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668 Vet Med Today: FARAD Digest JAVMA, Vol 217, No. 5, September 1, 2000
Table 1—List of approved macrolide endectocides for specific species and routes and
approved withdrawal times (WDT)
NA ⫽ Not available.
per os. These calculations assume that the kinetics of servative for oral administration, as the WDI was based
ivermectin are linear. The milk WDI would be 6 days on intraruminal administration of a 3H-labeled drug and
based on a study by Scott et al,8 that demonstrated that a dose greater than the approved label.
at 6 days, goats’ milk was clear of the drug after an oral
dose of 0.2 mg/kg. Based on this information, oral Subcutaneous route in goats—Ivermectin was
administration up to 0.4 mg/kg will require a milk detected up to 25 days in milk from lactating goats given
WDI of at least 8 days in dairy goats. 0.2 mg/kg SC.2 There were no differences between plas-
ma and milk pharmacokinetic variables, and the
Oral route in cattle—Ivermectin has the same half- milk:plasma AUC ratio was 1.08, as stated earlier. The
life in cattle as it does in sheep; however, because of a elimination half-life was 4 days for plasma and milk, and
larger volume of distribution, plasma clearance is more it would take 40 days (10 half-lives) to eliminate 99% of
rapid in sheep.9 For these reasons, WDT and WDI will the drug via milk when administered by this route.
be shorter in sheep and goats than in cattle. Surprisingly, Limited tissue residue data from an NRSP-7 study10 pro-
there is limited depletion data for oral administration of vided an ERH of 4.34 days (ke = 0.1594 days-1) in fat,
ivermectin in cattle. Following intraruminal administra- which is the slowest depleting tissue. Application of our
tion in cattle, depletion half-lives for 3H-ivermectin in fat algorithm resulted in a WDI of 22 days. As this FARAD
and the liver were 4.2 and 5.9 days, respectively.5 This estimate is less than the cattle WDT, and there were lim-
suggests a longer meat WDI (42 days) for the intraru- ited available data, we recommend the cattle WDT of 35
minal route than the approved meat WDT (24 days) days for an extra margin of safety.
with the approved oral paste. Plasma data from that
study demonstrated a plasma concentration of 1.0 ng/ml Subcutaneous route in cattle—Ivermectin was
of total residues at 21 days and undetectable at 28 days detected in milk at 17.8 days and even beyond 29 days
after a 0.3 mg/kg dose. In the absence of milk residue when lactating cows were given 0.2 mg/kg SC.1 The
data, it is possible to estimate a conservative milk WDI mean milk depletion half-life was 4.72 days, which
of 28 days if we assume parallel depletion for plasma suggests that it would take at least 47 days to eliminate
and milk and use published data in which the milk:plas- 99% of the drug via the milk. As seen with goats, a par-
ma AUC ratio is 0.766 in cattle.1 This WDI will be con- allel disposition in milk and plasma was observed, and
JAVMA, Vol 217, No. 5, September 1, 2000 Vet Med Today: FARAD Digest 669
the milk-plasma AUC ratio was 0.766. These data and This may be related to its greater persistence once
WDI estimates are further supported by the observed absorbed systemically and, therefore, caution should
plasma half-life of 4.32 days in another study of sub- be exercised when using this drug in an extralabel
cutaneous administration in cattle.11 manner, especially when administering the pour-on
formulation orally to goats.
Topical route in goats—Topical application of
ivermectin (0.5 mg/kg [0.23 mg/lb]) to dairy goats Subcutaneous route—There are limited pharma-
resulted in about 0.5 ng/ml of milk at 6 days.8 Because cokinetic data available in the literature for subcuta-
milk residues were not detected at 7 days, this time can neous administration in goats,6 which makes estima-
be used as a milk WDI for goats given ivermectin top- tion of meat or milk WDI difficult. In cattle, the half-
ically. Tissues were not assayed, but plasma concentra- lives for total residue of moxidectin in fat, liver, kidney,
tions were less than 1.0 ng/ml at 6 days, supporting the and muscle ranged from 9.0 to 12.2 days after SC
milk-plasma relationship described. administration (0.2 mg/kg).17 At 49 days, injection sites
and back fat concentrations were 1,178 and 141 µg/kg,
Topical route in cattle—There are no available respectively, and liver and kidney concentrations were
studies on topical application of ivermectin in dairy less than 11 µg/kg. As European maximum residue
cattle. However, plasma concentrations were less than concentrations for fat, kidney, and liver are 200, 20,
0.1 ng/ml at 42 days, and terminal half-life in plasma and 20 µg/kg, respectively,18 then 49 days would be a
was 5.3 days in steers treated topically at the label conservative WDI for moxidectin given by the subcu-
dose.12 Assuming that milk-plasma ratios were 0.776, taneous route to cattle. The FDA has also established
as described earlier, milk concentrations at 42 days tolerances of 50 µg/kg and 200 µg/kg for parent mox-
should be 0.0776 ng/ml, and it would take at least 2 idectin in muscle and liver, respectively, in cattle.19
more half-lives (11 days) to arrive at a milk concentra- Unfortunately, FARAD has no milk residue information
tion of approximately 0.02 ng/ml. This milk concen- or milk-plasma AUC relationship from which to base
tration is equivalent to a safe concentration or a provi- milk WDI for this drug if given subcutaneously to
sional acceptable residue for ivermectin in milk recent- dairy goats or dairy cattle.
