Editorial Type:
Pharmacology

Posaconazole pharmacokinetics after administration of an intravenous solution, oral suspension, and delayed-release tablet to dogs

Jennifer Kendall Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607.

Search for other papers by Jennifer Kendall in
Current site
Google Scholar
PubMed Close
 BS
and
Mark G. Papich Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607.

Search for other papers by Mark G. Papich in
Current site
Google Scholar
PubMed Close
 DVM, MS
DOI:
https://doi.org/10.2460/ajvr.76.5.454
Volume/Issue:
Volume 76: Issue 5
Online Publication Date:
01 May 2015
Restricted access
Sign In Reprints and Permissions Purchase Article

Abstract

OBJECTIVE To determine pharmacokinetics of posaconazole in dogs given an IV solution, oral suspension, and delayed-release tablet.

ANIMALS 6 healthy dogs.

PROCEDURES Posaconazole was administered IV (3 mg/kg) and as an oral suspension (6 mg/kg) to dogs in a randomized crossover study. Blood samples were collected before (time 0) and for 48 hours after each dose. In an additional experiment, 5 of the dogs received posaconazole delayed-release tablets (mean dose, 6.9 mg/kg); blood samples were collected for 96 hours. Plasma concentrations were analyzed with high-performance liquid chromatography.

RESULTS IV solution terminal half-life (t1/2) was 29 hours (coefficient of variation [CV], 23%). Clearance and volume of distribution were 78 mL/h/kg (CV, 59%) and 3.3 L/kg (CV, 38%), respectively. Oral suspension t1/2 was 24 hours (CV, 42%). Maximum plasma concentration (Cmax) of 0.42 μg/mL (CV, 56%) was obtained at 7.7 hours (CV, 92%). Mean bioavailability was 26% (range, 7.8% to 160%). Delayed-release tablet t1/2 was 42 hours (CV, 25%), with a Cmax of 1.8 μg/mL (CV, 44%) at 9.5 hours (CV, 85%). Mean bioavailability of tablets was 159% (range, 85% to 500%). Bioavailability of delayed-release tablets was 497% (range, 140% to 1,800%) relative to that of the oral suspension.

CONCLUSIONS AND CLINICAL RELEVANCE Absorption of posaconazole oral suspension in dogs was variable. Absorption of the delayed-release tablets was greater than absorption of the oral suspension, with a longer t1/2 that may favor its clinical use in dogs. Administration of delayed-release tablets at a dosage of 5 mg/kg every other day can be considered for future studies.

Abstract

OBJECTIVE To determine pharmacokinetics of posaconazole in dogs given an IV solution, oral suspension, and delayed-release tablet.

ANIMALS 6 healthy dogs.

PROCEDURES Posaconazole was administered IV (3 mg/kg) and as an oral suspension (6 mg/kg) to dogs in a randomized crossover study. Blood samples were collected before (time 0) and for 48 hours after each dose. In an additional experiment, 5 of the dogs received posaconazole delayed-release tablets (mean dose, 6.9 mg/kg); blood samples were collected for 96 hours. Plasma concentrations were analyzed with high-performance liquid chromatography.

RESULTS IV solution terminal half-life (t1/2) was 29 hours (coefficient of variation [CV], 23%). Clearance and volume of distribution were 78 mL/h/kg (CV, 59%) and 3.3 L/kg (CV, 38%), respectively. Oral suspension t1/2 was 24 hours (CV, 42%). Maximum plasma concentration (Cmax) of 0.42 μg/mL (CV, 56%) was obtained at 7.7 hours (CV, 92%). Mean bioavailability was 26% (range, 7.8% to 160%). Delayed-release tablet t1/2 was 42 hours (CV, 25%), with a Cmax of 1.8 μg/mL (CV, 44%) at 9.5 hours (CV, 85%). Mean bioavailability of tablets was 159% (range, 85% to 500%). Bioavailability of delayed-release tablets was 497% (range, 140% to 1,800%) relative to that of the oral suspension.

CONCLUSIONS AND CLINICAL RELEVANCE Absorption of posaconazole oral suspension in dogs was variable. Absorption of the delayed-release tablets was greater than absorption of the oral suspension, with a longer t1/2 that may favor its clinical use in dogs. Administration of delayed-release tablets at a dosage of 5 mg/kg every other day can be considered for future studies.

Contributor Notes

Address correspondence to Dr. Papich (mgpapich@ncsu.edu).
Cover American Journal of Veterinary Research
American Journal of Veterinary Research
Publication Date:
01 May 2015

  • 1. Sykes JE, Papich MG. Chapter 9: antifungal drugs. In: Sykes JE, ed. Canine and feline infectious diseases. St Louis: Elsevier, 2014; 87–96.

    • Search Google Scholar
    • Export Citation

  • 2. Sabatelli F, Patel R, Mann PA, et al. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob Agents Chemother 2006; 50: 2009–2015.

    • Crossref
    • Search Google Scholar
    • Export Citation

  • 3. Kim H, Likhari P, Kumari P, et al. High-performance liquid chromatographic analysis of the anti-fungal agent SCH 56592 in dog serum. J Chromatogr B Biomed Sci Appl 2000; 738: 93–98.

    • Crossref
    • Search Google Scholar
    • Export Citation

  • 4. Katragkou A, Tsikopoulou F, Roilides E, et al. Posaconazole: when and how? The clinician's view. Mycoses 2012; 55: 110–122.

  • 5. Nomeir AA, Kumari P, Hilbert MJ, et al. Pharmacokinetics of SCH 56592, a new azole broad-spectrum antifungal agent, in mice, rats, rabbits, dogs, and cynomolgus monkeys. Antimicrob Agents Chemother 2000; 44: 727–731.

    • Crossref
    • Search Google Scholar
    • Export Citation

  • 6. Cendejas-Bueno E. HPLC/UV or bioassay: two valid methods for posaconazole quantification in human serum samples. Clin Microbiol Infect 2012; 18: 1229–1235.

    • Crossref
    • Search Google Scholar
    • Export Citation

  • 7. United States Pharmacopeia (USP-NF). USP 37-NF 32. General chapter on validation of compendial procedures. Rockville, Md: United States Pharmacopeial Convention, 2014.

    • Search Google Scholar
    • Export Citation

  • 8. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982.

  • 9. Krishna G, Ma L, Martinho M, et al. A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers. J Antimicrob Chemother 2012; 67: 2725–2730.

    • Crossref
    • Search Google Scholar
    • Export Citation

  • 10. Courtney R, Pai S, Laughlin M, et al. Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother 2003; 47: 2788–2795.

    • Crossref
    • Search Google Scholar
    • Export Citation

  • 11. Posaconazole, Noxafil [package insert]. Whitehouse Station, NJ: Merck & Co Inc, 2014.

  • 12. Ashbee HR, Barnes RA, Johnson EM, et al. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother 2014; 69: 1162–1176.

    • Crossref
    • Search Google Scholar
    • Export Citation

  • 13. Jang SH, Colangelo PM, Gobburu JVS. Exposure–response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma. Clin Pharmacol Ther 2010; 88: 115–119.

    • Crossref
    • Search Google Scholar
    • Export Citation

  • 14. Sun H, Su X, Shi Y. Current status of in vitro and in vivo antifungal activities of posaconazole. J Transl Intern Med 2013; 1: 18–22.

  • 15. Toutain PL, Bousquet-Mélou A. Bioavailability and its assessment. J Vet Pharmacol Ther 2004; 27: 455–466.

  • 16. Toutain PL, Bousquet-Mélou A. Plasma terminal half-life. J Vet Pharmacol Ther 2004; 27: 427–439.

Advertisement