Drug Interactions between amoxicillin / clarithromycin / lansoprazole and capecitabine

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 of proton pump inhibitors (PPIs) has been reported to reduce the antitumor efficacy of capecitabine, although available data are inconsistent and conflicting. Several retrospective studies and post-hoc analyses of randomized controlled trials have demonstrated an adverse impact of PPI use on disease progression, recurrence rates, and/or survival outcomes in patients receiving capecitabine-containing chemotherapy for the treatment of gastroesophageal and colorectal cancers. A reduction in dissolution and subsequent absorption of capecitabine due to PPI-induced elevations in gastric pH has been proposed as the underlying mechanism of interaction. However, three pharmacokinetic studies conducted with antacid (Maalox) and PPIs (esomeprazole, rabeprazole) failed to show significant effects on plasma concentrations of capecitabine and its metabolites. Additionally, the association between PPIs and poorer oncologic outcomes was not seen with concomitant use of other acid-suppressing agents such as H2-receptor antagonists in a retrospective post hoc analysis of data from six completed colorectal cancer clinical trials. Subgroup analyses in this investigation also did not find a significant negative association with survival for concomitant PPI use across 980 patients receiving capecitabine and oxaliplatin (CapOx) with or without bevacizumab. Meanwhile, one retrospective study reported positive effects of omeprazole on response rate and disease-free survival in advanced rectal cancer treated with CapOx chemoradiotherapy (CRT) for two cycles prior to surgery. In vitro data have shown that PPIs may possess direct antitumor effects and can also re-sensitize drug-resistant colon adenocarcinoma cell lines to cytotoxic drugs by inhibiting a membranous proton pump known as vacuolar-ATPase (V-ATPase), which is overexpressed in resistant cancer cells. It is possible that suppressing the activity of V-ATPases helps to modulate the abnormal pH gradients in tumor microenvironment associated with tumorigenesis, tumor progression, and drug resistance. More recently, some investigators have conducted systematic reviews and meta-analyses that have cast doubt on the occurrence of a significant interaction between PPIs and capecitabine based on existing clinical, pharmacokinetic, and in vitro evidence. It is also unclear whether the potential negative effects of PPI use reported during capecitabine treatment in gastroesophageal and colorectal cancers may occur in other cancers.

MANAGEMENT: Based on available data, it may be advisable to avoid PPI use during treatment with capecitabine when possible. Alternative acid suppressing agents such as antacids and H2-receptor antagonists may be preferable in some cases. If PPIs are required, patients should be monitored and evaluated at regular intervals to ascertain the continued need for their use.

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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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