Proton pump inhibitors are used extensively for the treatment of gastric acid-related disorders because they produce a greater degree and longer duration of gastric acid suppression and, thus, better healing rates, than histamine H(2) receptor antagonists. The need for long-term treatment of these disorders raises the potential for clinically significant drug interactions in patients receiving proton pump inhibitors and other medications. Therefore, it is important to understand the mechanisms for drug interactions in this setting. Proton pump inhibitors can modify the intragastric release of other drugs from their dosage forms by elevating pH (e.g. reducing the antifungal activity of ketoconazole). Proton pump inhibitors also influence drug absorption and metabolism by interacting with adenosine triphosphate-dependent P-glycoprotein (e.g. inhibiting digoxin efflux) or with the cytochrome P450 (CYP) enzyme system (e.g. decreasing simvastatin metabolism), thereby affecting both intestinal first-pass metabolism and hepatic clearance. Although interactions based on the change of gastric pH are a group-specific effect and thus may occur with all proton pump inhibitors, individual proton pump inhibitors differ in their propensities to interact with other drugs and the extent to which their interaction profiles have been defined. The interaction profiles of omeprazole and pantoprazole have been studied most extensively. A number of studies have shown that omeprazole carries a considerable potential for drug interactions, since it has a high affinity for CYP2C19 and a somewhat lower affinity for CYP3A4. In contrast, pantoprazole appears to have lower potential for interactions with other medications. Although the interaction profiles of esomeprazole, lansoprazole and rabeprazole have been less extensively investigated, evidence suggests that lansoprazole and rabeprazole seem to have a weaker potential for interactions than omeprazole. Although only a few drug interactions involving proton pump inhibitors have been shown to be of clinical significance, the potential for drug interactions should be taken into account when choosing a therapy for gastric acid-related disorders, especially for elderly patients in whom polypharmacy is common, or in those receiving a concomitant medication with a narrow therapeutic index.

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Low-molecular-weight heparins (LMWHs) differ considerably in their influence on clotting tests and release of tissue factor pathway inhibitor (TFPI). Biosimilarity therefore becomes an issue when generic forms of LMWHs are developed. So far, no bioequivalence study with a generic LMWH has been reported. A generic enoxaparin (test) was compared with the originator (reference) in 20 volunteers after single-dose subcutaneous administration (40 mg enoxaparin sodium, 4000 IU/mL anti-factor Xa (anti-FXa; activity). Target variables were anti-FXa and anti-FIIa activity, activated partial thromboplastin time (aPTT), prothrombinase-induced clotting time (PiCT), and TFPI over 24 hours. The statistical evaluation of the anti-FXa activity profile demonstrated bioequivalence of test and reference with confidence intervals of area under the plasma concentration-time curve (AUC0-tlast) (93%-99%) and Amax (88%-95%). Confidence intervals of AUC(0-tlast) (89%-102%) and Amax (90%-103%) of anti-FIIa activity also fulfill bioequivalence criteria. The 90% confidence interval for the maximum concentration of TFPI ranged from 90% to 113%. The claim of similarity was also supported by aPTT and PiCT profiles. Bioequivalence with the originator enoxaparin could be demonstrated by ex vivo inhibition of FXa and FIIa activity, by coagulation tests (aPTT and PiCT), and by in vivo release of TFPI. Whether such data also prove biosimilarity of the generic enoxaparin needs to be determined.

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Objectives: To establish the relative bioavailability and to assess bioequivalence of oral, immediate-release tablets containing pridinol and to determine the pharmacokinetic properties of the compound. Methods and materials: In this single-center, open-label, randomized, crossover trial, healthy male and female adult subjects received single doses of the test and reference product containing 4 mg pridinol mesylate (equivalent to 3 mg pridinol) each under fasting conditions. For pharmacokinetic evaluation, blood samples were withdrawn until 72 hours post dose. Pridinol in plasma was quantified by validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Adverse events (AEs) were analyzed descriptively. Results: Of 34 randomized subjects, 33 completed all treatments. The determined pharmacokinetic parameters were quite similar for both products, with geometric means for maximum exposure (C max ) of 29.27 ng/mL (test) and 27.44 ng/mL (reference), reached after 1.00 and 0.90 hours (mean t max ), respectively. The extents of bioavailability (geometric mean AUC 0–tlast ) were 187.93 h×ng/mL (test) and 183.51 h×ng/mL (reference). Elimination half-lives (T 1/2 ) ranged from 8.97 to 34.85 hours with comparable mean T 1/2 of 19.14 hours (test) and 18.85 hours (reference). The point estimates of the test/reference-adjusted geometric mean ratios of AUC 0–tlast , C max (primary), and AUC 0–∞ (secondary) were 102.54% (90% confidence interval: 96.19 – 109.32%), 106.79% (99.00 – 115.20%), and 102.60% (96.20 – 109.43%), respectively. Overall, 23 subjects experienced 50 AEs; headache and dizziness (15 cases each) were most frequently reported. Conclusion: Bioequivalence of both pridinol products was demonstrated in terms of rate and extent of absorption. Safety and tolerability were in accordance with the known AE profile of the drug substance.