Editorial pubs.acs.org/molecularpharmaceutics
Physical Chemical Drug−Drug Interactions from Drug Discovery to Registration: New Opportunities for the Pharmaceutical Scientist To Impact Drug Development
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cancer therapeutics. This is an important point to consider as approximately 50−70% of recently approved orally administered molecular targeted cancer therapies display pH-dependent solubility.2 Smelick et al. have captured the prevalence of the ARA-DDI potential of orally administered targeted anticancer agents with pH-dependent solubility in (1) their epidemiological analysis of ARA use in cancer populations and (2) their in silico evaluation of the ARA-DDI liability of investigational drugs currently being evaluated for oncologic indications.3 Due to the multivariate intra/interdependencies between drug physicochemical properties, formulation, and absorption, preclinical assessments to predict and clinical methodologies to def ine the impact of pH-dependent solubility on drug absorption remain complex. Moreover, cycle time for prototype formulation development and human absorption testing is prohibitively long to permit multiple iterations of formulation improvement in most cases. Therefore, improved predictive tools are needed to evaluate and mitigate the risks of pHdependent absorption. In this special issue of Molecular Pharmaceutics, an attempt has been made to define the scope of physicochemical DDIs and to define integrated strategies to characterize and improve our current understanding of the determinants of drug absorption.4 To this end, Mathias et al. have done an excellent job to systematically assess the risk of clinical pH-effect for new molecular entities which integrates physicochemical analysis, in vitro, in vivo, and in silico approaches.5 A number of elegant mechanistic absorption and physiologybased PK studies are included in this special issue. As highlighted by Chiang et al., in their submission, “Systemic Concentrations Can Limit the Oral Absorption of Poorly Soluble Drugs: An Investigation of Non-Sink Permeation Using Physiologically Based Pharmacokinetic Modeling”, using the probe molecule 1,3-dicyclohexyl urea presents compelling results to challenge a key fundamental assumption of the drug absorption process, namely, that “sink” conditions during permeation occur across the gastrointestinal epithelium, as the authors propose the hypothesis that “non-sink” conditions can occur for a poorly soluble compound when the systemic concentrations of the compound are high enough to inhibit intestinal permeation.6 In addition to improving our understanding of pH-mediated DDIs, there is great interest in understanding and predicting food−drug interactions. In particular, for many BCS III drugs there is often a reduction in absorption with food. Using the model organic cation, trospium chloride, Heinen et al. suggest that ion pair formation
rug discovery efforts frequently yield molecules with challenging physicochemical attributes that affect formulation, product development, and robustness of drug absorption across patient populations. Low aqueous solubility and/or low permeability rates have been conveniently classified via the Biopharmaceutical Classification System (BCS).1 Within the solubility axis, drugs frequently exhibit pH-dependent solubility, where the potential for extensive drug dissolution may vary dramatically as a function of pH over the course of the gastrointestinal (GI) tract. For example weakly basic drugs may be sufficiently soluble in the stomach under standard conditions, yet these same drugs may rapidly become insufficiently soluble once exiting the stomach into the higher pH duodenum or later. For patients with limited gastric acid secretion (hypochlorhydria, or achlorhydria), their stomach pH may be higher than standard conditions, and for these individuals, drug absorption may be significantly lower (for weak base drugs) or higher (for weak acid drugs). Further, patients taking acid-reducing agents (proton pump inhibitors, H2-receptor antagonists, antacids), which elevate gastric pH, are similarly prone to the interaction of variable gastric pH affecting the extent of drug dissolution or precipitation in the GI tract. This special edition of Molecular Pharmaceutics focuses specifically on physicochemical DDI effects and formulation approaches as well as in vivo and in silico methodologies to support robust product development despite the challenges presented by undesirable physicochemical properties. It is often said in business “one should begin with the end result in mind”. Therefore, in addition to the fundamental physicochemical challenges that are encountered in drug discovery and development, we must always consider the patient. In particular, concomitant medications, infectious diseases (HIV/AIDS, Helicobacter pylori), diet, ethnicity, and GI surgery may have a significant effect on gastric pH and drug absorption. In addition, acid-reducing agents (ARAs), most notably proton pump inhibitors (PPIs), are the most commonly prescribed medications in North America, Japan, and Europe and are used for the palliative relief of symptoms arising from conditions of gastroesophageal hyperacidity. Drug−drug interactions (DDIs) between ARA “perpetrators” may impact clinical outcomes of “victim” NMEs/drugs which display pH-dependent solubility with the clinical impact of increased gastric pH imparting a negative effect on the dissolution, absorption, and pharmacokinetics of the orally administered “victim” drugs. Moreover, gastric pH is also an important source of pharmacokinetic variability for many drugs, however, direct evidence linking clinical outcomes or response to ARA therapy remains debated. For anti-infective therapeutics, there remains a generally stronger link with respect to pharmacokinetics (PK) and pharmacodynamics (PD) with clinical outcomes. It is hypothesized that the same PK/PD relationship will emerge for some molecular targeted anti© 2013 American Chemical Society
Special Issue: Impact of Physical Chemical Drug-Drug Interactions from Drug Discovery to Clinic Published: November 4, 2013 3967
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for the opportunity to contribute to this important realm of drug discovery and development.
