Prediction of pH-Dependent Drug-Drug Interactions for Basic Drugs Using Physiologically Based Biopharmaceutics Modeling: Industry Case Studies

Mitra, Amitava; Parrott, Neil; Miller, Neil A.; Lloyd, Richard C.; Tistaert, Christophe; Heimbach, Tycho; Ji, Yan; Kesisoglou, Filippos

doi:10.1016/j.xphs.2019.11.017

Cited by 40 publications

(23 citation statements)

References 43 publications

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“…Another advantage of this simple modeling strategy is that it can provide insight into the rate-limiting step of gastric dissolution. The gastric dissolution can be diagnosed as SL and DRL by Equation (14). In addition, the contribution of gastric dissolution on Fa can be estimated by Equation ( 16).…”

Section: Discussionmentioning

confidence: 99%

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Bottom-Up Physiologically Based Oral Absorption Modeling of Free Weak Base Drugs

et al. 2020

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In this study, we systematically evaluated “bottom-up” physiologically based oral absorption modeling, focusing on free weak base drugs. The gastrointestinal unified theoretical framework (the GUT framework) was employed as a simple and transparent model. The oral absorption of poorly soluble free weak base drugs is affected by gastric pH. Alternation of bulk and solid surface pH by dissolving drug substances was considered in the model. Simple physicochemical properties such as pKa, the intrinsic solubility, and the bile micelle partition coefficient were used as input parameters. The fraction of a dose absorbed (Fa) in vivo was obtained by reanalyzing the pharmacokinetic data in the literature (15 drugs, a total of 85 Fa data). The AUC ratio with/without a gastric acid-reducing agent (AUCr) was collected from the literature (22 data). When gastric dissolution was neglected, Fa was underestimated (absolute average fold error (AAFE) = 1.85, average fold error (AFE) = 0.64). By considering gastric dissolution, predictability was improved (AAFE = 1.40, AFE = 1.04). AUCr was also appropriately predicted (AAFE = 1.54, AFE = 1.04). The Fa values of several drugs were slightly overestimated (less than 1.7-fold), probably due to neglecting particle growth in the small intestine. This modeling strategy will be of great importance for drug discovery and development.

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Section: Discussionmentioning

confidence: 99%

“…Physiologically based pharmacokinetic (PBPK) modeling has been anticipated to be a powerful tool to improve the productivity of drug discovery and development [ 11 ]. There have been many case studies of oral absorption PBPK modeling [ 12 , 13 , 14 , 15 , 16 ]. However, case studies are prone to publication bias.…”

Section: Introductionmentioning

confidence: 99%

Bottom-Up Physiologically Based Oral Absorption Modeling of Free Weak Base Drugs

et al. 2020

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“…Starting from a value of ∼1.5 in the stomach, it rises to ∼6.0 in the duodenum, reaches ∼7.4 in the terminal ileum, and falls again to ∼6.7 in the colon [438] . An additional consideration is that these values can vary with age, presence of food, diseases, and also by the co-administration of other drugs [439] , [440] , [441] , [442] . Finally, we note that the influence of pH on bioavailability could, in pH-disturbed states, result in underdose or overdose.…”

Section: Ph-dependent Aspects Of Pharmaceutical Therapymentioning

confidence: 99%

The therapeutic importance of acid-base balance

Quade

Parker

Occhipinti

2021

Biochemical Pharmacology

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Baking soda and vinegar have been used as home remedies for generations and today we are only a mouse-click away from claims that baking soda, lemon juice, and apple cider vinegar are miracles cures for everything from cancer to COVID-19. Despite these specious claims, the therapeutic value of controlling acid-base balance is indisputable and is the basis of Food and Drug Administration-approved treatments for constipation, epilepsy, metabolic acidosis, and peptic ulcers. In this narrative review, we present evidence in support of the current and potential therapeutic value of countering local and systemic acid-base imbalances, several of which do in fact involve the administration of baking soda (sodium bicarbonate). Furthermore, we discuss the side effects of pharmaceuticals on acid-base balance as well as the influence of acid-base status on pharmacokinetic properties of drugs. Our review considers all major organs systems as well as information relevant to several clinical specialties such as anesthesiology, infectious disease, oncology, dentistry, and surgery.

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“…For example, during model development some optimization of the precipitation time against observed data in the fasted state is not an uncommon practice for weak bases. 11 However, one should be cautioned that optimization of precipitation based on PK data should be done carefully and does assume that there is sufficient confidence in other model parameters. For compounds for which no/very slow precipitation occurs in vitro, confidence in the model is even higher.…”

Section: What Are the Major Gaps In Food Effect Predictions?mentioning

confidence: 99%

“…Furthermore, it should be pointed out that the importance of these parameters is compound dependent, and some model fitting during the model development phase should not be seen as negative. For example, during model development some optimization of the precipitation time against observed data in the fasted state is not an uncommon practice for weak bases 11 . However, one should be cautioned that optimization of precipitation based on PK data should be done carefully and does assume that there is sufficient confidence in other model parameters.…”

Section: What Are the Major Gaps In Food Effect Predictions?mentioning

confidence: 99%

Can PBPK Modeling Streamline Food Effect Assessments?

Kesisoglou

2020

The Journal of Clinical Pharma

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Physiologically based pharmacokinetic (PBPK) modeling is routinely used to study drug-drug interactions, replace some dedicated clinical studies, and inform product labeling. More recently, there has been increased application of PBPK models in the oral absorption field around drug product quality. Given the success of the models to characterize absorption of several orally administered drug products, a question arises whether PBPK could be used in a clinical setting to model food-drug interactions and thus streamline food effect assessments. Multiple publications have reported food effect predictions and comparisons with clinical data, primarily focusing on 2 food effect mechanisms: slowing down of gastric emptying and luminal solubilization by bile salts. Based on the available literature, this commentary proposes a workflow that PBPK model could be used to streamline food effect assessment during clinical development for different Biopharmaceutics Classification System classes.

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Prediction of pH-Dependent Drug-Drug Interactions for Basic Drugs Using Physiologically Based Biopharmaceutics Modeling: Industry Case Studies

Cited by 40 publications

References 43 publications

Bottom-Up Physiologically Based Oral Absorption Modeling of Free Weak Base Drugs

Bottom-Up Physiologically Based Oral Absorption Modeling of Free Weak Base Drugs

The therapeutic importance of acid-base balance

Can PBPK Modeling Streamline Food Effect Assessments?

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