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Mechanistic modelling of enzyme-restoration effects of new recombinant liver-targeted proteins in acute intermittent porphyria.
Vera-Yunca, Diego; Córdoba, Karol M; Parra-Guillen, Zinnia P; Jericó, Daniel; Fontanellas, Antonio; Trocóniz, Iñaki F.
Afiliação
  • Vera-Yunca D; Pharmacometrics & Systems Pharmacology, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.
  • Córdoba KM; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
  • Parra-Guillen ZP; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
  • Jericó D; Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • Fontanellas A; Pharmacometrics & Systems Pharmacology, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.
  • Trocóniz IF; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
Br J Pharmacol ; 179(14): 3815-3830, 2022 07.
Article em En | MEDLINE | ID: mdl-35170015
ABSTRACT
BACKGROUND AND

PURPOSE:

Acute intermittent porphyria (AIP) is a rare disease caused by a genetic mutation in the hepatic activity of the porphobilinogen-deaminase. We aimed to develop a mechanistic model of the enzymatic restoration effects of a novel therapy based on the administration of different formulations of recombinant human-PBGD (rhPBGD) linked to the ApoAI lipoprotein. This fusion protein circulates in blood, incorporating into HDL and penetrating hepatocytes. EXPERIMENTAL

APPROACH:

Single i.v. dose of different formulations of rhPBGD linked to ApoAI were administered to AIP mice in which a porphyric attack was triggered by i.p. phenobarbital. Data consist on 24 h urine excreted amounts of heme precursors, 5-aminolevulinic acid (ALA), PBG and total porphyrins that were analysed using non-linear mixed-effects analysis. KEY

RESULTS:

The mechanistic model successfully characterized over time the amounts excreted in urine of the three heme precursors for different formulations of rhPBGD and unravelled several mechanisms in the heme pathway, such as the regulation in ALA synthesis by heme. Treatment with rhPBGD formulations restored PBGD activity, increasing up to 51 times the value of the rate of tPOR formation estimated from baseline. Model-based simulations showed that several formulation prototypes provided efficient protective effects when administered up to 1 week prior to the occurrence of the AIP attack. CONCLUSION AND IMPLICATIONS The model developed had excellent performance over a range of doses and formulation type. This mechanistic model warrants use beyond ApoAI-conjugates and represents a useful tool towards more efficient drug treatments of other enzymopenias as well as for acute intermittent porphyria.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Porfiria Aguda Intermitente Limite: Animals Idioma: En Revista: Br J Pharmacol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Espanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Porfiria Aguda Intermitente Limite: Animals Idioma: En Revista: Br J Pharmacol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Espanha