ly described in the literature.13 Based on these data and
assumptions, a milk WDI of 53 days would be a con- Topical route—Moxidectin is approved as a pour-
servative estimate for dairy cattle exposed to iver- on only (0.5mg/kg) in cattle with zero meat and milk
mectin pour-on. WDT, and it is possible that increasing the dose sub-
stantially by this route will most likely require estima-
Extralabel Use of Moxidectin tion of meat and milk WDI (Table 1). In the absence of
Oral route—Moxidectin is not approved for use in data for goats, FARAD assumes that plasma and tissue
goats. Several goat farmers have been administering clearance would be greater in goats than in cattle, as
moxidectin to goats orally at the labeled pour-on dose described for ivermectin. However, FARAD would err
(0.5 mg/kg) for cattle. It should be stressed that on the side of caution and recommend a milk and meat
although the cattle label states that this drug has a zero WDI of 1 day if this drug was applied topically to goats.
meat and milk WDT by the topical route, it does not The calculated WDI in this article were based on
imply that the meat and milk WDI will be zero if given limited available pharmacokinetic data. Updated WDI
orally. Until FARAD obtains sufficient pharmacokinet- can be obtained from our FARAD web site
ic data for the topical formulation given orally at 0.5 (www.farad.org) as more relevant data become avail-
mg/kg in goats, FARAD has based its WDI recommen- able. It should also be noted that the recommended
dation on European Union approvals in sheep and WDI are case specific and are not applicable for other
published studies on oral administration. It should be doses or routes of administration, nor should they be
noted that oral bioavailability of moxidectin is 2.7 extrapolated to other food animal species. If veterinar-
times lower in goats than in sheep,6,11 and the half-life ians are interested in obtaining such information,
in goats is 1.8 times shorter in sheep. This suggests please contact us at 1-888-USFARAD, farad@ncus.edu,
that European Union WDI for moxidectin in sheep will or farad@ucdavis.edu.
be more than adequate for estimation of WDI for mox-
idectin drench in goats. In France and the United References
Kingdom, the oral formulation for sheep at a dose of 1. Toutain PL, Campan M, Galtier P, et al. Kinetic and insecti-
0.2 mg/kg [0.09 mg/lb] has a 14-day meat WDT.14,15 On cidal properties of ivermectin residues in the milk of dairy cows. J Vet
the basis of these data, FARAD estimates an ERH of 3 Pharmacol Ther 1988;11:288–291.
days for this dose and, therefore, includes an addition- 2. Alvinerie M, Sutra JF, Galtier P. Ivermectin in goat plasma and
milk after subcutaneous injection. Ann Rech Vet 1993;24:417–421.
al 3 ERH (9 days; WDI, 23 days) for goats given of a 3. Riviere JE, Webb AI, Craigmill AL. Primer on estimating
moxidectin pour-on formulation (0.8 to 1.6 mg/kg withdrawal times after extralabel drug use. J Am Vet Med Assoc
[0.36 to 0.73 mg/lb]) orally. It must be recognized that 1988;213:966–968.
there are pharmaceutical differences between the der- 4. Martin T, Baynes RE, Craigmill AL, et al. Extrapolated with-
mal formulations being used in goats and the European drawal-interval estimator (EWE) algorithm. A quantitative approach
approved drench, and these differences may influence to establishing extralabel withdrawal times. Pharm Res 2000;(in press).
5. Chiu S-Hl, Green ML, Bayliss FP, et al. Absorption, tissue
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a longer mean residence time than ivermectin in sheep 6. Escudero E, Carceles CM, Diaz MS, et al. Pharmacokinetics
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11. Toutain PL, Upson DW, Terhune TN, et al. Comparative 18. FAO. Moxidectin: residues of some veterinary drugs in ani-
pharmacokinetics of doramectin and ivermectin in cattle. Vet Parasitol mals and foods. Monographs prepared by the forty-eighth meeting of
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Toxicol Pharmacol 1999;29:287–299. (original); cydectin (moxidectin); Jan 28th, 1998.
JAVMA, Vol 217, No. 5, September 1, 2000 Vet Med Today: FARAD Digest 671