Establishing bioequivalence of veterinary premixes (Type A medicated articles)

Abstract

a) Key issues concerning Premix (Type A medicated articles) Bioequivalence evaluations: 1) This is a complex issue concerning both route of administration and formulation. 2) If the animal is not at the bunk/trough, the animal is not self-administering (eating medicated feed), thus there can be no drug absorption. b) Differing opinions among scientists and regulatory authorities/expert bodies regarding: 1) No harmonization on how to design, conduct, and interpret in vivo studies. 2) Applicability of biowaivers to Type A (premix) products. 3) Why are topdress and complete feed considered differently? Are they different formulations or different routes of administration? 4) Single dose vs. multi-dose studies. 5) What is the final formulation? c) What are the next steps: 1) Harmonize current bioequivalence guidelines through the VICH process. 2) Determine the applicability/non-applicability of the Biopharmaceutical Classification System (BCS). 3) Establish the Total Mixed Ration (i.e. formulation) effects. 4) Define the test subject (individual, pen, etc.).

Pharmacokinetics and bioequivalence in the pig of two ivermectin feed formulations

“…Hunter et al . () provided guidance on steps to minimize sources of variability in bioequivalence studies for premixes. This study adopted the principles outlined by these authors.…”

“…(,b), Martinez and Hunter () and Hunter et al . () have commented that bioequivalence determination for medicated feeds has several complexities and major challenges. Issues to be addressed include (i) homogeneous dispersion of the drug in complete feed; (ii) likely variability between animals infeed intake and therefore drug dose received, which increases pharmacokinetic variability; (iii) competition between animals for feed, if group housed; (iv) disruption of feeding behaviour because of the act of collecting blood samples; (v) effect of palatability on feed intake; (vi) the possibilities that a change in excipients will have a similar impact as that associated with normal and unavoidable differences in the composition and nutrient quality of food materials; (vii) in‐premix differences in meal composition, for example the carrier may differ between products and is likely to contain minerals, vitamins and vegetable matter from various sources, including corn, wheat, soybean; (viii) variability in the feed into which the premix is incorporated, across feed manufacturers, as well as time because of year crop variation.…”

Comparison of bioequivalence study regulatory requirements for human and veterinary drugs

“…Optimization of such studies still causes many problems, which is emphasized by other authors (Baynes et al, 2012;Toutain et al, 2012). As it is pointed by other authors (Hunter et al, 2012), the current guideline does not solve the problem of optimization of BE studies in relation to premixes.…”

Limites scientifiques de l’autorisation de mise sur le marché des médicaments génériques

“…La qualité et la nature des aliments utilisés avec le prémélange médica-menteux, les modalités de réalisation de cet aliment médica-menteux (température, interaction avec d'autres composants tels que le calcium par exemple, et c) peuvent elles influencer la biodisponibilité finale des animaux traités ? Toutes ces questions légitimes ne trouvent pas de réponse dans cette ligne directrice sur les médicaments génériques (Hunter et al, 2012).…”