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

Pépin, Xavier; Huckle, James E.; Alluri, Ravindra Varma; Basu, Sumit; Dodd, Stephanie; Parrott, Neil; Riedmaier, Arian Emami

doi:10.1208/s12248-020-00548-8

Cited by 25 publications

(11 citation statements)

References 57 publications

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“…In silico prediction accuracy was evaluated by calculating the absolute average fold error ( AAFE ) of the predicted values for AUC 0-inf , C max , T max , and C p versus time. AAFE can be calculated using Equation (1), where n is the number of individuals and subscript i is the parameter of interest for determining AAFE (e.g., AUC) [ 32 , 33 ].

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Section: Methodsmentioning

confidence: 99%

“…Subsequently, the surface pH of the dissolving solid was taken into account using the method of Pepin et al, where the bulk pH in the gastric compartment was adjusted to the estimated surface pH (i.e., slurry pH values) [ 6 ]. Doing so more accurately captures the solubility and dissolution driving force of acalabrutinib at the solid surface, resulting in a more accurate dissolution rate prediction than would be obtained using the bulk stomach pH (see Appendix A.5 ) [ 30 , 32 ].…”

Section: Methodsmentioning

confidence: 99%

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In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets

et al. 2021

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Amorphous solid dispersion (ASD) dosage forms can improve the oral bioavailability of poorly water-soluble drugs, enabling the commercialization of new chemical entities and improving the efficacy and patient compliance of existing drugs. However, the development of robust, high-performing ASD dosage forms can be challenging, often requiring multiple formulation iterations, long timelines, and high cost. In a previous study, acalabrutinib/hydroxypropyl methylcellulose acetate succinate (HPMCAS)-H grade ASD tablets were shown to overcome the pH effect of commercially marketed Calquence in beagle dogs. This study describes the streamlined in vitro and in silico approach used to develop those ASD tablets. HPMCAS-H and -M grade polymers provided the longest acalabrutinib supersaturation sustainment in an initial screening study, and HPMCAS-H grade ASDs provided the highest in vitro area under the curve (AUC) in gastric to intestinal transfer dissolution tests at elevated gastric pH. In silico simulations of the HPMCAS-H ASD tablet and Calquence capsule provided good in vivo study prediction accuracy using a bottom–up approach (absolute average fold error of AUC0-inf < 2 except for Calquence + famotidine ≈ 3). This streamlined approach combined an understanding of key drug, polymer, and gastrointestinal properties with in vitro and in silico tools to overcome the acalabrutinib pH effect without the need for reformulation or multiple studies, showing promise for reducing time and costs to develop ASD drug products.

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…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets

et al. 2021

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“…A whole PBPK model was developed to describe the kinetics of ST-246 in plasma using the middle-out approach ( Tsamandouras et al, 2013 ; Pepin et al, 2021 ) by a GastroPlus ™ simulator (version 9.8). This PBPK model integrated 14 organs (brain, adipose, spleen, heart, lung, muscle, kidney, liver, gut, skin, reproductive organ, red marrow, yellow marrow, and the rest of the body) which are connected with arteries and veins exchanging through blood perfusion.…”

Section: Methodsmentioning

confidence: 99%

A PBPK Model of Ternary Cyclodextrin Complex of ST-246 Was Built to Achieve a Reasonable IV Infusion Regimen for the Treatment of Human Severe Smallpox

Zhang¹,

Fu²,

Wang³

et al. 2022

Front. Pharmacol.

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ST-246 is an oral drug against pathogenic orthopoxvirus infections. An intravenous formulation is required for some critical patients. A ternary complex of ST-246/meglumine/hydroxypropyl-β-cyclodextrin with well-improved solubility was successfully developed in our institute. The aim of this study was to achieve a reasonable intravenous infusion regimen of this novel formulation by a robust PBPK model based on preclinical pharmacokinetic studies. The pharmacokinetics of ST-246 after intravenous injection at different doses in rats, dogs, and monkeys were conducted to obtain clearances. The clearance of humans was generated by using the allometric scaling approach. Tissue distribution of ST-246 was conducted in rats to obtain tissue partition coefficients (Kp). The PBPK model of the rat was first built using in vivo clearance and Kp combined with in vitro physicochemical properties, unbound fraction, and cyclodextrin effect parameters of ST-246. Then the PBPK model was transferred to a dog and monkey and validated simultaneously. Finally, pharmacokinetic profiles after IV infusion at different dosages utilizing the human PBPK model were compared to the observed oral PK profile of ST-246 at therapeutic dosage (600 mg). The mechanistic PBPK model described the animal PK behaviors of ST-246 via intravenous injection and infusion with fold errors within 1.2. It appeared that 6h-IV infusion at 5 mg/kg BID produced similar Cmax and AUC as oral administration at 600 mg. A PBPK model of ST-246 was built to achieve a reasonable regimen of IV infusion for the treatment of severe smallpox, which will facilitate the clinical translation of this novel formulation.

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“…Novel approaches suggest that it might also be possible to apply physiologically based pharmacokinetic (PBPK) models that combine drug properties and physiological data to predict mechanisms and potential clinical relevance of food effects. With these models, it should be possible to estimate the food effects and their magnitude with regard to pharmacokinetic parameters [ 142 , 143 , 144 ]. Although establishing these models affords in vitro and in vivo verification at the start, at later stages these approaches would provide large health benefits.…”

Section: Dietmentioning

confidence: 99%

The Impact of Diet and Exercise on Drug Responses

Niederberger

Parnham

2021

IJMS

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It is well known that lifestyle changes can alter several physiological functions in the human body. For exercise and diet, these effects are used sensibly in basic therapies, as in cardiovascular diseases. However, the physiological changes induced by exercise and a modified diet also have the capacity to influence the efficacy and toxicity of several drugs, mainly by affecting different pharmacokinetic mechanisms. This pharmacological plasticity is not clinically relevant in all cases but might play an important role in altering the effects of very common drugs, particularly drugs with a narrow therapeutic window. Therefore, with this review, we provide insights into possible food–drug and exercise–drug interactions to sharpen awareness of the potential occurrence of such effects.

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

Cited by 25 publications

References 57 publications

In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets

In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets

A PBPK Model of Ternary Cyclodextrin Complex of ST-246 Was Built to Achieve a Reasonable IV Infusion Regimen for the Treatment of Human Severe Smallpox

The Impact of Diet and Exercise on Drug Responses

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