Andres Gonzalez-Jimenez1, Kristin McEuen2, Minjun Chen2, Ayako Suzuki3,4, Mercedes Robles-Diaz1, Inmaculada Medina-Caliz1, Fernando Bessone5, Nelia Hernandez6, Marco Arrese7, Raymundo Parana8, M Isabel Lucena1,9, Camilla Stephens1, Raúl J Andrade1. 1. Unidad de Gestión Clínica del Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Málaga, Spain. 2. Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas, USA. 3. Gastroenterology, Duke University, Durham, North Carolina, USA. 4. Gastroenterology, Durham VA Medical Center, Durham, North Carolina, USA. 5. Facultad de Medicina, Hospital Provincial del Centenario, Universidad de Rosario, Rosario, Argentina. 6. Facultad de Medicina, Hospital de Clínicas, UDELAR, Montevideo, Uruguay. 7. Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile y Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile. 8. Hospital Universitario Prof. Edgard Santos, Universidad Federal da Bahía, Salvador de Bahía, Brazil. 9. UICEC IBIMA, Plataforma SCReN (Spanish Clinical Research Network), Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Málaga, Spain.
Abstract
BACKGROUND & AIMS: Most patients with drug-induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry. METHODS: Clinical information from 388 patients (69 presented delayed onset) and drug properties of 43 causative drugs (45 active ingredients) were analysed. A two-tier regression-based model was used to assess host/drug interactions affecting the probability of delayed onset. RESULTS: Antibacterial and anti-inflammatory drugs accounted for the delayed onset cases. Drug property of <50% hepatic metabolism (odds ratio [OR] 11.06, 95% confidence interval [95% CI]: 4.4-32.2, P = 0.0003), daily dose ≥1000 mg (OR: 2.77, 95% CI: 1.3-6.1, P = 0.0063) and the absence of pre-existing conditions in a patient (OR: 2.55, 95% CI: 1.3-4.9, P = 0.0043) were independently associated with delayed onset. The findings were consistent when externally validated using Latin American DILI Network cases (N = 131). Likewise, drug properties of mitochondrial liability and Pauling electronegativity were associated with delayed onset, but dependent on specific host factors such as age, sex and pre-existing cardiac diseases. CONCLUSIONS: This study demonstrated that delayed onset, a specific DILI phenotype, is explained by complex interactions among drug properties and host factors and provided mechanistic hypotheses for future studies. These findings can help improve the diagnostic capability and causality assessment.
BACKGROUND & AIMS: Most patients with drug-induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry. METHODS: Clinical information from 388 patients (69 presented delayed onset) and drug properties of 43 causative drugs (45 active ingredients) were analysed. A two-tier regression-based model was used to assess host/drug interactions affecting the probability of delayed onset. RESULTS: Antibacterial and anti-inflammatory drugs accounted for the delayed onset cases. Drug property of <50% hepatic metabolism (odds ratio [OR] 11.06, 95% confidence interval [95% CI]: 4.4-32.2, P = 0.0003), daily dose ≥1000 mg (OR: 2.77, 95% CI: 1.3-6.1, P = 0.0063) and the absence of pre-existing conditions in a patient (OR: 2.55, 95% CI: 1.3-4.9, P = 0.0043) were independently associated with delayed onset. The findings were consistent when externally validated using Latin American DILI Network cases (N = 131). Likewise, drug properties of mitochondrial liability and Pauling electronegativity were associated with delayed onset, but dependent on specific host factors such as age, sex and pre-existing cardiac diseases. CONCLUSIONS: This study demonstrated that delayed onset, a specific DILI phenotype, is explained by complex interactions among drug properties and host factors and provided mechanistic hypotheses for future studies. These findings can help improve the diagnostic capability and causality assessment.
Authors: Antonio Segovia-Zafra; Daniel E Di Zeo-Sánchez; Carlos López-Gómez; Zeus Pérez-Valdés; Eduardo García-Fuentes; Raúl J Andrade; M Isabel Lucena; Marina Villanueva-Paz Journal: Acta Pharm Sin B Date: 2021-11-18 Impact factor: 11.413