Drug Interaction With Proton Pump Inhibitors for Nifedipine ER Tablets
Condition: Healthy Volunteers
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to measure the amount of study drug present in blood after being
      administered a generic version of nifedipine extended-release tablets, 60 mg (Valeant
      Pharmaceuticals, LLC) and brand-name version PROCARDIA XL extended-release tablets, 60 mg
      (Pfizer Inc.) individually and in presence of stomach acid reducing drug (antacid),
      omeprazole/sodium bicarbonate capsules, 40 mg/1100 mg (generic) on separate occasions, on an
      empty stomach. This study also involves administrations of an FDA-cleared capsule,
      SmartPill™, which will measure stomach acid, prior to each study arm.
    

Detailed description: 
      A question that arises with generic oral extended-release (ER) products is related to
      pH-dependent dissolution kinetics in comparison with that of their reference listed drug
      (RLD). For example, poorly water-soluble drugs with the presence of pKa in the
      gastrointestinal (GI) pH range have pH-dependent solubility and dissolution behaviors during
      in vivo drug release. In this case, the generic product which utilizes a different release
      mechanism could amplify or reduce such a pH dependence (e.g. osmotic pump RLD vs. matrix
      generic counterparts). This may render these generic ER products more or less dependent on
      gastric pH modification, commonly occurred in patients taking concomitant over-the-counter
      (OTC) proton pump inhibitors (PPIs) for the treatment of gastric acid-related disorders. It
      has been noted that PPIs (e.g. lansoprazole, omeprazole, esomeprazole) and PPIs with antacids
      (e.g. omeprazole/sodium bicarbonate) can drastically elevate the gastric pH, thus potentially
      changing the equilibrium solubility of co-administered drug substances or altering their
      release profiles.

      For instance, nifedipine is a calcium channel blocker, indicated for the long-term treatment
      of hypertension and angina. The drug substance is a weak acid (pKa 3.9) and practically
      insoluble in water. Currently, there is one RLD of oral ER nifedipine tablets based on an
      osmotic pump design (Procardia XL) and a generic counterpart of ER nifedipine tablets
      employing a matrix formulation design which is different from this RLD product. Due to
      complicated release mechanisms, quality attribute profiles, and in vivo pharmacokinetics (PK)
      behaviors of ER products, FDA is assessing the need of a drug-drug interaction study between
      PPIs/antacids (e.g. omeprazole/sodium bicarbonate) and generic nifedipine ER products based
      on a formulation design which is different from that of its RLD.

      To this end, the objective of this proposal is to investigate the dependence of in vivo PK on
      the formulation design of generic oral extended-release products in comparison with that of
      their RLD when co-administered with PPIs/antacids. The outcome of this study will help the
      Agency advance further understanding about product PK performance in potential patient
      population with abnormal gastric pH and improve review standards for equivalence of this
      category of oral ER products if necessary. The study results will help the Agency gain a
      better understanding of drug-drug interaction between oral modified-release products and
      PPIs/antacids and establish regulatory standards of bioequivalence approaches for this
      category of generic oral ER products.
    

Intervention name(s): Nifedipine 60 MG Extended Release Oral Tablet; Nifedipine 60 MG Extended Release Oral Tablet; omeprazole/sodium bicarbonate; SmartPill (TM)
Intervention type(s): Drug; Drug; Drug; Device
Intervention description(s): Reference Drug (Brand); Test Drug (Generic); Proton Pump Inhibitor/Antacid for drug-drug interaction; Gastric pH measurement using SmartPill (TM) Technology
Other intervention name(s): Procardia XL
Intervention MeSH terms: Nifedipine; Omeprazole; Omeprazole, sodium bicarbonate drug combination
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: A single-dose, randomized, open-label, drug-drug interaction (DDI), 4-way crossover, four-treatment, four-sequence, bioequivalence study
Masking: None (Open Label)
Primary purpose: Other
Keywords: Proton Pump Inhibitor; Bioequivalence; Drug-Drug Interaction; Modified Release; Nifedipine