Effect of food and acid-reducing agents on the absorption of oral targeted therapies in solid tumors

Willemsen, Annelieke E.C.A.B.; Lubberman, Floor J E; Tol, Jolien; Gerritsen, Winald R.; Herpen, Carla M.L. van; Erp, Nielka P. van

doi:10.1016/j.drudis.2016.03.002

Cited by 50 publications

(45 citation statements)

References 80 publications

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“…Although the primary regulatory purpose of the BCS is guiding in vivo bioequivalence study waivers, its scientific rationale is used in other areas, including food effect predictions . As per the BCS specifications, all 10 model anticancer drugs have been classified as poorly soluble based on the drug substance . Of note, the dose number for imatinib is less than unity in our calculation ( Table ), which would qualify it as a BCS I drug.…”

Section: Discussionmentioning

confidence: 99%

“…The BCS classification presented in literature is summarized in Table . Additionally, the dose number ( D o ) was calculated to confirm whether the highest clinical dose ( M 0 ) can be completely dissolved in 250 mL intestinal fluid according to Amidon et al with Eq.…”

Section: Methodsmentioning

confidence: 99%

“…6,7 Second, although poorly water-soluble, lipophilic compounds are generally expected to show a better solubilization in gastrointestinal fluids in the presence of food and, thus, a better oral absorption in the fed state, 9 poorly water-soluble anticancer drugs, such as imatinib and trametinib, show only a modest food effect, if any. 10 Last, enabling formulations meant to improve the kinetic solubility of poorly water-soluble active ingredients do not always enhance oral bioavailability, 11 indicating that poor oral bioavailability may be caused by other factors. 12,13 Physiologically-based pharmacokinetic (PBPK) models are powerful tools that describe drug pharmacokinetic (PK) through the integration of PK mechanisms, compound data, and physiology.…”

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confidence: 99%

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Evaluating the Role of Solubility in Oral Absorption of Poorly Water‐Soluble Drugs Using Physiologically‐Based Pharmacokinetic Modeling

Fink

Sun

Wagner

et al. 2019

Clin Pharma and Therapeutics

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Poor aqueous solubility and dissolution of drug candidates drive key decisions on lead series optimization during drug discovery, on formulation optimization, and clinical studies planning during drug development. The interpretation of the in vivo relevance of early pharmaceutical profiling is often confounded by the multiple factors affecting oral systemic exposure. There is growing evidence that in vitro drug solubility may underestimate the true in vivo solubility and lead to drug misclassification. Based on 10 poorly water‐soluble tyrosine kinase inhibitors, this paper demonstrates the use of physiologically‐based pharmacokinetic (PK) analysis in combination with early clinical PK data to identify drugs whose absorption is truly limited by solubility in vivo and, therefore, expected to exhibit food effect. Our study supports a totality of evidence approach using early clinical data to guide decisions on conducting drug interaction studies with food and acid‐reducing agents.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Evaluating the Role of Solubility in Oral Absorption of Poorly Water‐Soluble Drugs Using Physiologically‐Based Pharmacokinetic Modeling

Fink

Sun

Wagner

et al. 2019

Clin Pharma and Therapeutics

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“…Moreover, TKI bioavailability can be profoundly influenced when taken with food (e.g. lapatinib) [22]. Food may significantly enhance TKI bioavailability by elevating intragastric pH and drug absorption, resulting in high intra- and interpatient variability.…”

Section: Unraveling Drug–drug Interactions Between Tyrosine Kinase Inmentioning

confidence: 99%

Tyrosine Kinase Inhibitors and Proton Pump Inhibitors: An Evaluation of Treatment Options

et al. 2017

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Tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies. Use of the oral administration route of TKIs offers flexibility and is convenient for the patient; however, despite these advantages, the oral route of administration also causes a highly relevant new problem. Acid-inhibitory drugs, such as proton pump inhibitors (PPIs), increase the intragastric pH, which may subsequently decrease TKI solubility, bioavailability, and treatment efficacy. Clear and practical advice on how to manage PPI use during TKI therapy is currently not available in the literature. Since PPIs are extensively used during TKI therapy, prescribers are presented with a big dilemma as to whether or not to continue the combined treatment, resulting in patients possibly being deprived of optimal therapy. When all pharmacological characteristics and data of either TKIs and PPIs are considered, practical and safe advice on how to manage this drug combination can be given.

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“…The importance of food on the bioavailability, and subsequently safety and efficacy, of oral targeted therapies has been reported [40][41][42] and is highlighted in recent regulatory authority interactions. 43 First-in-human oncology studies are typically conducted on an empty stomach.…”

Section: Food Effectmentioning

confidence: 99%

Clinical Pharmacology Tools and Evaluations to Facilitate Comprehensive Dose Finding in Oncology: A Continuous Risk‐Benefit Approach

Bullock

Lin

Bilic

2017

The Journal of Clinical Pharma

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Targeted therapies are now considered an integral component in the treatment armamentarium for many malignancies, and the approach to developing these drugs needs to be refined from the previous cytotoxic paradigm of toxicity-guided dose finding and identification of maximum tolerated dose to a paradigm driven by target activity. Moving away from the toxicity-driven dose finding and justification model requires an integrated approach in order to adequately characterize the risk-benefit of a drug. This approach starts with understanding the importance of collecting samples for pharmacokinetic and pharmacodynamic assessments in all phases of clinical development to fully characterize the pharmacokinetics and identify covariates and then correlating exposure to key markers of safety and efficacy in pharmacometric analyses to perform a robust risk-benefit assessment and establish the right dose. In addition, for oral agents, decisions on administering the drug with respect to food can impact dose among other clinical trial outcomes such as tolerability and patient compliance. Understanding the importance of model-based drug development as a decision-making tool to support drug development through incorporation of all relevant data allows for a robust risk-benefit assessment at key decision points. Utilization of clinical pharmacology tools and assessments throughout development will provide the key components of a successful oncology development program.

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Effect of food and acid-reducing agents on the absorption of oral targeted therapies in solid tumors

Cited by 50 publications

References 80 publications

Evaluating the Role of Solubility in Oral Absorption of Poorly Water‐Soluble Drugs Using Physiologically‐Based Pharmacokinetic Modeling

Evaluating the Role of Solubility in Oral Absorption of Poorly Water‐Soluble Drugs Using Physiologically‐Based Pharmacokinetic Modeling

Tyrosine Kinase Inhibitors and Proton Pump Inhibitors: An Evaluation of Treatment Options

Clinical Pharmacology Tools and Evaluations to Facilitate Comprehensive Dose Finding in Oncology: A Continuous Risk‐Benefit Approach

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