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Pharmacokinetics and Tolerability of Oseltamivir (Tamiflu?) Combined with Probenecid
Pharmacokinetics and Tolerability of Oseltamivir (Tamiflu?) Combined with Probenecid
Mark Holodniy*, Scott R. Penzak, Timothy M. Straight, Richard T. Davey, Kelvin K. Lee, Matthew Bidwell Goetz, Dennis W. Raisch, Francesca Cunningham, Emil T. Lin, Noemi Olivo, and Lawrence R. Deyton
Office of Public Health and Environmental Hazards, Department of Veterans Affairs, Washington, DC; Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA; VA Palo Alto Health Care System, Palo Alto, CA; Clinical Pharmacokinetics Research Laboratory, National Institutes of Health, Bethesda, MD; Department of Clinical Investigation, Brooke Army Medical Center, Ft Sam Houston, TX; CRS/LIR/NIAID, National Institutes of Health, Bethesda, MD; VA Cooperative Studies Program Coordinating Center, Palo Alto, CA; Greater Los Angeles Health Care System, Los Angeles, CA; Infectious Diseases Section, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA; VA Cooperative Studies Program, Clinical Research Pharmacy Coordinating Center, Albuquerque, NM; Pharmacy Benefits Management Group, Department of Veterans Affairs, Hines, IL; Department of Biopharmaceutical Sciences, UCSF, San Francisco, CA; George Washington University School of Medicine and Health Sciences, Washington, DC
* To whom correspondence should be addressed. Email: Holodniy@stanford.edu; mark.holodniy@va.gov.
Abstract
Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for treatment and prophylaxis against influenza A and B.
In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored.
Healthy volunteers were randomized to a 3-arm, open label study and given 75 mg oral oseltamivir q24h (group 1), 75 mg oseltamivir q48h combined with 500 mg probenecid QID (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid BID (group 3) for 15 days.
Pharmacokinetic data, determined using noncompartmental methods, and safety data are reported.
Forty eight subjects completed the pharmacokinetic analysis.
The study drugs were generally well tolerated except for one case of reversible grade-4 thrombocytopenia in group 2.
Calculated 90% confidence intervals for the geometric mean ratios between Groups 2 and 3 vs. Group 1 were outside the bioequivalence criteria boundary (0.80-1.25) at 0.63 - 0.89 for Group 2 vs. 1 and 0.57 - 0.90 for Group 3 vs. 1.
Steady state oseltamivir carboxylate apparent oral clearance (L/hr) was significantly less in groups 2 (7.4, 6.08-8.71) and 3 (7.19, 6.41-7.98) versus group 1 (9.75 6.91-12.60) (p < 0.05 for both comparisons [ANOVA]).
The (arithmetic) mean 48 hr concentration (C48) for Group 2 was not significantly different compared to Group 1 C24 (42 ? 76 vs. 81 ? 54 ng/mL; P = 0.194), but was significantly less for Group 3 versus Group 1 C24 (23 ? 26 vs. 81 ? 54 ng/mL; P=0.012).
Alternate day dosing of oseltamivir plus four times daily probenecid achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro; and this combination should be studied further.
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Mark Holodniy*, Scott R. Penzak, Timothy M. Straight, Richard T. Davey, Kelvin K. Lee, Matthew Bidwell Goetz, Dennis W. Raisch, Francesca Cunningham, Emil T. Lin, Noemi Olivo, and Lawrence R. Deyton
Office of Public Health and Environmental Hazards, Department of Veterans Affairs, Washington, DC; Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA; VA Palo Alto Health Care System, Palo Alto, CA; Clinical Pharmacokinetics Research Laboratory, National Institutes of Health, Bethesda, MD; Department of Clinical Investigation, Brooke Army Medical Center, Ft Sam Houston, TX; CRS/LIR/NIAID, National Institutes of Health, Bethesda, MD; VA Cooperative Studies Program Coordinating Center, Palo Alto, CA; Greater Los Angeles Health Care System, Los Angeles, CA; Infectious Diseases Section, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA; VA Cooperative Studies Program, Clinical Research Pharmacy Coordinating Center, Albuquerque, NM; Pharmacy Benefits Management Group, Department of Veterans Affairs, Hines, IL; Department of Biopharmaceutical Sciences, UCSF, San Francisco, CA; George Washington University School of Medicine and Health Sciences, Washington, DC
* To whom correspondence should be addressed. Email: Holodniy@stanford.edu; mark.holodniy@va.gov.
Abstract
Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for treatment and prophylaxis against influenza A and B.
In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored.
Healthy volunteers were randomized to a 3-arm, open label study and given 75 mg oral oseltamivir q24h (group 1), 75 mg oseltamivir q48h combined with 500 mg probenecid QID (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid BID (group 3) for 15 days.
Pharmacokinetic data, determined using noncompartmental methods, and safety data are reported.
Forty eight subjects completed the pharmacokinetic analysis.
The study drugs were generally well tolerated except for one case of reversible grade-4 thrombocytopenia in group 2.
Calculated 90% confidence intervals for the geometric mean ratios between Groups 2 and 3 vs. Group 1 were outside the bioequivalence criteria boundary (0.80-1.25) at 0.63 - 0.89 for Group 2 vs. 1 and 0.57 - 0.90 for Group 3 vs. 1.
Steady state oseltamivir carboxylate apparent oral clearance (L/hr) was significantly less in groups 2 (7.4, 6.08-8.71) and 3 (7.19, 6.41-7.98) versus group 1 (9.75 6.91-12.60) (p < 0.05 for both comparisons [ANOVA]).
The (arithmetic) mean 48 hr concentration (C48) for Group 2 was not significantly different compared to Group 1 C24 (42 ? 76 vs. 81 ? 54 ng/mL; P = 0.194), but was significantly less for Group 3 versus Group 1 C24 (23 ? 26 vs. 81 ? 54 ng/mL; P=0.012).
Alternate day dosing of oseltamivir plus four times daily probenecid achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro; and this combination should be studied further.
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