title: Reversible and pH-dependent weak drug-excipient binding does not affect oral bioavailability of high dose drugs.
abstract: OBJECTIVE
  Drug-excipient binding can affect in-vitro drug release. Literature suggests that drug-excipient ionic binding interaction that is not disrupted by physiological salt concentration in the dissolution medium can impact a drug's oral bioavailability. We investigated whether nondisruption of interaction by physiological salt concentration was an adequate predictor of its biorelevance using the binding of a model amine high dose drug brivanib alaninate (BA) to croscarmellose sodium (CCS) as an example.
  
  
  METHODS
  BA was formulated into an immediate release tablet using CCS as disintegrant by a wet granulation process. In-vitro drug release was carried out as a function of pH and buffer concentration of the medium. BA-CCS binding was studied in buffer solution and data fitted to a Langmuir isotherm. A simulation model and an isothermal titration calorimetry method were developed to assess the bioavailability risk and strength of drug-excipient binding interaction, independent of physiological salt concentration consideration.
  
  
  RESULTS
  BA-CCS binding was pH-dependent, reversible, ionic, and not disrupted by increasing the buffer concentration in the dissolution medium. Absorption simulation predictions of no effect of CCS binding on BA's bioavailability were confirmed by a monkey pharmacokinetic study.
  
  
  CONCLUSIONS
  A pH-dependent and reversible weak drug-excipient binding interaction is unlikely to affect the oral bioavailability of high dose drugs.
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb, Co., New Brunswick, NJ 08901, USA. ajit.narang@bms.com
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Narang
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Yamniuk
authors.forename: Limin
authors.initials: L
authors.lastname: Zhang
authors.forename: S Nilgun
authors.initials: SN
authors.lastname: Comezoglu
authors.forename: Dilbir S
authors.initials: DS
authors.lastname: Bindra
authors.forename: Sailesh
authors.initials: S
authors.lastname: Varia
authors.forename: Michael L
authors.initials: ML
authors.lastname: Doyle
authors.forename: Sherif
authors.initials: S
authors.lastname: Badawy
mesh_terms: D000284:Administration, Oral; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D002021:Buffers; D002151:Calorimetry / Q000379:methods; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry*; D004347:Drug Interactions; D005079:Excipients / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008252:Macaca fascicularis; D008297:Male; D008954:Models, Biological; D013607:Tablets; D014227:Triazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D002021:Buffers; D005079:Excipients; D013607:Tablets; D014227:Triazines; C509922:brivanib; D002266:Carboxymethylcellulose Sodium; D000409:Alanine