrent GBMs are often resistant to TMZ and other DNA-damaging agents. Thus, there is an urgent need to devise strategies to potentiate TMZ activity, to overcome drug resistance, and to reduce dose-dependent AEs. Here, we analyze major mechanisms of the TMZ resistance-mediated intracellular signaling activation of DNA repair pathways and the overexpression of drug transporters. We review some of the approaches investigated to counteract these mechanisms of resistance to TMZ, including the use of chemosensitizers and drug delivery strategies to enhance tumoral drug exposure.

Limnetrelvir is an oral inhibitor of the SARS-CoV-2 main protease (Mpro) and was developed with the aim of achieving broad-spectrum efficacy against SARS-CoV-2 and emerging variants. The aim of this work was to evaluate potential CYP3A4 drug-drug interactions (DDIs) of limnetrelvir. In two phase 1, open-label studies, limnetrelvir was evaluated for DDIs with midazolam (Study 1), a CYP3A4 substrate, and itraconazole (Study 2), a strong CYP3A4 inhibitor. Study 1 (N = 24) consisted of two parts (Studies 1A and 1B), each with two periods (Periods 1 and 2), and Study 2 (N = 12) consisted of one part with two periods. In Study 1A, 12 healthy adult participants received midazolam (1 mg) on Period 1 Day 1 and Period 2 Day 10 and limnetrelvir 400 mg once daily (QD) on Period 2 Days 1-10. In Study 1B, an additional 12 healthy adult participants received midazolam (1 mg) on Period 1 Day 1 and Period 2 Day 5 and limnetrelvir 200 mg QD on Period 2 Days 1-5. In Study 2, 12 participants received limnetrelvir (50 mg) and itraconazole (200 mg twice daily on Day 1 and QD on Days 2 to 6 in Period 2), with limnetrelvir administered as a single dose on Period 1 Day 1 and Period 2 Day 4. All study drugs were administered orally. Serial blood samples were collected and analyzed for drug concentrations. Pharmacokinetic parameters were determined with noncompartmental methods. Coadministration of limnetrelvir increased the maximum concentration (C_max) and area under the concentration-time curve from time 0 to infinity (AUC_inf) of midazolam by ~ 2.4- to 2.6-fold and ~ 4.6- to 4.3-fold, respectively. The pharmacokinetics of the active metabolite, 1-OH-midazolam, demonstrated a decrease in C_max by ~ 0.66-fold at Day 5 and ~ 0.96-fold at Day 10, while overall AUC remained stable at both time points. No clinically significant differences in CYP3A4 inhibition after 5 days and 10 days of limnetrelvir administration were observed. Limnetrelvir C_max and AUC_inf increased by ~ 1.7- and ~ 3.6-fold, respectively, when coadministered with itraconazole, suggesting that limnetrelvir is a moderately sensitive substrate of CYP3A4. Limnetrelvir was found to be a moderate CYP3A4 inhibitor and substrate, suggesting that dosing adjustment or careful monitoring may be necessary when coadministered with medications highly metabolized by CYP3A4 or with strong CYP3A4 inhibitors to ensure safe and effective treatment. NCT05691699, NCT05895266. Date of registration: 01/09/2023, 05/31/2023.