Despite warnings, co‐medication with proton pump inhibitors and dasatinib is common in chronic myeloid leukemia, but <scp>XS004</scp>, a novel oral dasatinib formulation, provides reduced <scp>pH‐dependence</scp>, minimizing undesirable <scp>drug–drug</scp> interactions

Larfors, Gunnar; Andersson, Per; Jesson, Gérald; Liljebris, Charlotta; Brisander, Magnus; Lennernäs, Hans; Stenke, Leif

doi:10.1111/ejh.14059

Cited by 9 publications

(2 citation statements)

References 66 publications

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“…This allows for the development of oral products with less variable plasma PK and more effective doses, which can improve patient compliance and overall treatment outcomes. 153,154 Determining the intestinal permeability of drug candidates has significantly contributed to reducing the attrition rates of drugs in development. Previously, about 40% of drug candidates were discarded due to poor ADME (absorption, distribution, metabolism, and excretion) properties.…”

Section: Q4: What Are the Best Practices For Modeling Precipitation U...mentioning

confidence: 99%

“…On the other hand, if a drug has high permeability and a poor pH-dependent solubility (BCS class II), the low and erratic rate and extent of absorption may be overcome with a sophisticated and innovative formulation design, such as ASD. This allows for the development of oral products with less variable plasma PK and more effective doses, which can improve patient compliance and overall treatment outcomes. , …”

Section: Introductionmentioning

confidence: 99%

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Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report

Pepin,

Arora,

Borges

et al. 2024

Mol. Pharmaceutics

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This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid−base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.

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Section: Q4: What Are the Best Practices For Modeling Precipitation U...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report

Pepin,

Arora,

Borges

et al. 2024

Mol. Pharmaceutics

Self Cite

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Enhanced Bioavailability and Reduced Variability of Dasatinib and Sorafenib with a Novel Amorphous Solid Dispersion Technology Platform

Lennernäs,

Brisander,

Liljebris

et al. 2024

Clinical Pharm in Drug Dev

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Despite clinical advances with protein kinase inhibitors (PKIs), oral administration of many PKIs is associated with highly variable plasma exposure and a narrow therapeutic window. We developed a novel hybrid nanoparticle‐amorphous solid dispersion (ASD) technology platform consisting of an amorphous PKI embedded in a polymer matrix. The technology was used to manufacture immediate‐release formulations of 2 tyrosine kinase inhibitors (TKIs), dasatinib and sorafenib. Our primary objective was to improve the absorption properties and reduce the pharmacokinetic (PK) variability of each TKI. The PKs of XS004 (dasatinib‐ASD, 100 mg tablet) and XS005 (sorafenib‐ASD, 2 × 50 mg capsules) were compared with their crystalline formulated reference drugs (140 mg of dasatinib‐reference and 200 mg of sorafenib‐reference). The in vitro biopharmaceutics of dasatinib‐ASD and XS005‐granulate showed sustained increased solubility in the pH range 1.2‐8.0 compared to their crystalline references. In vivo, XS004 was bioequivalent at a 30% lower dose and showed increased absorption and bioavailability, with 2.1‐4.8 times lower intra‐ and intersubject variability compared to the reference. XS005 had an increased absorption and bioavailability of 45% and 2.2‐2.8 times lower variability, respectively, but it was not bioequivalent at the investigated dose level. Taken together, the formulation platform is suited to generate improved PKI formulations with consistent bioavailability and a reduced pH‐dependent absorption process.

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Severe Impact of Omeprazole Timing on pH‐Sensitive Dasatinib Absorption: Unveiling Substantial Drug–Drug Interaction

Andersson,

Brisander,

Liljebris

et al. 2024

The Journal of Clinical Pharma

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The absorption and bioavailability of most tyrosine kinase inhibitors are affected by gastrointestinal pH as they are weak basic lipophilic drugs. Hence, concomitant use of acid reducing agents (ARAs) is frequently restricted. Particularly comedication of crystalline dasatinib (Sprycel) and proton‐pump inhibitors (PPIs) should be avoided. Drug–drug interaction (DDI) studies with PPIs report approximately 40%‐80% bioavailability reduction of dasatinib. Limitations in the design of these studies do not allow for assessing the near maximum DDI as timing of PPI dosing was either not reported or 22 h prior to dasatinib intake. We conducted a DDI study of crystalline dasatinib and omeprazole in healthy, fasted participants, investigating the impact of PPI comedication on dasatinib plasma exposure at a time point when the near maximum DDI effect is expected. Participants were administered omeprazole (day 2‐5) to reach steady state. On day 6, a single dose of crystalline dasatinib was given. Crystalline dasatinib dosing alone on day 1 served as control (single dose). The dosing interval between omeprazole administration and crystalline dasatinib was 10 h (median [range: 9‐10 h]). Dasatinib Cmax and AUC0‐24 were reduced by 96% and 89% by omeprazole comedication. Cmax was 224.6 ± 104.7 ng/mL (mean ± SD) and 8.0 ± 4.5 ng/mL (P < .0001) and AUC0‐24 was 797.6 ± 274.5 and 90.6 ± 38.1 h·ng/mL (P < .0001) without and with omeprazole. T1/2 was 5.7 ± 1.5 h (mean ± SD) with crystalline dasatinib dosing alone and could not be reliably calculated with comedication. To ensure optimal patient outcome, it is vital to investigate bioavailability of pH‐sensitive drugs at the maximal DDI effect of ARAs to understand the worst‐case influence for efficient clinical management.

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Despite warnings, co‐medication with proton pump inhibitors and dasatinib is common in chronic myeloid leukemia, but XS004, a novel oral dasatinib formulation, provides reduced pH‐dependence, minimizing undesirable drug–drug interactions

Cited by 9 publications

References 66 publications

Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report

Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report

Enhanced Bioavailability and Reduced Variability of Dasatinib and Sorafenib with a Novel Amorphous Solid Dispersion Technology Platform

Severe Impact of Omeprazole Timing on pH‐Sensitive Dasatinib Absorption: Unveiling Substantial Drug–Drug Interaction

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