Drug Interactions between amoxicillin / clarithromycin / lansoprazole and atazanavir

GENERALLY AVOID: Concurrent use of proton pump inhibitors may decrease the oral bioavailability of atazanavir and substantially reduce its concentrations in plasma. Atazanavir solubility decreases with increasing pH, thus inhibition of gastric acid secretion may interfere with dissolution of the drug.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, use of proton pump inhibitors is not recommended in treatment-experienced patients receiving atazanavir with or without ritonavir or cobicistat. In treatment-naive patients receiving atazanavir with ritonavir or cobicistat, it is recommended that the dose of the proton-pump inhibitor not exceed 20 mg/day of omeprazole, or equivalent, and doses should be separated by 12 hours. Some authorities recommend increasing the dose of atazanavir to 400 mg with 100 mg ritonavir when this combination is given with a proton pump inhibitor (UK). Atazanavir without ritonavir or cobicistat should not be coadministered with proton pump inhibitors in treatment-naive patients.

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.

ADJUST DOSE: Coadministration with atazanavir may significantly increase the plasma concentration of clarithromycin but decrease that of the active metabolite, 14-OH clarithromycin. The mechanism is atazanavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolism of clarithromycin. In 21 study subjects, atazanavir (400 mg once a day for 10 days) increased the mean steady-state peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of clarithromycin (500 mg once a day) by 50% and 94%, respectively, compared to administration of clarithromycin alone. In contrast, the Cmax and AUC of 14-OH clarithromycin were significantly reduced by 72% and 70%, respectively.

MANAGEMENT: Because increased plasma concentrations of clarithromycin may cause prolongation of the QT interval of the electrocardiogram, a dose reduction of clarithromycin by 50% is recommended for patients with moderate renal insufficiency (CrCl 30 to 60 mL/min) and a dose reduction by 75% is recommended for patients with severe renal insufficiency (CrCl less than 30 mL/min). The daily dose of clarithromycin should not exceed 1000 mg during concomitant use with protease inhibitors. In addition, because plasma concentrations of the active metabolite is significantly reduced, alternative therapy should be considered for indications other than infections due to Mycobacterium avium complex. Some authorities recommend avoiding the use of the fixed combination atazanavir-cobicistat with clarithromycin.

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.