Investigation of Clinical Pharmacokinetic Variability of an Opioid Antagonist Through Physiologically Based Absorption Modeling

Ding, Xuan; He, Minxia M.; Kulkarni, Rajesh; Patel, Nita; Zhang, Xiaoyu

doi:10.1002/jps.23629

Cited by 5 publications

(3 citation statements)

References 45 publications

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“…By carefully examining the preclinical in vivo results, we believe this drug is able to permeate the intestinal membrane at a moderately high rate. Such an in silico-in vitro-in vivo approach has been successfully applied to determine effective in vivo permeability for another trial molecule (38). In our experience, such discrepancy of permeability between experimental and in vivo results is fairly common.…”

Section: Discussionmentioning

confidence: 99%

Assessment of In Vivo Clinical Product Performance of a Weak Basic Drug by Integration of In Vitro Dissolution Tests and Physiologically Based Absorption Modeling

Ding

Gueorguieva

Wesley

et al. 2015

AAPS J

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Abstract. Effective integration of in vitro tests and absorption modeling can greatly improve our capability in understanding, comparing, and predicting in vivo performances of clinical drug products. In this case, we used a proprietary drug candidate galunisertib to describe the procedures of designing key in vitro tests, analyzing relevant experimental and trial data, and integrating them into physiologically based absorption models to evaluate the performances of its clinical products. By simulating the preclinical study result, we estimated high in vivo permeability for the drug. Given the high sensitivity of its solubility to pH, supersaturation may play an important role in the absorption of galunisertib. Using the dynamic dissolution test, i.e., artificial stomach-duodenum (ASD) model and simulation, we concluded galunisertib in solution or tablet products could maintain supersaturation during the transit in the gastrointestinal tract (GIT). A physiologically based absorption model was established by incorporating these key inputs in the simulation of Trial 1 results of galunisertib solution. To predict the performance of three tablet products, we developed z-factor dissolution models from the multi-pH USP dissolution results and integrate them into the absorption model. The resultant biopharmaceutical models provided good prediction of the extent of absorption of all three products, but underestimated the rate of absorption of one tablet product. Leveraging the ASD result and optimization with the dissolution model, we identified the limitation of the model due to complexity of estimating the dissolution parameter z and its in vitro-in vivo correlation.

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Section: Discussionmentioning

confidence: 99%

Assessment of In Vivo Clinical Product Performance of a Weak Basic Drug by Integration of In Vitro Dissolution Tests and Physiologically Based Absorption Modeling

Ding

Gueorguieva

Wesley

et al. 2015

AAPS J

Self Cite

View full text Add to dashboard Cite

show abstract

“…The variability of plasma concentration time profiles in the absorption phase could not be explained by prior in vitro measurements. It was therefore concluded that the negatively-affected permeability and gastrointestinal transit was likely due to opioid receptor antagonism of intestinal receptors by the drug itself, explaining high intersubject variability ( Ding et al, 2013 ).…”

Section: Off-label Medication For Relapse Prophylaxismentioning

confidence: 99%

Off-label and investigational drugs in the treatment of alcohol use disorder: A critical review

Fischler

Soyka²,

Seifritz³

et al. 2022

Front. Pharmacol.

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Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist, Acamprosate, and the opioid receptor antagonists, Naltrexone and Nalmefene. Although all four are effective in maintaining abstinence or reduction of alcohol consumption, only a small percentage of patients receive pharmacological treatment. In addition, many other medications have been investigated for their therapeutic potential in the treatment of alcohol use disorder. In this review we summarize and compare Baclofen, Gabapentin, Topiramate, Ondansetron, Varenicline, Aripiprazole, Quetiapine, Clozapine, Antidepressants, Lithium, Neuropeptide Y, Neuropeptide S, Corticotropin-releasing factor antagonists, Oxytocin, PF-05190457, Memantine, Ifenprodil, Samidorphan, Ondelopran, ABT-436, SSR149415, Mifepristone, Ibudilast, Citicoline, Rimonabant, Surinabant, AM4113 and Gamma-hydroxybutyrate While some have shown promising results in the treatment of alcohol use disorder, others have disappointed and should be excluded from further investigation. Here we discuss the most promising results and highlight medications that deserve further preclinical or clinical study. Effective, patient-tailored treatment will require greater understanding provided by many more preclinical and clinical studies.

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“…It is also valuable for pharmaceutical scientists to look beyond standard pharmacokinetic readouts [C max , T max , and area under the curve (AUC)] and examine individual plasma profiles to observe the source of variability [23] (Fig. 2).…”

Section: In Vivo Study Support and Interpretationmentioning

confidence: 99%

Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates

2017

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Abstract. This commentary reflects the collective view of pharmaceutical scientists from four different organizations with extensive experience in the field of drug discovery support. Herein, engaging discussion is presented on the current and future approaches for the selection of the most optimal and developable drug candidates. Over the past two decades, developability assessment programs have been implemented with the intention of improving physicochemical and metabolic properties. However, the complexity of both new drug targets and non-traditional drug candidates provides continuing challenges for developing formulations for optimal drug delivery. The need for more enabled technologies to deliver drug candidates has necessitated an even more active role for pharmaceutical scientists to influence many key molecular parameters during compound optimization and selection. This enhanced role begins at the early in vitro screening stages, where key learnings regarding the interplay of molecular structure and pharmaceutical property relationships can be derived. Performance of the drug candidates in formulations intended to support key in vivo studies provides important information on chemotype-formulation compatibility relationships. Structure modifications to support the selection of the solid form are also important to consider, and predictive in silico models are being rapidly developed in this area. Ultimately, the role of pharmaceutical scientists in drug discovery now extends beyond rapid solubility screening, early form assessment, and data delivery. This multidisciplinary role has evolved to include the practice of proactively taking part in the molecular design to better align solid form and formulation requirements to enhance developability potential.

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Investigation of Clinical Pharmacokinetic Variability of an Opioid Antagonist Through Physiologically Based Absorption Modeling

Cited by 5 publications

References 45 publications

Assessment of In Vivo Clinical Product Performance of a Weak Basic Drug by Integration of In Vitro Dissolution Tests and Physiologically Based Absorption Modeling

Assessment of In Vivo Clinical Product Performance of a Weak Basic Drug by Integration of In Vitro Dissolution Tests and Physiologically Based Absorption Modeling

Off-label and investigational drugs in the treatment of alcohol use disorder: A critical review

Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates

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