Pharmacokinetics and therapeutic efficacy of rimantadine in horses experimentally infected with influenza virus A2

William A. Rees From the Graduate Center for Toxicology (Rees), the Maxwell H. Gluck Equine Research Center, Department of Veterinary Science (Harkins, Holland, Lehner, Tobin, Chambers), and The College of Pharmacy (Lu), University of Kentucky, Lexington, KY 40546-0099.

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J. Daniel Harkins From the Graduate Center for Toxicology (Rees), the Maxwell H. Gluck Equine Research Center, Department of Veterinary Science (Harkins, Holland, Lehner, Tobin, Chambers), and The College of Pharmacy (Lu), University of Kentucky, Lexington, KY 40546-0099.

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Ming Lu From the Graduate Center for Toxicology (Rees), the Maxwell H. Gluck Equine Research Center, Department of Veterinary Science (Harkins, Holland, Lehner, Tobin, Chambers), and The College of Pharmacy (Lu), University of Kentucky, Lexington, KY 40546-0099.

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Robert E. Holland Jr. From the Graduate Center for Toxicology (Rees), the Maxwell H. Gluck Equine Research Center, Department of Veterinary Science (Harkins, Holland, Lehner, Tobin, Chambers), and The College of Pharmacy (Lu), University of Kentucky, Lexington, KY 40546-0099.

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Andreas F. Lehner From the Graduate Center for Toxicology (Rees), the Maxwell H. Gluck Equine Research Center, Department of Veterinary Science (Harkins, Holland, Lehner, Tobin, Chambers), and The College of Pharmacy (Lu), University of Kentucky, Lexington, KY 40546-0099.

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Thomas Tobin From the Graduate Center for Toxicology (Rees), the Maxwell H. Gluck Equine Research Center, Department of Veterinary Science (Harkins, Holland, Lehner, Tobin, Chambers), and The College of Pharmacy (Lu), University of Kentucky, Lexington, KY 40546-0099.

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Thomas M. Chambers From the Graduate Center for Toxicology (Rees), the Maxwell H. Gluck Equine Research Center, Department of Veterinary Science (Harkins, Holland, Lehner, Tobin, Chambers), and The College of Pharmacy (Lu), University of Kentucky, Lexington, KY 40546-0099.

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Abstract

Objective

To determine pharmacokinetics of single and multiple doses of rimantadine hydrochloride in horses and to evaluate prophylactic efficacy of rimantadine in influenza virus-infected horses.

Animals

5 clinically normal horses and 8 horses seronegative to influenza A.

Procedure

Horses were given rimantadine (7 mg/kg of body weight, IV, once; 15 mg/kg, PO, once; 30 mg/kg, PO, once; and 30 mg/kg, PO, q 12 h for 4 days) to determine disposition kinetics. Efficacy in induced infections was determined in horses seronegative to influenza virus A2. Rimantadine was administered (30 mg/kg, PO, q 12 h for 7 days) beginning 12 hours before challenge-exposure to the virus.

Results

Estimated mean peak plasma concentration of rimantadine after IV administration was 2.0 µg/ml, volume of distribution (mean ± SD) at steady-state (VdSS) was 7.1 ± 1.7 L/kg, plasma clearance after IV administration was 51 ± 7 ml/min/kg, and β-phase halflife was 2.0 ± 0.4 hours. Oral administration of 15 mg of rimantadine/kg yielded peak plasma concentrations of < 50 ng/ml after 3 hours; a single oral administration of 30 mg/kg yielded mean peak plasma concentrations of 500 ng/ml with mean bioavailability (F) of 25%, β-phase half-life of 2.2 ± 0.3 hours, and clearance of 340 ± 255 ml/min/kg. Multiple doses of rimantadine provided steady-state concentrations in plasma with peak and trough concentrations (mean ± SEM) of 811 ± 97 and 161 ± 12 ng/ml, respectively. Rimantadine used prophylactically for induced influenza virus A2 infection was associated with significant decreases in rectal temperature and lung sounds.

Conclusions and Clinical Relevance

Oral administration of rimantadine to horses can safely ameliorate clinical signs of influenza virus infection. (Am J Vet Med 1999:60:888–894)

Abstract

Objective

To determine pharmacokinetics of single and multiple doses of rimantadine hydrochloride in horses and to evaluate prophylactic efficacy of rimantadine in influenza virus-infected horses.

Animals

5 clinically normal horses and 8 horses seronegative to influenza A.

Procedure

Horses were given rimantadine (7 mg/kg of body weight, IV, once; 15 mg/kg, PO, once; 30 mg/kg, PO, once; and 30 mg/kg, PO, q 12 h for 4 days) to determine disposition kinetics. Efficacy in induced infections was determined in horses seronegative to influenza virus A2. Rimantadine was administered (30 mg/kg, PO, q 12 h for 7 days) beginning 12 hours before challenge-exposure to the virus.

Results

Estimated mean peak plasma concentration of rimantadine after IV administration was 2.0 µg/ml, volume of distribution (mean ± SD) at steady-state (VdSS) was 7.1 ± 1.7 L/kg, plasma clearance after IV administration was 51 ± 7 ml/min/kg, and β-phase halflife was 2.0 ± 0.4 hours. Oral administration of 15 mg of rimantadine/kg yielded peak plasma concentrations of < 50 ng/ml after 3 hours; a single oral administration of 30 mg/kg yielded mean peak plasma concentrations of 500 ng/ml with mean bioavailability (F) of 25%, β-phase half-life of 2.2 ± 0.3 hours, and clearance of 340 ± 255 ml/min/kg. Multiple doses of rimantadine provided steady-state concentrations in plasma with peak and trough concentrations (mean ± SEM) of 811 ± 97 and 161 ± 12 ng/ml, respectively. Rimantadine used prophylactically for induced influenza virus A2 infection was associated with significant decreases in rectal temperature and lung sounds.

Conclusions and Clinical Relevance

Oral administration of rimantadine to horses can safely ameliorate clinical signs of influenza virus infection. (Am J Vet Med 1999:60:888–894)

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