Prediction of ARA/PPI Drug-Drug Interactions at the Drug Discovery and Development Interface

Dodd, Stephanie; Kollipara, Sivacharan; Sánchez-Félix, Manuel; Kim, Hyungchul; Meng, Qingshu; Heimbach, Tycho

doi:10.1016/j.xphs.2018.10.032

Cited by 28 publications

(19 citation statements)

References 49 publications

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“…The precise impact of the observed fluid volume changes, in combination with the PPI-induced drop in gastric pH, on the absorption of ritonavir will be further evaluated using in vitro dissolution testing in combination with physiologically-based pharmacokinetic (PBPK) modelling. PBPK modelling has previously been utilized to predict in vivo drug-drug interactions between weakly basic compounds and PPIs or other acid-reducing agents [ 31 , 32 , 33 ]. From a broader perspective, the results of this study should be taken into consideration when developing and testing new drug candidates especially for populations in which PPI use is most frequent, including elderly [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

et al. 2020

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Proton-pump inhibitors (PPIs), frequently prescribed to lower gastric acid secretion, often exert an effect on the absorption of co-medicated drug products. A previous study showed decreased plasma levels of the lipophilic drug ritonavir after co-administration with the PPI Nexium (40 mg esomeprazole), even though duodenal concentrations were not affected. The present study explored if a PPI-induced decrease in gastrointestinal (GI) fluid volume might contribute to the reduced absorption of ritonavir. In an exploratory cross-over study, five volunteers were given a Norvir tablet (100 mg ritonavir) orally, once without PPI pre-treatment and once after a three-day pre-treatment with the PPI esomeprazole. Blood samples were collected for eight hours to assess ritonavir absorption and magnetic resonance imaging (MRI) was used to determine the gastric and duodenal fluid volumes during the first three hours after administration of the tablet. The results confirmed that PPI intake reduced ritonavir plasma concentrations by 40%. The gastric residual volume and gastric fluid volume decreased by 41% and 44% respectively, while the duodenal fluid volume was reduced by 33%. These data suggest that the PPI esomeprazole lowers the available fluid volume for dissolution, which may limit the amount of ritonavir that can be absorbed. Although additional factors may play a role, the effect of PPI intake on the GI fluid volume should be considered when simulating the absorption of poorly soluble drugs like ritonavir in real-life conditions.

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Section: Discussionmentioning

confidence: 99%

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

et al. 2020

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“…Publication bias and case-by-case parameter fitting reduce the reliability of the prediction model [ 19 ]. Recently, a commercial software product was systematically evaluated regarding ARA DDI prediction for weak base drugs [ 20 ]. The results suggest that scientific knowledge in this area is still premature (Figures 4 and 5 in [ 20 ]).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a commercial software product was systematically evaluated regarding ARA DDI prediction for weak base drugs [ 20 ]. The results suggest that scientific knowledge in this area is still premature (Figures 4 and 5 in [ 20 ]). In that study, free and salt forms were not differentiated as drug substances.…”

Section: Introductionmentioning

confidence: 99%

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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“…20 Recently, a study suggested that the PBPK model that was developed at the preclinical stage could correctly identify pH-dependent DDI potential for 78% drugs although false negative prediction was observed. 21 However, there is still limited application of PBPK modeling to address the questions related to absorption-related DDIs at the stage of regulatory submissions. [22][23][24][25] In the years of 2013-2017, PBPK modeling has been used in two New Drug Application submissions to predict the liability of pH-dependent DDIs to support the labeling recommendations.…”

Section: Discussionmentioning

confidence: 99%

Application of Physiologically‐Based Pharmacokinetic Modeling to Predict Gastric pH‐Dependent Drug–Drug Interactions for Weak Base Drugs

Dong

et al. 2020

CPT Pharmacom & Syst Pharma

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Weak-base drugs are susceptible to drug-drug interactions (DDIs) when coadministered with gastric acid-reducing agents (ARAs). We developed PBPK models to evaluate the potential of such pH-dependent DDIs for four weak-base drugs, i.e., tapentadol, darunavir, erlotinib, and saxagliptin. The physiologically-based pharmacokinetic (PBPK) models of these drugs were first optimized using pharmacokinetic (PK) data following oral administration without ARAs, which were then verified with data from additional PK studies in the presence and absence of food. The models were subsequently used to predict the extent of DDIs with ARA coadministration. Sensitivity analysis was conducted to explore the impact of gastric pH on quantitative prediction of drug exposure in the presence of ARA. The results suggested that the PBPK models developed could adequately describe the lack of the effect of ARA on the PK of tapentadol, darunavir, and saxagliptin and could qualitatively predict the effect of ARA in reducing the absorption of erlotinib. Further studies involving more drugs with positive pH-dependent DDIs are needed to confirm the findings and broaden our knowledge base to further improve the utilization of PBPK modeling to evaluate pH-dependent DDI potential. Many weak base drugs (WBDs) exhibit pH-dependent solubility. Generally, the solubility of a WBD decreases as pH increases. Thus, when WBDs are administered orally, elevation of gastric pH induced by another drug or disease state may lead to a decrease in WBD absorption and consequently result in reduced systemic exposure to the drug. pH-dependent drug-drug interactions (DDIs) have been observed for many WBDs, including various anticancer and antiretroviral drugs when they are coadministered with gastric acid-reducing agents (ARAs) such as histamine H 2receptor antagonists and proton pump inhibitors. 1,2 One example is erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. The area under the plasma concentration-time curve (AUC) and maximum concentration (C max

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Prediction of ARA/PPI Drug-Drug Interactions at the Drug Discovery and Development Interface

Cited by 28 publications

References 49 publications

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

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

Application of Physiologically‐Based Pharmacokinetic Modeling to Predict Gastric pH‐Dependent Drug–Drug Interactions for Weak Base Drugs

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