Effect of food or proton pump inhibitor treatment on the bioavailability of dacomitinib in healthy volunteers

Abstract

This phase 1, open-label crossover study evaluated the relative bioavailability of dacomitinib in healthy volunteers under fed and fasted conditions and following coadministration with rabeprazole, a potent acid-reducing proton pump inhibitor (PPI). Twenty-four male subjects received a single dacomitinib 45-mg dose under 3 different conditions separated by washout periods of ≥ 16 days: coadministered with rabeprazole 40 mg under fasting conditions; alone under fasting conditions; and alone after a high-fat, high-calorie meal. Increased peak exposure of 23.7% (90% confidence interval [CI], 5.3%-45.2%) was detected with dacomitinib taken after food versus fasting. The adjusted geometric mean ratio (fed/fasted) for area under the plasma concentration-time curve from time zero to infinity (AUCinf ) was 114.2% (90%CI, 104.7%-124.5%) and not considered clinically meaningful. In the fasted state, a decrease in dacomitinib AUCinf was observed following rabeprazole versus dacomitinib alone (PPI+fasted/fasted alone): 71.1% (90%CI, 61.7%-81.8%). Dacomitinib was generally well tolerated. Dacomitinib may be taken with or without food. Use of long-acting acid-reducing agents, such as PPIs with dacomitinib should be avoided if possible. Shorter-acting agents such as antacids and H2-receptor antagonists may have lesser impact on dacomitinib exposure and may be preferable to PPIs if acid reduction is clinically required.

Effect of Sustained Elevated Gastric pH Levels on Gefitinib Exposure

“…Median time to maximal plasma concentration and the mean elimination half‐life of gefitinib under conditions of elevated gastric pH were unchanged, however. A similar effect of elevated gastric pH on bioavailability has also been observed with other oral EGFR TKIs, such as erlotinib and dacomitinib …”

“…A similar effect of elevated gastric pH on bioavailability has also been observed with other oral EGFR TKIs, such as erlotinib and dacomitinib. 17,18 During the study, the gastric pH level was monitored before and after gefitinib administration using a microelectrode, which was placed in the stomach in the same position for each recording. Some level of inaccuracy is possible and is to be expected with such methodology because of factors that affect the the gastric acid level during monitoring, for example, eating patterns and movement by the volunteer.…”

Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

“…The most common EGFR mutations are the short in-frame deletions in exon 19 (ex19del), or point mutations in exon 21, the latter resulting in arginine replacing a leucine in codon 858 (L858 R). These genetic aberrations are typically clustered around the ATP-binding pocket of the enzyme (coded by exons [18][19][20][21][22][23][24] and cause a constitutive activation of signal transduction pathways, unrelated to the presence of ligands, and therefore lead to uncontrolled cell proliferation or evasion from apoptosis. For this reason, EGFR has become such an interesting target for cancer therapy [5,6].…”

“…In addition, pharmacokinetics was not altered by the administration of a high-fat, high-calorie meal, whereas its exposure, after the administration of acid-reducing proton pump inhibitors (PPI), was reduced. Therefore, dacomitinib could be taken both in fasted or fed state, but the use of PPI with long-lasting effects should be avoided, when possible [21].…”

Pharmacokinetic Models to Characterize the Absorption Phase and the Influence of a Proton Pump Inhibitor on the Overall Exposure of Dacomitinib

“…The in vitro binding of dacomitinib to human plasma proteins is approximately 98%. Following a single 45 mg oral dose of dacomitinib, the mean plasma half-life of dacomitinib ranged from 55 to 90 h, and the geometric mean apparent plasma clearance of dacomitinib was approximately 27 to 38 L/h [6][7][8][9][10].…”