Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy?
A majority of the novel orally administered, molecularly targeted anticancer therapies are weak bases that exhibit pH-dependent solubility, and suppression of gastric acidity with acid-reducing agents could impair their absorption. In addition, a majority of cancer patients frequently take acid-reducing agents to alleviate symptoms of gastroesophageal reflux disease, thereby raising the potential for a common but underappreciated drug-drug interaction (DDI) that could decrease the exposure of anticancer medication and result in subsequent failure of therapy. This article is a review of the available clinical literature describing the extent of the interaction between 15 orally administered, small-molecule targeted anticancer therapies and acid-reducing agents. The currently available clinical data suggest that the magnitude of this DDI is largest for compounds whose in vitro solubility varies over the pH range 1-4. This range represents the normal physiological gastric acidity (pH ~1) and gastric acidity while on an acid-reducing agent (pH ~4).
Department of Clinical Pharmacology, Genentech, South San Francisco, California, USA.
N R
NR
Budha
A
A
Frymoyer
G S
GS
Smelick
J Y
JY
Jin
M R
MR
Yago
M J
MJ
Dresser
S N
SN
Holden
L Z
LZ
Benet
J A
JA
Ware
D016588:Anticarcinogenic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004347:Drug Interactions; D005744:Gastric Acid; D005745:Gastric Acidity Determination; D005764:Gastroesophageal Reflux / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D054328:Proton Pump Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012995:Solubility
D016588:Anticarcinogenic Agents; D054328:Proton Pump Inhibitors