Drug Interactions between amoxicillin / clarithromycin / lansoprazole and pazopanib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of pazopanib, which is primarily metabolized by the isoenzyme. In healthy subjects, administration of a single dose of pazopanib eye drop with the potent CYP450 3A4 inhibitor ketoconazole resulted in a 150% increase in pazopanib peak plasma concentration (Cmax) and a 220% increase in systemic exposure (AUC). Although not studied, the interaction may increase the risk of QT interval prolongation and torsade de pointes arrhythmia as well as severe and fatal hepatotoxicity associated with the use of pazopanib.

MANAGEMENT: Concomitant use of pazopanib with potent CYP450 3A4 inhibitors should generally be avoided. Some authorities recommend avoiding concomitant use of pazopanib during and for 2 weeks after treatment with itraconazole. If coadministration is unavoidable, a reduction of the pazopanib dosage to 400 mg once daily should be considered. Based on pharmacokinetic studies, this dosage is predicted to adjust the pazopanib systemic exposure (AUC) to the range observed without inhibitors. However, clinical data are lacking. Patients should have liver function tests (ALT, AST, bilirubin), electrocardiograms, and serum electrolyte levels performed at baseline and regular intervals as recommended in the product labeling. Further dosage reductions may be needed if adverse effects occur during therapy. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice. In addition, they should seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. Following discontinuation of the potent CYP450 3A4 inhibitor, a washout period of approximately one week should be allowed before the pazopanib dosage is adjusted upward.

GENERALLY AVOID: Coadministration with proton pump inhibitors or H2-receptor antagonists may significantly decrease the oral bioavailability of pazopanib and reduce its concentrations in plasma. The solubility of pazopanib is pH-dependent, thus an increase in pH may interfere with its absorption. According to the product labeling, pazopanib is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media. When pazopanib (800 mg once daily in the morning) was coadministered with esomeprazole (40 mg once daily in the evening) for 5 days in 12 patients with advanced solid tumors, mean steady-state pazopanib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by approximately 40% each. The AUCs of three metabolites were also decreased. Mean steady-state trough concentration of pazopanib was reduced to 17.3 mcg/mL, which is close to the reported threshold of >=15 mcg/mL for clinical efficacy as suggested by a phase I trial of pazopanib. However, the potential for subtherapeutic pazopanib exposure in some patients cannot be excluded.

MANAGEMENT: Concomitant use of pazopanib with proton pump inhibitors and H2-receptor antagonists should generally be avoided. If acid-suppression therapy is required, short-acting antacids should be considered, with dosing separated by several hours from pazopanib dosing. Some experts recommend administering pazopanib at least 1 hour before or 2 hours after antacids. Alternatively, a group of Dutch clinical pharmacologists and the EMA (European Medicines Agency) suggest that pazopanib may be given with a proton pump inhibitor, when necessary, if pazopanib is administered without food once daily in the evening concomitantly with the proton pump inhibitor. This recommendation is based on physiological considerations rather than actual clinical data. Since gastric pH has been reported to be lowest just before dinner in patients treated with esomeprazole daily in the evening, the thought is that impact on pazopanib solubility and absorption should be minimized when pazopanib is also administered in the evening. Similarly, when coadministration with an H2-receptor antagonist is required, it has been recommended that pazopanib be taken without food at least 2 hours before or 10 hours after a dose of the H2-receptor antagonist.

MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.