Effect of antacid on imatinib absorption
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- Sparano, B.A., Egorin, M.J., Parise, R.A. et al. Cancer Chemother Pharmacol (2009) 63: 525. doi:10.1007/s00280-008-0778-7
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Imatinib often causes gastric upset resulting in frequent co-administration of an antacid. Elevated gastric pH, delayed gastric emptying, or introduction of Mg2+/Al3+ could potentially change imatinib absorption, thereby affecting the therapeutic effectiveness of imatinib. Indeed, antacid co-administration with dasatinib does result in a twofold decrease in dasatinib absorption. We aimed to define the effect of antacid on the pharmacokinetics of imatinib.
Twelve healthy subjects were enrolled in a 2-period, open-label, randomized cross-over, fixed-sequence study. In one period, each subject received 400 mg imatinib p.o., and in the other, the same dose of imatinib preceded by 20 mL antacid, containing 1.6 g Al(OH)3 + 1.6 g Mg(OH)2, 15 min before imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were determined by LC–MS, and data were analyzed non-compartmentally.
Antacid administration did not significantly affect the area under the plasma imatinib concentration versus time curve (AUC) [31.7 μg/(mL h) alone versus 32.6 μg/(mL h) with antacid, P = 0.37; 80% power].
Our results indicate that the use of Mg2+-Al3+-based antacid does not significantly affect imatinib absorption.
Imatinib mesylate (Gleevec®, Glivec®), a potent inhibitor of Bcr-Abl and c-Kit tyrosine kinases, is widely used to treat Philadelphia chromosome-positive leukemias and gastrointestinal stromal tumors [4–6]. Imatinib is associated with dyspepsia (18%) and nausea (43%)  and is therefore frequently administered with an acid-neutralizing antacid. Antacids increase the pH of the stomach content, delay gastric emptying, and introduce Mg2+ and Al3+ into the gastrointestinal tract. Each of these perturbations could theoretically decrease imatinib absorption, which normally exceeds 97%. Indeed, antacids are known to be associated with a nearly twofold decrease in dasatinib absorption . Whether, and to what extent, antacids used for imatinib-associated gastrointestinal upset influence imatinib pharmacokinetics is unknown.
The purpose of this study was to examine the effect of antacids containing magnesium and aluminum hydroxide salts on the pharmacokinetics of imatinib in healthy volunteers.
Materials and methods
The study was approved by the University of Pittsburgh Institutional Review Board. After providing written informed consent, 12 healthy subjects (6 men, 6 women; 20–51 years) completed the study. Eligible subjects were healthy men or women who were 18 years of age or older and had a body mass index (BMI) <31 kg/m2. Exclusion criteria included: pregnancy or breast-feeding; abnormal marrow function; evidence of renal dysfunction (proteinuria, estimated creatinine clearance <80 mL/min); impaired hepatic function (liver enzymes or bilirubin > the upper limit of normal); use of any medications (including over the counter products, herbal products, or mineral supplements) with the exception of a daily multivitamin preparation or oral contraceptives (for women).
The study had a 2-period, open-label, randomized cross-over, fixed-sequence design, and could detect a 30% difference in imatinib AUC with 80% power and a 5% type I error, assuming a within-subject variability of 30% . In one period, subjects received 400 mg imatinib (Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ) p.o., and in the other, 20 mL Maximum Strength Maalox®Max® Antacid/Anti-gas (Novartis) [1.6 g Al(OH)3, 1.6 g Mg(OH)2, 160 mg simethicone] was administered 15 min prior to 400 mg imatinib p.o. Imatinib was taken with 200 mL of water. The imatinib doses were separated by a wash-out period of 14 days in 11 patients and 21 days in 1 male patient.
Venous blood samples (N = 13 per subject, 6 mL each) were drawn from an indwelling catheter into heparin-containing tubes before and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, and 72 h after imatinib administration. Blood samples were centrifuged at 3,000 × g for 10 min, and the resulting plasma was aspirated and stored at −20°C or colder until analyzed.
Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were determined using a previously described LC–MS method  that was developed and validated in our laboratory, after adaptation for use with a new instrument. Briefly, 0.2 mL plasma samples were mixed in a micro-centrifuge tube with 10 μL internal standard solution (5 μg/mL imatinib-D8; Novartis) before plasma proteins were precipitated with 1 mL of acetonitrile. Samples were centrifuged for 5 min at 16,000 × g at room temperature, and the resulting supernatants were evaporated to dryness under a gentle stream of nitrogen at 37°C. Each dried residue was dissolved in 100 μL methanol:distilled water (30:70, v/v), transferred to an autosampler vial, and 3 μL were injected into the HPLC system. The HPLC system consisted of an Agilent model 1100 autosampler and quaternary pump (Agilent Technologies, Palo Alto, CA) and a Phenomenex Luna C18(2) (5 μm, 150 × 2 mm) reverse-phase analytical column (Phenomenex, Torrance, CA). Determination of imatinib, CGP74588, and the internal standard was achieved using a ThermoFinnigan MSQ Mass Spectrometer (Thermo Electron, San Jose, CA) operating in positive electrospray, single-ion mode monitoring m/z 493.7 for imatinib, m/z 479.7 for CGP74588 and m/z 501.7 for imatinib-D8. Standard curves were linear over the range of 10–1,000 ng/mL, and exhibited acceptable performance (imatinib: accuracy −13.1 to 9.8% and precision within 6.8% CV; CGP74588: accuracy −5.3 to 6.7% and precision within 15.0% CV).
The pharmacokinetic parameters of imatinib and CGP74588 were determined by standard non-compartmental methods (WinNonlin Professional 4.1, Pharsight, Mountain View, CA). The maximum concentration (Cmax) and time to reach the maximum concentration (tmax) were determined by visual inspection of the plasma concentration versus time curves. The imatinib elimination rate constant (ke) was obtained using non-linear least-square regression of the terminal concentration versus time data. The imatinib area under the concentration versus time curve (AUC) was calculated by the trapezoidal rule (linear up, log down) with extrapolation to infinity (AUC0–∞) beyond the last sample time (Clast). The percentage of AUC0–∞ extrapolated beyond Clast indicates what fraction of the AUC0–∞ is not based on our plasma determinations, but is estimated by extrapolation. Ideally the percentage extrapolated is less than 20%.
Calculations were performed using SPSS 15.0 for Windows (SPSS Inc., Chicago, IL). The pharmacokinetic parameter estimates of imatinib and CGP74588 determined in the presence and absence of antacid were compared (after logarithmic transformation) with a two-tailed, paired t test, where a P < 0.05 was considered significant. We also tested for a sequence effect, to determine if there was a difference between the pharmacokinetics during the first and second study visit, unrelated to antacid co-administration. The values for imatinib tmax, CGP74588 tmax, and CGP74588 half-life, after log transformation, did not follow a normal distribution (significance observed by the Kolmogorov–Smirnov test for normality). Therefore, the untransformed values for these parameters were analyzed by the two-tailed exact Wilcoxon signed rank test.
We also performed an analysis of bioequivalence by calculating the 90% confidence intervals of the imatinib AUC ratio and the Cmax ratio, based on log-transformed data, both of which should fall within the equivalence limits of 80–125% .
Mean pharmacokinetic parameter estimates for imatinib and N-desmethyl-imatinib (CGP74588) alone and with co-administration of antacid (N = 12)
AUC0–inf (μg/mL h)
Alone + antacid
Alone + antacid
The primary pharmacokinetic parameter to which this study was powered was imatinib AUC, a measure of the amount of imatinib absorbed. There was no significant difference in imatinib plasma AUC after dosing imatinib alone, compared to in the presence of antacid (P = 0.37). The 90% confidence intervals of the imatinib AUC ratio (mean 1.04, 90% confidence interval 0.96–1.12) and the Cmax ratio (mean 1.00, 90% confidence interval 0.92–1.08), both fall well within the limits set for bioequivalence .
We also examined the effect of antacids on other pharmacokinetic parameters for imatinib and CGP74588 (Table 1). We only detected a small difference in the AUC and clearance of CGP74588 (approximately 10%; P = 0.03).
In conclusion, this study demonstrates that concomitant administration of a Mg2+-Al3+-based antacid is not associated with meaningful alterations in imatinib absorption. This is in striking contrast to dasatinib, where antacids have been associated with a nearly twofold decrease in dasatinib absorption . The reason for this interaction is not clear, but may be due to limited dissolution of the dasatinib base in an environment with elevated pH, or due to chelation of the abundant Mg2+ or Al3+ cations by dasatinib, resulting in unabsorbable complexes. The small difference in the AUC and clearance of CGP74588 would not be expected to have any clinical relevance.
We thank the nursing staff of the University of Pittsburgh Clinical Translational Research Center for their invaluable assistance, and the University of Pittsburgh Cancer Institute Hematology/Oncology Writing Group for constructive suggestions regarding the manuscript. This work was supported by Novartis Pharmaceuticals Corporation (East Hanover, NJ), and NIH/NCRR/CTSA Grant UL1 RR024153. WinNonlin software was provided as part of the Pharsight Academic Licensing Program.