Drug Interactions between ponatinib and Prevpac

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of ponatinib, which is a substrate of the isoenzyme. In 22 healthy volunteers, administration of a single 15 mg oral dose of ponatinib in combination with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily) increased ponatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 47% and 78%, respectively, compared to administration of ponatinib alone.

MANAGEMENT: Caution is recommended if concomitant use is required, and the dosage of ponatinib should be reduced according to the manufacturer's recommendations. Patients may be at increased risk for adverse effects such as thromboembolism, ischemia, congestive heart failure, hypertension, hepatotoxicity, pancreatitis, myelosuppression, hemorrhage, and fluid retention. Some authorities recommend that, following discontinuation and after an appropriate washout period of the CYP450 3A4 inhibitor (i.e., 3 to 5 half-lives), the ponatinib dosage taken prior to initiating the potent CYP450 3A4 inhibitor may be resumed (US).

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.

Coadministration with drugs that elevate the gastric pH such as proton pump inhibitors, H2-receptor antagonists, and antacids may decrease the oral bioavailability of ponatinib and reduce its concentrations in plasma. The aqueous solubility of ponatinib has been shown to be pH-dependent, with higher pH resulting in decreased solubility. However, in a drug interaction study in healthy volunteers, coadministration of ponatinib after multiple doses of lansoprazole resulted in a minor reduction in ponatinib Cmax but no change in overall systemic exposure (AUC) compared to ponatinib administered alone. Therefore, ponatinib may be coadministered with medicines that increase gastric pH without dose adjustment or separation of administration.