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).

A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors.

BACKGROUND: To evaluate the toxicity and pharmacological and biological properties of the farnesyl protein transferase (FPTase) inhibitor, tipifarnib (R115777, ZARNESTRAtrade mark) and capecitabine administered for 14 days every 3 weeks. PATIENTS AND METHODS: Patients with advanced cancers received twice daily tipifarnib (100-500 mg) and capecitabine (1000-1125 mg/m(2)) for 14 days every 3 weeks. Pharmacokinetics of tipifarnib, capecitabine and 5-fluorouracil (5-FU) were determined. Peripheral blood mononuclear cells were analyzed for farnesylation of the HDJ2 chaperone protein and FPTase activity. RESULTS: Forty-one patients received 185 courses of treatment. Diarrhea and palmar-plantar erythrodysesthesia were dose limiting at 300 mg tipifarnib/1125 mg/m(2) capecitabine b.i.d. When the capecitabine dose was fixed at 1000 mg/m(2) b.i.d., neutropenia was dose limiting at 400 and 500 mg b.i.d. of tipifarnib. Capecitabine did not affect the pharmacology of tipifarnib at 100-300 mg b.i.d., although tipifarnib significantly increased the C(max) of 5-FU at 400 mg b.i.d. HDJ2 farnesylation and FPTase activity decreased between 200 and 400 mg b.i.d. doses of tipifarnib, without a dose-response relationship. Five patients demonstrated partial remissions and 11 patients maintained prolonged stable disease. CONCLUSIONS: Tipifarnib and capecitabine are well tolerated at 300 mg/1000 mg/m(2) b.i.d., respectively, resulting in biologically relevant plasma concentrations and antitumor activity. The recommended dose for further disease-focused studies is 300 mg b.i.d. tipifarnib and 1000 mg/m(2) b.i.d. capecitabine, given for 14 days every 3 weeks.

Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors.

BACKGROUND: ZD6474 selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor and epidermal growth factor receptor. The safety, tolerability and pharmacokinetics of ZD6474 were assessed in a phase I dose-escalation study of patients with advanced solid tumors. PATIENTS AND METHODS: Adult patients with tumors refractory to standard treatments received once-daily oral ZD6474 (50-600 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed. RESULTS: Seventy-seven patients were treated at doses of 50 mg (n=9), 100 mg (n=19), 200 mg (n=8), 300 mg (n=25), 500 mg (n=8), and 600 mg (n=8). Adverse events were generally mild, and the most common dose-limiting toxicities (DLT) were diarrhea (n=4), hypertension (n=4), and rash (n=3). The incidence of most adverse events appeared to be dose-dependant. In the 500 mg/day cohort, 3/8 patients experienced DLT and this dose was therefore considered to exceed the maximum tolerated dose. Pharmacokinetic analysis confirmed that ZD6474 was suitable for once-daily oral dosing. CONCLUSIONS: Once-daily oral dosing of ZD6474 at 300 mg/day is generally well tolerated in patients with advanced solid tumors, and this dose is being investigated in phase II trials.

C-reactive protein (CRP) of the Syrian hamster.

Complementary and genomic clones encoding the mRNA and gene for a protein in the Syrian hamster that is highly homologous to C-reactive protein (CRP) have been isolated and studied. Coding sequence of the genomic clone is identical with that of the cDNA clone and predicts a mature protein of 206 amino acids and a 19 amino acid signal peptide. The single intron is 217 base pairs long and contains a short repetitive (GT)n motif. RNA blot analysis demonstrates that mRNA for hamster CRP is approximately 2.0 kb long, and unlike the closely related pentraxin female protein (FP), expression of this mRNA is not affected by the gender of the animal and accumulates equally in males and females during inflammation. In vivo administration of interleukin 1, interleukin 6, and tumor necrosis factor induces accumulation of hepatic CRP mRNA, and the acute-phase alterations in CRP mRNA levels arise as a result of enhanced gene transcription.

Effects of atrial natriuretic factor on cyclic nucleotides, bone resorption, collagen and deoxyribonucleic acid synthesis, and prostaglandin E2 production in fetal rat bone cultures.

We examined the effects of synthetic human atrial natriuretic factor (human ANF 99-126) on adenylate cyclase activity, cAMP and cyclic GMP (cGMP) levels, bone resorption, collagen and DNA synthesis, and prostaglandin E2 (PGE2) production in fetal rat bone organ cultures. ANF (100 nM) inhibited PTH- and PGE2-stimulated cAMP production but had no effect on basal cAMP production in 21-day fetal rat calvaria. ANF increased cGMP levels, and this was not affected by PTH. ANF (10 nM) partially inhibited bone resorption stimulated by PGE2 but had no effect on control or PTH-stimulated resorption in 19-day fetal rat long bones. ANF had no effect on collagen and DNA synthesis or PGE2 production and did not alter responses to PTH or PGE2 in the fetal rat calvaria. Thus, ANF has no major direct effect on bone resorption or formation, but it is possible that ANF modulates the local regulatory function of PGE2 in bone.