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Washington/FDA/January 2005

NATIONAL VETERINARY COLLEGE T O U L O U S E. UMR 181 Physiopathologie & Toxicologie Expérimentales. Endectocides pour-on formulations An individual topical or collective oral modality of drug administration in cattle?. Washington/FDA/January 2005. Pierre-Louis Toutain A. Bousquet-Melou

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Washington/FDA/January 2005

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  1. NATIONAL VETERINARY COLLEGE T O U L O U S E UMR 181 Physiopathologie & Toxicologie Expérimentales Endectocides pour-on formulationsAn individual topical or collective oral modality of drug administration in cattle? Washington/FDA/January 2005 Pierre-Louis Toutain A. Bousquet-Melou C. Laffont M. Alvinerie

  2. The beginning of a strange story • Comparison of PK profiles of doramectin and ivermectin pour-on formulation in cattle (Gayrard et al., Vet. Parasitol. 1999, 81: 47-55) • 24 young beef cattle • 2 groups (parallel design)

  3. The two initial papers(sponsored by Pfizer)

  4. 40 30 20 10 0 0 0 10 20 30 Doramectin vs ivermectin: pour-on administration (500 µg/kg) AUC range (ng.days.mL-1) Concentrations (ng/mL) DORAMECTINE IVERMECTINE 104-258 51-182 Highly variable drugs Doramectin Ivermectin Time (days)

  5. Questions raised by a highly variable drug (CV>30%) for a bioequivalence study: 1- Inter- or intra-animal variability ? 2- If mainly of inter-animal origin: • crossover design to estimate the intra-animal variability • But cross-over is nearly impossible for avermectins due to a too long required washout between 2 periods (10 times the terminal half-life)

  6. Question how to demonstrate BE with a powerful parallel design? • Hypothesis : the rescourse to pairs of monozygotic twin cattle in a parallel design could be an alternative to a conventional cross-over design assuming that 2 animals within the same pair are the same animal?

  7. The twin cattle story

  8. The twin cattle story • Getting 6 pairs of monozygotic twin cattle by micro-manipulation and cervical transfer to cow (Ozil et al. Vet. rec. 1982) • same father (bull) • maintained under identical conditions

  9. The twin cattle story: Checking the pharmacokinetics homogeneity of twin cattle by an IV ivermectin study • very high intra- and inter-reproducibility of ivermectin disposition IV administration of ivermectin in a pair of twin cattle Ivermectin cocnentration (ng/mL) Time (h)

  10. The twin cattle story: Checking the pharmacokinetic homogeneity of twin cattle for a pour-on administration 40 period I 35 period II Example period IV 30 25 Very high inter and intra-individual variability! Plasma concentrations (ng/mL) 20 15 10 5 0 0 10 20 30 40 50 Time (day) What is the origin of that ? The answer is given thanks to a secondary question about clearance

  11. The twin cattle story: origin of the large intra-individual variability of the drug exposure after a pour-on administration • There was a secondary question in this experiment: • Is it possible to compute, using only fecal clearance (easily obtainable after any route of administration), the total amount of drug eliminated by the feces (environmental issue) Total amount eliminated by feces = Fecal clearance  AUC(plasma)

  12. The twin cattle story: the fecal clearance • Fecal clearance >> plasma clearance Rate of drug eliminated in feces Plasma concentration Overall rate of drug elimination Plasma concentration >> ! Conceptually impossible if the plasma is the only driving force for ivermectin excretion into feces

  13. IVM 40% IVM parental + 60% metabolites * How ivermectin may gain access to feces? Parenteral administration * Halley et al. (1989) in: Ivermectin and abamectin. Ed. Campbell, Springer NY, pp. 162 • Route of ivermectin elimination Gut Secretion - biliary - intestinal Plasma IVM urine < 2% feces For a systemic route of administration plasma is the only driving force

  14. IVM is extensively secreted by intestinal efflux pump

  15. s.c. pour-on feces Plasma IVM metabolism The twin cattle story: plasma as a driving force Similar inconsistent results from observational study on higher fecal concentrations of ivermectin reported following pour-on application than SQ injection (Herd et al. 1996, Int. J. Parasitol. 26: 1087) Plasma Feces pour-on s.c.