with bile salts is most likely to contribute to the negative food effect that is observed with this compound.7 High gastric pH (due to hypochlorhydria or ARAs) has been shown to negatively impact the absorption of weakly basic drugs with a steep pH-dependent solubility profile. This is due to the ionization characteristics of such molecules, where higher gastric pH can result in slower dissolution or faster precipitation, thus resulting in decreased absorption. Preclinical assessment of such molecules will aid in compound selection in the discovery stages and, when possible, evaluate the implementation of mitigation strategies during drug development. In this theme issue, we have seen the application of both rodent and nonrodent models to evaluate the risk of pHdependent oral absorption. In the manuscript by Pang et al. dogs were pretreated with either pentagastrin or famotidine to evaluate the risk of pH-dependent absorption using two weakly basic anti-cancer drugs.8 The results confirmed the negative impact of acid-reducing agents on the oral absorption of these weakly basic drugs. Lubach et al. evaluated the use of rats as an alternate preclinical model, which is less expensive and more material-sparing compared to the canine model.9 Pentagastrin and famotidine were also used to induce or reduce acid secretion, respectively. Their work showed that a rat model can be used to evaluate pH-dependent absorption, and potentially aid the early development stages of candidate selection. An emphasis on mitigation strategies included several different approaches. Coadministration with an acidic beverage with the antifungal drug posaconazole can be successfully modeled using a physiological-based PK (PBPK) approach.10 Alternately, formulating the HIV antiviral drug cenicriviroc with a slowly dissolving acidic excipient (fumaric acid) to decrease the microenvironmental pH and maximize absorption and resilience to pH variability was optimized via a unique in vitro test (FBRM probe) and confirmed in the canine pentagastrin/ famotidine model.10−12 These mitigation strategies are all viable approaches to overcome pH-dependent absorption driven by the physicochemical properties of the “victim” NMEs. Drug− drug interactions between ARAs and “victim” NMEs have been studied in clinical pharmacology studies for a number of years, however, there remains no regulatory guidance regarding how best to identify and assess pH-dependent liability and impact of hypochlorhydria on pharmacokinetics of weakly basic drugs. Moreover, if a drug displays a meaningful interaction with an ARA, it is typical to contraindicate the use of “PPIs” or to recommend the use of an alternate agent such as H2-receptor antagonist with a time-staggering dosing regimen in an effort to leverage the rapid on/off benefit of the ARA relative to the “victim” drug. An alternate mitigation strategy is gastric reacidification using betaine HCl, as published by Yago et al.13 We believe that the manuscripts provided in this theme issue will provide additional insight into determinants of absorptionrelated DDIs with orally administered therapies which display pH-dependent solubility. In particular, we must be able to understand the “totality of the data” before regulatory guidance is proposed. Certainly, this will take a major cross-functional initiative of pharmaceutical scientists, medicinal chemists, clinical pharmacologists, and clinicians with diverse experience ranging from drug discovery to drug development, regulatory science, and clinical practice to develop an integrated risk assessment and management schema that patients can easily follow. The Guest Editors wish to thank authors, reviewers, and the Molecular Pharmaceutics editorial staff (Ms. Kimberly Barrett, Coordinating Editor, and Gordon Amidon, Editor)
Joseph A. Ware,*,† Guest Editor Gena Dalziel,§ Guest Editor †
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Small Molecule Clinical Pharmacology and §Small Molecule Pharmaceutical Sciences, Genentech Research and Early Development, 1 DNA Way, South San Francisco, California 94080, United States
AUTHOR INFORMATION
Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS or Genentech.
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DEDICATION This theme issue is dedicated to the memory of Chad Stoner (1973−2009) whose passionate research efforts helped to elucidate the impact of physicochemical properties of drugs on ADME. Chad’s warm and outgoing personality and way of life may be exemplified by one of his favorite sayings, “Work HardPlay Harder”.
