Drug Interaction With Proton Pump Inhibitors for Nifedipine ER Tablets

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.

Inclusion Criteria:

1. Healthy, males and non-pregnant female volunteers, 18 to 55 years of age, inclusive.

2. Smoking status: Only non-tobacco/nicotine users (for at least 6 months prior to the
clinical study) will be eligible to participate in this study.

3. BMI that is within 18.5-35.0 kg/m², inclusive.

4. Healthy, according to the medical history, ECG, vital signs, laboratory results and
physical examination as determined by the PI/Sub-Investigator.

5. Ability to comprehend and be informed of the nature of the study, as assessed by BPSI
staff. Capable of giving written informed consent prior to receiving any study
procedure. Must be able to communicate effectively with clinic staff.

6. Ability to fast for at least 14 hours.

7. Availability to volunteer for the entire study duration and willing to adhere to all
protocol requirements.

8. Female subjects must fulfill at least one of the following:

- Be surgically sterile for a minimum of 6 months;

- Post-menopausal for a minimum of 1 year;

- Agree to avoid pregnancy and use medically acceptable method of contraception
from at least 30 days prior to the study until 30 days after the study has ended
(last study procedure).

Medically acceptable methods of contraception include non-hormonal contraceptives,
intrauterine device, or double barrier method (condom with foam or vaginal spermicidal
suppository, diaphragm with spermicide). Complete abstinence alone can be used as a method
of contraception.

Exclusion Criteria:

1. Known history or presence of any clinically significant hepatic, renal/genitourinary,
gastrointestinal (e.g., gastrointestinal obstruction, gastrointestinal ulcers),
cardiovascular (e.g., severe obstructive coronary artery disease, myocardial
infarction, angina, heart failure), cerebrovascular, pulmonary, endocrine,
immunological, musculoskeletal, neurological, psychiatric, dermatological or
hematological disease or condition unless determined as not clinically significant by
the PI/Sub-Investigator.

2. Clinically significant history or presence of any clinically significant
gastrointestinal pathology (e.g. chronic diarrhea, inflammatory bowel disease),
unresolved gastrointestinal symptoms (e.g. diarrhea, vomiting, swallowing disorder),
or other conditions known to interfere with the absorption, distribution, metabolism
or excretion of the drug experienced within 7 days prior to first dosing, as
determined by the PI/Sub-Investigator.

3. QTc interval > 430 milliseconds for males and > 450 milliseconds for females, unless
deemed otherwise by the PI/Sub-Investigator.

4. Abnormal clinical laboratory values, unless values are deemed by the
PI/Sub-Investigator as "Not Clinically Significant".

5. Hemoglobin values less than 11.5 g/dl.

6. Abnormal vital signs (blood pressure [BP], heart rate [HR], respiratory rate [RR] and
temperature) measurements, unless deemed otherwise by the PI/Sub-Investigator.

7. Presence of any clinically significant illness within 30 days prior to first dosing,
as determined by the PI/Sub-Investigator.

8. Presence of any significant physical or organ abnormality as determined by the
PI/Sub-Investigator.

9. Individuals who have implanted or portable electro-mechanical medical device such as a
cardiac pacemaker, defibrillator or infusion pump.

10. A positive test result for any of the following: HIV, Hepatitis B surface antigen,
Hepatitis C, drugs of abuse (marijuana, amphetamines, barbiturates, cocaine, opiates,
phencyclidine and benzodiazepines), alcohol test and cotinine. Positive pregnancy test
for female subjects.

11. Known history or presence of:

- Alcohol abuse or dependence within one year prior to first study period;

- Drug abuse or dependence;

- Hypersensitivity or idiosyncratic reaction to nifedipine, omeprazole/sodium
bicarbonate, its excipients, and/or related substances;

- Hypotension;

- Bartter's syndrome;

- Gastric bezoar;

- Crohn's disease or diverticulitis;

- severe dysphagia to food or pills;

- Food allergies and/or presence of any dietary restrictions;

- Severe allergic reactions (e.g. anaphylactic reactions, angioedema).

12. History of intolerance to and/or difficulty with blood sampling through venipuncture.

13. Abnormal diet patterns (for any reason) during the four weeks preceding the study,
including fasting, high protein diets, vegan, etc.

14. Individuals who have donated, in the days prior to first study period:

- 50-499 mL of blood in the previous 30 days;

- 500 mL or more in the previous 56 days.

15. Donation of plasma by plasmapheresis within 7 days prior to first study period.

16. Individuals who have participated in another clinical trial or who received an
investigational drug within 30 days prior to first study period.

17. Use of any enzyme-modifying drugs and/or other products, including strong inhibitors
of cytochrome P450 (CYP) enzymes (e.g. cimetidine, fluoxetine, quinidine, fluconazole,
ketoconazole, voriconazole, itraconazole, clarithromycin, erythromycin, nefazodone,
atazanavir, saquinavir, indinavir, and nelfinavir) and strong inducers of CYP enzymes
(e.g. barbiturates, carbamazepine, glucocorticoids, phenytoin, St. John´s Wort and
rifampin) in the previous 30 days before first study period.

18. Use of drugs such as, proton pump inhibitors, clopidogrel, tacrolimus, digoxin,
cyclosporine, disulfiram, benzodiazepines, diazepam, warfarin, methotrexate, iron
salts, erlotinib, and mycophenolate mofetil (MMF) in the previous 30 days before first
study period, or individuals with vitamin B-12 deficiency (as long-term dosing (more
than 3 years) of omeprazole/sodium bicarbonateZegerid may lead to vitamin B-12
deficiency)

19. Individuals having undergone gastrointestinal (GI) surgery within 3 months prior to
first study period, unless deemed otherwise by PI/Sub-Investigator.

20. Use of any prescription medication within 14 days prior to first study period (except
for contraceptives).

21. Use of any over-the-counter medications (including oral multivitamins, herbal and/or
dietary supplements and/or teas) within 14 days prior to first study period (except
for spermicidal/barrier contraceptive products).

22. Consumption of food or beverages containing grapefruit and grapefruit juice and/or
pomelo within 10 days prior to first study period.

23. Consumption of food or beverages containing caffeine/methylxanthines, poppy seeds
and/or alcohol within 48 hours before dosing.

24. Use of diuretics (drugs or food, see Appendix D) within 24 hours before dosing of
SmartPillTM.

25. Individuals having undergone any major surgery within 6 months prior to the start of
the study, unless deemed otherwise by PI/Sub-Investigator.

26. Difficulty with swallowing whole tablets or large capsules.

27. Have had a tattoo or body piercing within 30 days prior to first study period and
during the study.