  16. Licking cattle The twin cattle story: Origin of the high “fecal clearance” • Hypothesis: cattle lick (auto and allo-licking). It is a natural behavior in cattle (Sato et al. 1991, 993)

  17. Question: what is the extent of ivermectin topically administered to cattle, actually ingested by licking? • Laffont et al. Licking behaviour and environmental contamination arising from pour-on ivermectin for cattle. Int. J. Parasitol. 2001, 31: 1687-1692

  18. What is the fraction of ivermectin topically administered to cattle that is actually ingested by licking? • Experimental design: • 6 pairs of twin cattle (567 ± 24 kg BW) • Ivermectin IV (200 µg/kg) • Washout 5 months • Ivermectin topical (500 µg/kg) to n=6 non licking; n=6 licking • Feces and blood samples

  19. Licking vs non-licking cattle: Pour-on Administration 6 pairs of twin cattle Starsky Hutch 19

  20. Licking vs non-licking cattle Non-licking cattle

  21. Results • IV data Plasma Cl= 270 ± 57 mL/kg/day Plasma t1/2= 137 ± 2.7h Fecal Cl= 38% plasma Cl meaning that 38% of ivermectin is eliminated as parent drug in the feces 10000 1000 100 plasma concentration (ng/mL) 10 1 0 10 20 30 Time (day)

  22. 60 50 40 30 20 10 0 Licking Non-licking 0 10 20 30 40 50 60 Results : plasma disposition after pour-on administration • Half-life • lickers: 144 ± 3.04h (no flip-flop) • non lickers: 363 ± 16h (flip-flop) • Bioavailability • lickers: 33 ± 18% • non lickers: 19 ± 4.9% 100 10 Ivermectin (ng/mL) Concentrations (ng/mL) 1 0.1 0 10 20 30 40 50 60 Time (day) Time (days) Laffont et al. (2001) Int J Parasitol 31:1687

  23. Results: fecal disposition after a pour-on administration • Lickers : much higher fecal clearance after pour-on than IV administration (x2) • Non lickers : same fecal clearance after IV and pour-on administration 35 30 69 % 100 lickers 25 non-lickers 80 20 Total amounts of faecal ivermectin (mg) excreted per day 60 15 % dose 40 10 6.6 % 20 5 0 0 0 10 20 30 0 10 20 30 Time (days) Time (days)

  24. Lickers Non-lickers 100 80 69 % 60 60 % dose 12 % 40 40 6.6 % 20 0 20 0 10 20 30 Time (days) 0 0 10 20 30 40 50 60 Results plasma feces Actually observed F= 33% F= 19% IVM (ng/mL) Expected plasma AUC Time (days) Laffont et al., Int. J. Parasitol., 2001, 31:1687

  25. Conclusion • An important amount of topically administered drug was actually ingested by licking and transited directly in the digestive tract into feces

  26. 500 µg/kg Pour-on ingestion 58 - 87% 7 - 14 % of the dose absorbed by skin 55 % Oral absorption 22 % Plasma overall bioavailability IVM 13 % of the dose Ftotal = 18 - 68 % FECES A model of ivermectin disposition after a pour-on formulation administration Assumption: the 2 twin cattle are analyzed as the “same individual” observed twice

  27. A comprehensive model of IVM disposition

  28. Drug transfer between grazing cattle after topical administration of doramectin, ivermectin and moxidectin

  29. ? ? Objective: to document the potential drug transfer between cattle after pour-on formulations • for different endectocides • for cattle maintained in grazing conditions Pour-on about 70% of the dose orally ingested

  30. Material and methods • 4 pairs of twin cattle Control DORA MOXI IVM MOXI IVM DORA Dose : 500 µg/kg Blood and fecal samples

