Assessment of 2012 Bioequivalence Standards for Warfarin

Assessment of 2012 Bioequivalence Standards for Narrow Therapeutic Index Drugs: a Study With Warfarin

The purpose of this study is to assess the 2012 bioequivalence statistical criteria for warfarin, a narrow therapeutic index drug, set forth in the draft guidance issued by the Food and Drug Administration (FDA).

This study is a reasonable starting point to assess the appropriateness of the 2012 FDA bioequivalence (BE) statistical criteria for narrow therapeutic index drugs (NTIDs). The idea stems from an earlier study conducted in Dr. Benet's lab with the drug furosemide. The furosemide study yielded triplicate data that were unable to purely meet the BE statistical criteria set forth by the FDA due to the inherent study design. Furosemide is not an NTID to be considered by the FDA for BE studies, however. Hence, the investigators have proposed a new study to assess the BE statistical criteria with warfarin, an NTID with a draft guidance issued by the FDA. By providing the reference product (brand name warfarin) three times to each study participant and recording the relevant pharmacokinetic parameters for BE (AUC and Cmax), the investigators can make three comparisons between the data (R1 and R2 vs. R2 and R3; R1 and R2 vs. R1 and R¬3; R2 and R3 vs. R1 and R3).

The investigators have three concerns that can be tested here.

1. Will normal within subject variability potentially lead to inequivalence of the reference product using the new NTID BE regulations?
2. Is it possible that the BE interval could be less than the United States Pharmacopeia (USP) content uniformity limits for warfarin?
3. Provide a comparison of the within-subject variance for the 2.5 ratio comparison.

Inclusion Criteria:

• Male or female aged 18-60 years
• Healthy adult without active medical problems or chronic diseases based on medical history, physical exam, and laboratory results
• BMI 18.5-32 kg/m2
• Ceased all medications 2 weeks prior to start of study and during study enrollment (includes drugs of abuse, prescription medications, and over-the-counter (OTC) medications [exception: acetaminophen])
• Maintain adequate birth control independent of hormonal contraceptive use throughout study
• Provide written informed consent to take part in and comply with the requirements of the study
• Speak, read, and understand English
• Avoid alcohol, caffeine, and orange juice from 6pm the night before the study day until the completion of the study day
• Avoid contact sports and/or other activities with significant risk of trauma injury for 7 days after each study day
• Do not eat food or consume beverages at least 8 hours before medication dosing
• Present with wild type VKORC1, VKORC-1639G>A and wild type CYP2C9 genotype

Exclusion Criteria:

• Subjects on prescription or chronic OTC medications (including hormonal contraceptives)
• Subjects with known allergy to warfarin
• Subjects with a history of or diagnosis of hemorrhagic tendencies or blood dyscrasias
• Subjects with liver failure or liver function tests (LFTs) > 2x upper limit normal
• Subjects with clinically significant elevations of international normalized ratio (INR), prothrombin time (PT), partial thromboplastin time (PTT), serum creatinine (Scr), blood urea nitrogen (BUN), or other screening laboratory tests as determined by study physician
• Subjects with hematocrit (Hct) < 30 mg/dL
• Subjects with history of GI bleed or peptic ulcer disease
• Subjects with recent history of trauma
• Subjects with recent history of or upcoming plan for surgery
• Subjects who smoke tobacco
• Subjects with ongoing alcohol use
• Subjects with ongoing illegal drug use
• Subjects who are pregnant, attempting to become pregnant, or lactating
• Subjects who are unable to maintain adequate birth control during the study
• Subjects who are unable to follow protocol instructions or criteria
• Subjects with genotypes that are not wild type VKORC1, VKORC-1639G>A and wild type CYP2C9