Role of metabolites for drugs that undergo nonlinear first-pass effect: Impact on bioequivalency assessment using single-dose simulations
✍ Scribed by April C. Braddy; Andre J. Jackson
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 280 KB
- Volume
- 99
- Category
- Article
- ISSN
- 0022-3549
No coin nor oath required. For personal study only.
✦ Synopsis
We investigated the effects of dose and intrasubject variability (ISV) on bioequivalence (BE) of a parent drug with a single metabolite formed by nonlinear firstpass. A BE simulation was done using a four-compartment model at doses of 17.5, 35.0, and 70.0 mg. ISV was set at either 10% or 20% for clearance and either 20% or 50% for the absorption rate constant, K a . The ratio of K a test =K a reference was fixed at 1.00 while fraction available ratios, F test /F reference , were varied from 1.00 to 1.25. Results showed the probability of passing the 90% confidence interval (CI) BE requirement for AUC I , area-under-the-concentration curve to time infinity, and C max , concentration maximum, were greater for the metabolite than the parent at all F test /F reference ratios. For the parent, the probability of meeting BE criteria for AUC I and C max declined from 100% to 60% at the 70 mg dose as the ISV for K a increased from 20% to 50% with an increased F test /F reference ratio. For the metabolite, the probability of meeting BE criteria was above 80% for all doses and ISV values and F test /F reference ratios less than 1.15. Results show that the parent, reflected absorption, is more informative for determining BE than the metabolite. Clinical data gave a similar result.