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1.
CPT Pharmacometrics Syst Pharmacol ; 13(4): 563-575, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38130003

RESUMO

Considerable interest remains across the pharmaceutical industry and regulatory landscape in capabilities to model oral contraceptives (OCs), whether combined (COCs) with ethinyl estradiol (EE) or progestin-only pill. Acceptance of COC drug-drug interaction (DDI) assessment using physiologically-based pharmacokinetic (PBPK) is often limited to the estrogen component (EE), requiring further verification, with extrapolation from EE to progestins discouraged. There is a paucity of published progestin component PBPK models to support the regulatory DDI guidance for industry to evaluate a new chemical entity's (NCE's) DDI potential with COCs. Guidance recommends a clinical interaction study to be considered if an investigational drug is a weak or moderate inducer, or a moderate/strong inhibitor, of CYP3A4. Therefore, availability of validated OC PBPK models within one software platform, will be useful in predicting the DDI potential with NCEs earlier in the clinical development. Thus, this work was focused on developing and validating PBPK models for progestins, DNG, DRSP, LNG, and NET, within Simcyp, and assessing the DDI potential with known CYP3A4 inhibitors (e.g., ketoconazole) and inducers (e.g., rifampicin) with published clinical data. In addition, this work demonstrated confidence in the Simcyp EE model for regulatory and clinical applications by extensive verification in 70+ clinical PK and CYP3A4 interaction studies. The results provide greater capability to prospectively model clinical CYP3A4 DDI with COCs using Simcyp PBPK to interrogate the regulatory decision-tree to contextualize the potential interaction by known perpetrators and NCEs, enabling model-informed decision making, clinical study designs, and delivering potential alternative COC options for women of childbearing potential.


Assuntos
Citocromo P-450 CYP3A , Progestinas , Humanos , Feminino , Anticoncepcionais Orais , Interações Medicamentosas , Etinilestradiol , Inibidores do Citocromo P-450 CYP3A/farmacologia , Modelos Biológicos
2.
J Pharmacol Exp Ther ; 366(1): 37-45, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29653960

RESUMO

Atovaquone, an antiprotozoal and antipneumocystic agent, is predominantly cleared by biliary excretion of unchanged parent drug. Atovaquone is ≥10,000-fold concentrated in human bile relative to unbound plasma. Even after correcting for apparent nonspecific binding and incomplete solubility in bile, atovaquone is still concentrated ≥100-fold in bile, consistent with active biliary excretion. Mechanisms of atovaquone hepatobiliary disposition were studied using a multiexperimental in vitro and in vivo approach. Atovaquone uptake was not elevated in HEK293 cells singly overexpressing OATP1B1, OATP1B3, OATP2B1, OCT1, NTCP, or OAT2. Hepatocyte uptake of atovaquone was not impaired by OATP and OCT inhibitor cocktail (rifamycin and imipramine). Atovaquone liver-to-blood ratio at distributional equilibrium was not reduced in Oatp1a/1b and Oct1/2 knockout mice. Atovaquone exhibited efflux ratios of approximately unity in P-gp and BCRP overexpressing MDCK cell monolayers and did not display enhanced uptake in MRP2 vesicles. Biliary and canalicular clearance were not decreased in P-gp, Bcrp, Mrp2, and Bsep knockout rats. In the present study, we rule out the involvement of major known basolateral uptake and bile canalicular efflux transporters in the hepatic uptake and biliary excretion of atovaquone. This is the first known example of a drug cleared by biliary excretion in humans, with extensive biliary concentration, which is not transported by the mechanisms investigated herein.


Assuntos
Atovaquona/farmacocinética , Sistema Biliar/metabolismo , Fígado/metabolismo , Animais , Atovaquona/química , Atovaquona/metabolismo , Transporte Biológico , Células HEK293 , Humanos , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade , Distribuição Tecidual
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