  31. Material and methods • IV study using a cocktail approach i.e. simultaneous drug administrations (70 µg/kg BW) i.e. 210 µg/kg in toto Faecal clearance Total clearance (mL.kg-1.d-1) Vss t1/2 Dora Iver Moxi (L/kg) (days) %total 10000 (mL.kg-1.d-1) 1000 185 146 79 14 3.3 Dora 100 Plasma conc. (ng/mL) 10 347 104 30 7 2.7 Iver 1 636 250 39 21 15 0.1 Moxi 0 10 20 30 40 50 Time (day)

  32. Results: plasma exposure • The 3 endectocides were exchanged between animals kept together on the same pasture

  33. Non-treated 10 10 8 8 6 6 4 4 2 2 0 0 0 10 20 30 40 50 0 10 20 30 40 50 Results: plasma exposure Treated Doramectin Ivermectin Moxidectin 4 3 2 Plasma conc. (ng/mL) 1 0 0 10 20 30 40 50 Time (day)

  34. Non-treated CONTROL Results: fecal excretion Treated µg.kg-1 DORAMECTIN IVERMECTIN MOXIDECTIN 200 150 100 50 0 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 cows

  35. Pour-on administration

  36. Results in control animals • The total amount of ingested endectocides by the hetero-licking animals was equivalent to 22 and 27% of a standard pour-on dose (500 µg/kg)

  37. Results in “treated” animals (n=6) • The cumulated amounts of drug ingested by allo-licking by the group for the 2 treated cows (excluding self licking) • doramectin 29% • ivermectin 19% • moxidectin 8.6%

  38. General conclusion • At the herd level and, considering the 2 sources of drug ingestion (self and allo-licking), the oral (licking) route is the main pathway for an endectocide poured on the back of cattle, to enter the plasma and to have a systemic effect

  39. Concerns raised by this social drug exposition • Efficacy • Safety • Environment • Regulation (GLP study?)

  40. Efficacy concern raised by licking • Inter-animal variability on drug efficacy • possible outliers in clinical trials due to under-exposure • necessity to increase the dose from 200 to 500 µg/kg in attempt to guarantee that animals with the lowest dose are nevertheless efficiently exposed • undesirable over-exposure of environment

  41. Efficacy concern raised by licking • Development of drug resistance due to sub-therapeutic levels in some animals?

  42. Efficacy concern raised by licking • Experimental design of comparative trials • if on the same pasture drug exchanges exist • significant efficacy in control animals • If comparing pour-on vs non pour-on formulations (e.g. doramectin vs fenbendazole) (Hooffschmidt et al 2003) • Fenbendazole group: advantage due to exposure to both fenbendazole and doramectin • Doramectin group: disadvantage due to under-exposure for doramectin because of allo-licking

  43. Safety concerns raised by licking • Presence of unexpected high residue levels in some treated and/or untreated animals (a frequent situation in European conditions) • e.g. beef cattle with dairy cattle on the same pasture  milk residue • ingestion of 2-11% of a pour-on dose would be sufficient to produce detectable (LOD = 0.01 ng/mL) ivermectin concentration in milk for 44 days

  44. Safety concerns raised by licking • Local residue on the tongue ? • Actually it is likely to be a perlingual absorption • What about the validity of the 95/95 withdrawal time ?

  45. Efficacy concerns raised by licking • Due to the high inter-individual variations, how is it possible to demonstrate a bioequivalence? • If CV% = 45%  84 to 140 subjects are necessary •  BE are actually demonstrated meaning that drug companies are aware of the phenomenon

  46. Regulatory concerns raised by licking • How to explain that none of the so-called GLP trials revealed the phenomenon? • Do you think that here GLP is synonymous to good science? • Population kinetics (in field conditions) would have immediately evidenced this phenomenon

  47. Conclusion of this story • We need a better balance between rigid GLP studies and more open field studies under GCP conditions

  48. A more recent publication

  49. The last review paper on licking written with the FDA and the Tandil group to establish a regulatory doctrine for bioequivalence (generics) Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

  50. Thèse de Céline Laffont soutenue à Utrecht 2003 avec des aspects mécanistiques

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