Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: an Industry Perspective

Riedmaier, Arian Emami; DeMent, Kevin; Huckle, James E.; Bransford, Phil; Stillhart, Cordula; Lloyd, Richard C.; Alluri, Ravindra Varma; Basu, Sumit; Chen, Yuan; Dhamankar, Varsha; Dodd, Stephanie; Kulkarni, Priyanka; Olivares‐Morales, Andrés; Peng, Chi-Chi; Pépin, Xavier; Ren, Xiaojun; Tran, Thuy; Tistaert, Christophe; Heimbach, Tycho; Kesisoglou, Filippos; Wagner, Christian; Parrott, Neil

doi:10.1208/s12248-020-00508-2

Cited by 64 publications

(61 citation statements)

References 53 publications

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“…The observed food effect on selumetinib capsule and granule PK involves several mechanisms. A reduction in C max is expected due to the delayed gastric emptying and a reduction in first pass liver extraction is expected due to a higher blood flow in the fed state compared to the fasted state 15 . For capsules, the PBBM indicated a reduction in absorption due to a higher precipitation upon stomach emptying and an increase in first pass gut extraction, due to a higher dilution of the drug in the stomach chyme, combined with a slower gastric emptying in the fed state (data on file).…”

Section: Discussionmentioning

confidence: 99%

Effect of food on capsule and granule formulations of selumetinib

Cohen-Rabbie

Mattinson

et al. 2022

Clinical Translational Sci

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Selumetinib is an oral, potent, and highly selective allosteric MEK1/2 inhibitor approved for the treatment of pediatric patients (aged ≥2 years) with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. A granule formulation of selumetinib is under development to improve dosing precision for younger pediatric patients who may be unable to swallow capsules. This phase I crossover study investigated the effect of food on the pharmacokinetic (PK) properties of selumetinib capsule and granule formulations. Healthy male volunteers were randomized to receive selumetinib granules (25 mg) or capsules (50 mg [2 × 25 mg]) under fasted or fed conditions (a low‐fat meal). Plasma concentrations and PK parameters were determined less than or equal to 48 h postdose. Safety and tolerability were assessed. Across 24 volunteers, selumetinib was absorbed quickly, with a time to maximum concentration (T max ) ranging from ~1–3 h. Geometric mean ratios (90% confidence interval [CI]) for maximum plasma concentration (C max ) in the fed versus fasted state were 0.61 (90% CI 0.51–0.72) and 0.40 (90% CI 0.33–0.48) for the granule and capsule formulations, respectively, whereas geometric mean ratios (90% CI) for area under the plasma drug concentration‐time curve in the fed versus fasted state were 0.97 (90% CI 0.91–1.02) and 0.62 (90% CI 0.55–0.70), respectively. Levels of less than 10% conversion to the N‐desmethyl selumetinib metabolite were observed. Selumetinib was well‐tolerated, with only a few adverse events of mild intensity reported. Selumetinib administration with a low‐fat meal resulted in lower C max and longer T max for both formulations versus fasted conditions. However, area under the curve for selumetinib granules was similar under fasted and fed conditions. Overall, these findings support further development of this formulation for pediatric patients.

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Section: Discussionmentioning

confidence: 99%

Effect of food on capsule and granule formulations of selumetinib

Cohen-Rabbie

Mattinson

et al. 2022

Clinical Translational Sci

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“…PBPK input parameters in this work such as permeability, solubility, or dissolution were measured by consistent methods. For more detailed description of methods used to generate this data, the reader is directed to Emami Riedmaier et al (10). The surface pH of nefazodone HCl was determined according to Serajuddin et al (12) with minor modifications.…”

Section: Methodsmentioning

confidence: 99%

“…The pH of each unbuffered solution was determined immediately before starting the experiment. For nefazodone HCl, 3 mL of each solution was added to 500 mg drug substance in an appropriate container, and stirred on a vortex for 10 s, and the pH of the obtained slurry was measured immediately and after 10 min, 1 h, 2 h, and 24 h. The thresholds for definition of "no-food effect" for the drugs of this study are based on the AUC ratio being comprised between 0.8 and 1.25 (10).…”

Section: Methodsmentioning

confidence: 99%

“…It also helps in minimizing the number of clinical FE studies by simulating the food effect when changes are made to critical quality attributes of formulations during drug development. In an accompanying manuscript, a unique approach was utilized to build and verify mechanistic PBPK models for 30 compounds while controlling for common variables, such as differences in input data, method of data generation, and subjective optimization and/or verification (10). The focus of that work was to identify food effect mechanisms associated with high, moderate, or low prediction confidence.…”

Section: Introductionmentioning

confidence: 99%

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Understanding Mechanisms of Food Effect and Developing Reliable PBPK Models Using a Middle-out Approach

Pépin

Huckle

Alluri

et al. 2021

AAPS J

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Over the last 10 years, 40% of approved oral drugs exhibited a significant effect of food on their pharmacokinetics (PK) and currently the only method to characterize the effect of food on drug absorption, which is recognized by the authorities, is to conduct a clinical evaluation. Within the pharmaceutical industry, there is a significant effort to predict the mechanism and clinical relevance of a food effect. Physiologically based pharmacokinetic (PBPK) models combining both drug-specific and physiology-specific data have been used to predict the effect of food on absorption and to reveal the underlying mechanisms. This manuscript provides detailed descriptions of how a middle-out modeling approach, combining bottom-up in vitro-based predictions with limited top-down fitting of key model parameters for clinical data, can be successfully used to predict the magnitude and direction of food effect when it is predicted poorly by a bottom-up approach. For nefazodone, a mechanistic clearance for the gut and liver was added, for furosemide, an absorption window was introduced, and for aprepitant, the biorelevant solubility was refined using multiple solubility measurements. In all cases, these adjustments were supported by literature data and showcased a rational approach to assess the factors limiting absorption and exposure.

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“…However, middle-out approaches (see Part 3 ) have been evaluated mostly by case studies (or the collection of case studies). Systematic evaluation is required for middle-out approaches using a standardized procedure (more precisely, for local middle-out dynamic PBPK models) [ 10 , 75 , 76 ].…”

Section: Part 2: Scientific Literacy For Physiologically-based Pharma...mentioning

confidence: 99%

Lost in modelling and simulation?

Sugano

2021

ADMET DMPK

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Over the past few decades, physiologically-based pharmacokinetic modelling (PBPK) has been anticipated to be a powerful tool to improve the productivity of drug discovery and development. However, recently, multiple systematic evaluation studies independently suggested that the predictive power of current oral absorption (OA) PBPK models needs significant improvement. There is some disagreement between the industry and regulators about the credibility of OA PBPK modelling. Recently, the editorial board of AMDET&DMPK has announced the policy for the articles related to PBPK modelling (Modelling and simulation ethics). In this feature article, the background of this policy is explained: (1) Requirements for scientific writing of PBPK modelling, (2) Scientific literacy for PBPK modelling, and (3) Middle-out approaches. PBPK models are a useful tool if used correctly. This article will hopefully help advance the science of OA PBPK models.

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Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: an Industry Perspective

Cited by 64 publications

References 53 publications

Effect of food on capsule and granule formulations of selumetinib

Effect of food on capsule and granule formulations of selumetinib

Understanding Mechanisms of Food Effect and Developing Reliable PBPK Models Using a Middle-out Approach

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