Drug Interactions between amoxicillin / clarithromycin / lansoprazole and quinine

GENERALLY AVOID: Coadministration with ketolide and macrolide antibiotics that inhibit CYP450 3A4 may significantly increase the plasma concentrations of quinine, which is primarily metabolized by the isoenzyme. In ten healthy volunteers, administration of a single 600 mg oral dose of quinine sulfate in combination with the potent CYP450 3A4 inhibitor troleandomycin (500 mg orally every 8 hours for 48 hours) significantly increased the mean quinine peak plasma concentration (Cmax), systemic exposure (AUC) and terminal elimination half-life by 26%, 90% and 63%, respectively, and decreased the mean oral clearance (Cl/F) by 45% compared to administration of quinine alone. Troleandomycin also reduced the average Cmax, AUC and apparent formation clearance of the main metabolite, 3-hydroxyquinine, by 75%, 58% and 81%, respectively. Other ketolides and macrolides that may significantly inhibit CYP450 3A4 include clarithromycin, erythromycin, and telithromycin. Azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4. Clinically, high plasma levels of quinine may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death. In addition, clarithromycin, erythromycin, and telithromycin have all been individually associated with QT interval prolongation, thus additive effects may occur during concomitant use with quinine. Fatal torsade de pointes arrhythmia was reported in an elderly patient who received quinine in combination with erythromycin and dopamine. However, a causal relationship was not established in this case.

MANAGEMENT: The use of quinine in combination with ketolide and macrolide antibiotics that inhibit CYP450 3A4 should generally be avoided. Azithromycin may be a safer alternative during therapy with quinine.

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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.

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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.

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