Impact of Sotorasib, a KRAS G12C Inhibitor, on the Pharmacokinetics and Therapeutic Window of Digoxin, a P-Glycoprotein Substrate.

Sotorasib is a small-molecule Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C inhibitor indicated for the treatment of KRAS G12C-driven cancers. KRAS G12C is a common mutation in solid tumors, including non-small cell lung cancer. In vitro studies suggested that sotorasib is a weak inhibitor of P-glycoprotein transporter.

Impact of Acid-Reducing Agents on Sotorasib Pharmacokinetics and Potential Mitigation of the Impact by Coadministration With an Acidic Beverage.

Sotorasib exhibits pH-dependent solubility, making it susceptible to altered exposures when coadministered with acid-reducing agents (ARAs). Several clinical studies were conducted to investigate the impact of ARAs on sotorasib pharmacokinetics under different clinically relevant scenarios and to identify potential mitigation strategies. Upon coadministration of 960 mg of sotorasib and 40 mg of omeprazole under fasted conditions, sotorasib area under the concentration-time curve (AUC) and maximum observed plasma concentration (C) decreased approximately 42% and 57%, respectively.

Relative Bioavailability of Sotorasib Following Administration as a Water Dispersion to Healthy Subjects and Compatibility With Enteral Administration.

Sotorasib is approved to be taken as 960 mg orally once daily (8 × 120-mg tablets) for the treatment of KRAS G12C-mutated nonsmall cell lung cancer. Dispersion of tablets in water could be an alternative method for patients who require a liquid formulation due to dysphagia and enteral administration. A clinical study was conducted to assess the pharmacokinetics of 960 mg of sotorasib administered as tablets and as tablets dispersed in water in healthy volunteers.

Impact of a High-Fat Meal on the Pharmacokinetics of Sotorasib, a KRAS G12C Inhibitor.

Sotorasib is a small molecule drug that specifically and irreversibly inhibits the KRAS p.G12C mutant protein. This analysis investigated the impact of a high-calorie high-fat meal on the pharmacokinetics, safety, and tolerability of sotorasib in both healthy volunteers and patients with KRAS G12C advanced solid tumors.

Effect of Strong CYP3A4 Inhibition, CYP3A4 Induction, and OATP1B1/3 Inhibition on the Pharmacokinetics of a Single Oral Dose of Sotorasib.

Sotorasib is a small molecule that irreversibly inhibits the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein with a G12C amino acid substitution mutant protein. The impact of cytochrome P450 (CYP) 3A4 inhibition and induction on sotorasib pharmacokinetics (PKs) was evaluated in 2 separate studies in healthy volunteers (N = 14/study). The impact of CYP3A4 inhibition was interrogated utilizing repeat doses of 200 mg of itraconazole, a strong CYP3A4 inhibitor, on 360 mg of sotorasib PKs.

Novel Mechanisms of Valproate Hepatotoxicity: Impaired Mrp2 Trafficking and Hepatocyte Depolarization.

Drug-induced liver injury (DILI) remains a major challenge in drug development. Although numerous mechanisms for DILI have been identified, few studies have focused on loss of hepatocyte polarization as a DILI mechanism. The current study investigated the effects of valproate (VPA), an antiepileptic drug with DILI risk, on the cellular mechanisms responsible for loss of hepatocyte polarization.