New Drug Update 2009-2010 - LAFP

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DEXLANSOPRAZOLE - Kapidex by Takeda 2S Now Dexilant INDICATIONS: Dexlansoprazole is indicated for the healing of all grades of erosive esophagitis, the maintenance of healing of erosive esophagitis, and the treatment of heartburn associated with nonerosive gastroesophageal reflux disease (GERD). The Food and <strong>Drug</strong> Administration (FDA)-approved indications for the oral proton pump inhibitors are summarized in Table 1. Table 1. FDA-Approved Indications for Oral Proton Pump Inhibitors Dexlansoprazole (Kapidex) Esomeprazole (Nexium) Lansoprazole (Prevacid) Omeprazole (Prilosec) Pantoprazole (Protonix) Rabeprazole (AcipHex) Erosive esophagitis Healing X X X X X Maintenance X X X X X Symptomatic GERD X X X X X Duodenal ulcers Healing X X X Maintenance Helicobacter pylori eradication to prevent recurrence X X X X X Gastric ulcers Healing X X Healing NSAIDassociated a gastric ulcers Risk reduction of NSAIDassociated gastric ulcer X X X Pathological hypersecretory conditions (eg, Zollinger-Ellison syndrome) Treatment X X X X X a NSAID = nonsteroidal anti-inflammatory drug. CLINICAL PHARMACOLOGY: Dexlansoprazole is the R-enantiomer of lansoprazole. It is formulated as a dual delayed-release formulation for oral administration, with each capsule containing a mixture of enteric-coated granules with different pH-dependent dissolution profiles that are designed to release drug at different locations in the GI tract. The proton pump inhibitors suppress gastric acid secretion at the final step of acid production by specific inhibition of the (H+,K+)-ATPase in the gastric parietal cell. The effects of dexlansoprazole 60 mg and lansoprazole 30 mg once daily for 5 days on 24-hour intragastric pH have been assessed in healthy volunteers enrolled in a crossover study. On day 5, mean intragastric pH was 4.55 after dexlansoprazole and 4.13 after lansoprazole. The percentage of time with intragastric pH greater than 4 was 71% (17 hours) with dexlansoprazole and 60% (14 hours) with 52
lansoprazole. 1 In other pharmacodynamic studies, high doses of dexlansoprazole (60 to 120 mg) produced greater 24-hour mean pH than lansoprazole 30 mg. PHARMACOKINETICS: Following oral administration of the dexlansoprazole delayed-release capsules, peak dexlansoprazole concentrations occur at 1 to 2 hours after administration and again 4 to 5 hours after administration. In studies comparing the pharmacokinetics of dexlansoprazole 60 mg as the dual delayed-release capsules and lansoprazole 60 mg administered as the conventional delayed-release capsules, mean residence time was 5.5 hours for dexlansoprazole and 2.9 hours for lansoprazole. Dose proportionality was observed over a range of doses from 60 to 120 mg. Plasma protein binding is more than 96%. The dexlansoprazole half-life is 1 to 2 hours. Dexlansoprazole is extensively metabolized in the liver to inactive metabolites. Oxidative metabolites are formed via cytochrome P450 isozymes CYP2C19 and CYP3A4. Dexlansoprazole systemic exposure was increased up to 2-fold in CYP2C19 intermediate metabolizers and up to 12-fold in CYP2C19 poor metabolizers compared with CYP2C19 extensive metabolizers. No unchanged dexlansoprazole is excreted in the urine following dexlansoprazole administration. In patients with moderate hepatic impairment, single doses of dexlansoprazole 60 mg were associated with systemic exposure 2 times higher than in patients with healthy hepatic function. No adjustment in dosing is necessary in patients with mild hepatic impairment (Child-Pugh class A); however, a 30 mg doses is recommended for patients with moderate hepatic impairment (Child-Pugh class B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh class C). The pharmacokinetics of dexlansoprazole are not likely to be altered in patients with renal impairment because dexlansoprazole is extensively metabolized to inactive metabolites and no parent drug is recovered in the urine following oral dexlansoprazole dosing. The half-life of dexlansoprazole is increased in elderly subjects compared with younger subjects (2.23 h vs 1.5 h); however, the difference is not clinically important. Systemic exposure was also increased 34.5% in elderly subjects. Dosage adjustments are not necessary in elderly patients. Dexlansoprazole exposure was increased 42.8% in women compared with men following a single 60 mg oral dose; however, dosage adjustments are not necessary. The pharmacokinetic parameters of the oral proton pump inhibitors are compared in Table 2. Pharmacokinetic parameter Table 2. Pharmacokinetic Parameters of Oral Proton Pump Inhibitors Dexlansoprazole Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole Bioavailability — 64% to 90% 80% to 85% 30% to 40% 77% 52% Time to peak plasma concentration (h) 1 to 2; 4 to 5 1.5 1.7 0.5 to 3.5 2 to 3 2 to 5 Protein binding (%) 96% 97% 97% 95% 98% 96.3% Half-life (h) 1 to 2 1 to 1.5 1.6 0.5 to 1 1 to 1.9 1 to 2 Primary route excretion Excreted unchanged in urine Hepatic CYP2C19 CYP3A4 Hepatic CYP2C19 Hepatic CYP3A CYP2C19 Hepatic Hepatic CYP2C19 CYP3A4 Hepatic CYP3A CYP2C19 0% < 1% 0% 0% 0% 0% COMPARATIVE EFFICACY: Dexlansoprazole efficacy studies have not been published, but are summarized in the prescribing information and meeting abstracts. Dexlansoprazole was assessed in 2 randomized, double-blind, noninferiority studies enrolling a total of 4,092 patients 18 to 90 years of age (median age, 48 years) with endoscopically confirmed erosive esophagitis. Patients received oral dexlansoprazole 60 mg daily, dexlansoprazole 90 mg daily, or lansoprazole 30 mg daily. Patients who were H. pylori–positive, or had Barrett esophagus and/or definite 53
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