A Physiologically Based Pharmacokinetic Model of Vismodegib: Deconvoluting the Impact of Saturable Plasma Protein Bindin
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Research Article A Physiologically Based Pharmacokinetic Model of Vismodegib: Deconvoluting the Impact of Saturable Plasma Protein Binding, pH-Dependent Solubility and Nonsink Permeation Michael J. Dolton,1,4 Po-Chang Chiang,2 Fang Ma,3 Jin Y. Jin,1 and Yuan Chen3
Received 29 June 2020; accepted 18 August 2020 Abstract. Vismodegib displays unique pharmacokinetic characteristics including saturable plasma protein binding to alpha-1 acid glycoprotein (AAG) and apparent time-dependent bioavailability leading to non-linear PK with dose and time, significantly faster time to steady-state and lower than predicted accumulation. Given these unique characteristics, a PBPK model was developed to explore mechanistic insights into saturable protein binding and complex oral absorption processes and de-convolute the impact of these independent non-linear processes on vismodegib exposure. Simcyp V18 was used for model development; oral absorption was characterized using the multi-layer gut wall (M-ADAM) model and mechanistic permeability model, incorporating transport across an unstirred boundary layer (UBL) between the luminal fluid and enterocyte in each segment of the gastrointestinal tract. PBPK simulations were compared with observed PK data from clinical trials in oncology patients and healthy subjects. Saturation of vismodegib protein binding to AAG led to substantially lower total drug accumulation, time to steady-state, and Csstotal. For free exposure, Cssfree and accumulation were unchanged, but time to steady-state was substantially reduced. Vismodegib oral absorption declined with both dose and dosing frequency; the concentration gradient driving vismodegib oral absorption declined with multiple doses, leading to a 32% decrease in vismodegib fa from first dose to steady-state. Fed simulations suggested that increased solubility and dissolution are partially offset by reduced permeability across the UBL due to slower diffusion of micelle-bound drug. This work demonstrates the value of PBPK modeling to simultaneously capture and de-convolute multi-faceted absorption and disposition processes and provide mechanistic insights for compounds with complex pharmacokinetics. KEY WORDS: absorption; nonsink intestinal permeation; PBPK; physiologically based pharmacokinetic modeling; saturable protein binding; vismodegib.
INTRODUCTION Physiologically based pharmacokinetic (PBPK) modeling plays an increasingly important role in drug development (1,2). As confidence has grown in its application to novel areas including transporter-mediated drug-drug interactions (DDIs), special populations, and in-depth mechanistic insights in addition to traditional use in first-in-human PK and CYP-mediated DDI predictions, the inclusion of PBPK modeling in NDA submissions has expanded and diversified (1–3). 1
Clinical Pharmacology, Genentech Inc, 1 DNA Way, South San Francisco, California 94080, USA. 2 Small Molecule Pharmaceutical Sciences, Genentech Inc, 1 DNA Way, South San Francisco, California 94080, USA. 3 Drug Metabolism and Pharmacokinetics,
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