Drug Interactions between amoxicillin / clarithromycin / lansoprazole and fosamprenavir

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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MONITOR: Coadministration with H2-receptor antagonists or inhibitors of the proton pump (PPIs or potassium-competitive acid blockers [PCABs]) may decrease the oral bioavailability of amprenavir from its prodrug, fosamprenavir. In 30 study subjects, ranitidine (300 mg single oral dose) decreased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amprenavir from fosamprenavir (1400 mg single oral dose) by 51% and 30%, respectively, compared to administration of fosamprenavir alone. The mechanism of interaction has not been described. It is possible that fosamprenavir solubility decreases with increasing pH, thus inhibition of gastric acid secretion may interfere with dissolution of the drug. Subtherapeutic antiretroviral drug levels may lead to reduced viral susceptibility and development of resistance.

MANAGEMENT: Caution is advised if fosamprenavir is prescribed with H2-receptor antagonists or inhibitors of the proton pump. Antiretroviral response should be monitored closely during coadministration.

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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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Drugs that act as both substrate and inhibitor of the CYP450 3A4 isoenzyme may alter the plasma concentration of amprenavir. Amprenavir may increase blood levels of the CYP450 3A4 inhibitor. The extent of the alterations in serum drug levels is unknown and the clinical significance is uncertain. When concomitant therapy is required, the patient should be monitored for adverse effects of both drugs and dose adjustments made when indicated.

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