Investigating clinically adequate concentrations of oseltamivir carboxylate in end-stage renal disease patients undergoing hemodialysis using a population pharmacokinetic approach.
End-stage renal disease (ESRD) patients receiving hemodialysis (HD) are at heightened risk for influenza, but the optimal oseltamivir dosage regimen for treating or preventing influenza in this high-risk population is still uncertain. Pharmacokinetic data for 24 adults with ESRD were pooled from a single-dose and a multiple-dose study to develop a population pharmacokinetic model using nonlinear mixed-effects modeling. The final model comprised five compartments, two each to describe the systemic pharmacokinetics of oseltamivir phosphate and its metabolite, oseltamivir carboxylate (OC), and a delay compartment to describe oseltamivir metabolism. Estimated OC clearance in the model was markedly faster during HD sessions (7.43 liters/min) than at other times (0.19 liter/min). Model simulations showed that 30 mg oseltamivir given after every HD session is the most suitable regimen for influenza treatment, producing trough OC concentrations above the median value achieved with the 75-mg twice-daily regimen in patients with normal renal function and peak concentrations below the highest oseltamivir exposures known to be well tolerated (median exposures after twice-daily dosing of 450 mg). Administration of the first dose following diagnosis of influenza need not wait until after the next HD session: addition of a single 30-mg dose during the 12 h before the next HD session raises OC exposures quickly without posing any safety risk. Further simulation showed that 30 mg oseltamivir given after every other HD session is the most suitable regimen for influenza prophylaxis.
Clinical Pharmacology, Roche Pharmaceutical Research and Early Development, New York, New York, USA makamal1978@gmail.com.
Mohamed A
MA
Kamal
Clinical Pharmacology, Roche Pharmaceutical Research and Early Development, New York, New York, USA.
Kayla Yi Ting
KY
Lien
Christchurch Clinical Studies Trust, Christchurch, New Zealand.
Richard
R
Robson
Roche Translational and Clinical Research Center, Inc., New York, New York, USA.
Vishak
V
Subramoney
Roche Products Ltd., Welwyn Garden City, United Kingdom.
Barry
B
Clinch
d3 Medicine LLC, Parsippany, New Jersey, USA.
Craig R
CR
Rayner
QuantPharm LLC, North Potomac, Maryland, USA.
Leonid
L
Gibiansky
D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000628:therapy; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D053139:Oseltamivir / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D006435:Renal Dialysis; D055815:Young Adult
D000998:Antiviral Agents; D053139:Oseltamivir; C535162:oseltamivir carboxylate