Effect of Strong CYP3A4 Inhibition, CYP3A4 Induction, and OATP1B1/3 Inhibition on the Pharmacokinetics of a Single Oral Dose of Sotorasib.
Clin Pharmacol Drug Dev
; 13(7): 810-818, 2024 Jul.
Article
en En
| MEDLINE
| ID: mdl-38421129
ABSTRACT
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. The impact of CYP3A4 induction was interrogated utilizing multiple doses of 600 mg of rifampin, a strong CYP3A4 inducer. Additionally, the impact of organic anion transporting polypeptide (OATP) 1B1/3 inhibition on 960 mg of sotorasib PKs was interrogated after a single dose of 600 mg of rifampin. CYP3A4 inhibition did not significantly impact sotorasib Cmax but did lead to a 26% increase in sotorasib AUCinf. CYP3A4 induction decreased sotorasib Cmax by 35% and AUCinf by 51%. OATP1B1/3 inhibition decreased sotorasib Cmax and AUCinf by 16% and 23%, respectively. These results support that sotorasib can be given together with strong CYP3A4 and OATP1B1/3 inhibitors but the co-administration of sotorasib and strong CYP3A4 inducers should be avoided.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Rifampin
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Transportador 1 de Anión Orgánico Específico del Hígado
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Interacciones Farmacológicas
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Citocromo P-450 CYP3A
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Inductores del Citocromo P-450 CYP3A
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Inhibidores del Citocromo P-450 CYP3A
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Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos
Límite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Año:
2024
Tipo del documento:
Article