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REFERENCES
(1) Amidon, G. L.; Lennernas, H.; Shah, V. P.; Crison, J. R. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 1995, 12 (3), 413−20. (2) Budha, N. R.; Frymoyer, A.; Smelick, G. S.; Jin, J. Y.; Yago, M. R.; Dresser, M. J.; Holden, S. N.; Benet, L. Z.; Ware, J. A. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pHdependent solubility the Achilles heel of targeted therapy? Clin. Pharmacol. Ther. 2012, 92 (2), 203−13. (3) Smelick, G. S.; Heffron, T.; Chu, L.; Dean, B.; West, D. A.; DuVall, S. L.; Lum, B. L.; Budha, N.; Holden, S. N.; Benet, L. Z.; Frymoyer, A.; Dresser, M. J.; Ware, J. A. Prevalence of Acid-Reducing Agents (ARA) in Cancer Populations and ARA Drug−Drug Interaction Potential for Molecular Targeted Agents in Clinical Development. Mol. Pharmaceutics 2013, DOI: 10.1021/mp400403s. (4) Mitra, A.; Kesisoglou, F. Impaired Drug Absorption Due to High Stomach pH: A Review of Strategies for Mitigation of Such Effect To Enable Pharmaceutical Product Development. Mol. Pharmaceutics 2013, DOI: 10.1021/mp400256h. (5) Mathias, N. R.; Xu, Y.; Patel, D.; Grass, M.; Caldwell, B.; Jager, C.; Mullin, J.; Hansen, L.; Crison, J.; Saari, A.; Gesenberg, C.; Morrison, J.; Vig, B.; Raghavan, K. Assessing the Risk of pHDependent Absorption for New Molecular Entities: A Novel in Vitro Dissolution Test, Physicochemical Analysis, and Risk Assessment Strategy. Mol. Pharmaceutics 2013, DOI: 10.1021/mp400426f. (6) Chiang, P.-C.; La, H.; Zhang, H.; Wong, H. Systemic Concentrations Can Limit the Oral Absorption of Poorly Soluble Drugs: An Investigation of Non-Sink Permeation Using Physiologically Based Pharmacokinetic Modeling. Mol. Pharmaceutics 2013, DOI: 10.1021/mp400088q. (7) Heinen, C. A.; Reuss, S.; Amidon, G. L.; Langguth, P. Ion Pairing with Bile Salts Modulates Intestinal Permeability and Contributes to Food−Drug Interaction of BCS Class III Compound Trospium Chloride. Mol. Pharmaceutics 2013, DOI: 10.1021/mp400179v. (8) Pang, J.; Dalziel, G.; Dean, B.; Ware, J. A.; Salphati, L. Pharmacokinetics and Absorption of the Anticancer Agents Dasatinib and GDC-0941 under Various Gastric Conditions in Dogs Reversing the Effect of Elevated Gastric pH with Betaine HCl. Mol. Pharmaceutics 2013, DOI: 10.1021/mp400356m. (9) Lubach, J. W.; Chen, J. Z.; Hau, J.; Imperio, J.; Coraggio, M.; Liu, L.; Wong, H. Investigation of the Rat Model for Preclinical Evaluation of pH-Dependent Oral Absorption in Humans. Mol. Pharmaceutics 2013, DOI: 10.1021/mp400283j.
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(10) Fotaki, N.; Klein, S. Mechanistic Understanding of the Effect of PPIs and Acidic Carbonated Beverages on the Oral Absorption of Itraconazole Based on Absorption Modeling with Appropriate in Vitro Data. Mol. Pharmaceutics 2013, DOI: 10.1021/mp4003249. (11) Menning, M. M.; Dalziel, S. M. Fumaric Acid Microenvironment Tablet Formulation and Process Development for Crystalline Cenicriviroc Mesylate, a BCS IV Compound. Mol. Pharmaceutics 2013, DOI: 10.1021/mp400286s. (12) US Food and Drug Administration. Posaconazole (Noxafil) Prescribing Information; 2012. (13) Yago, M. R.; Frymoyer, A. R.; Smelick, G. S.; Frassetto, L. A.; Budha, N. R.; Dresser, M. J.; Ware, J. A.; Benet, L. Z. Gastric Reacidification with Betaine HCl in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria. Mol. Pharmaceutics 2013, DOI: 10.1021/mp4003738.
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