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Antimicrobial Agents and Chemotherapy, January 2004, p. 176-182, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.176-182.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Equivalent Steady-State Pharmacokinetics of Lamivudine in Plasma and Lamivudine Triphosphate within Cells following Administration of Lamivudine at 300 Milligrams Once Daily and 150 Milligrams Twice Daily

Geoffrey J. Yuen,1* Yu Lou,2 Nancy F. Bumgarner,1 Jim P. Bishop,3 Glenn A. Smith,3 Victoria R. Otto,3 and David D. Hoelscher4

Clinical Pharmacology and Discovery Medicine,1 Clinical Pharmacology Data Science,2 Bioanalysis and Drug Metabolism, GlaxoSmithKline, Research Triangle Park, North Carolina 27709,3 PPD Pharmaco, Austin, Texas 787044

Received 17 January 2003/ Returned for modification 27 April 2003/ Accepted 2 September 2003

Once-daily administration of 300 mg of lamivudine in combination with other antiretroviral agents has been proposed as a possible way to optimize anti-human immunodeficiency virus (HIV) treatment and to facilitate adherence. A single-center, randomized, two-way, crossover study was conducted in 60 healthy subjects to compare the steady-state pharmacokinetics of lamivudine in plasma and its putative active anabolite, lamivudine 5'-triphosphate (lamivudine-TP), in peripheral blood mononuclear cells (PBMCs) following 7 days of treatment with lamivudine at 300 mg once daily and 7 days of the standard regimen of 150 mg twice daily. Serial blood samples were collected over 24 h for determination of plasma lamivudine concentrations by liquid chromatography-mass spectrometry and intracellular lamivudine-TP concentrations in peripheral blood mononuclear cells by high-performance liquid chromatography/radioimmunoassay methods. Pharmacokinetic parameters were calculated based on lamivudine and lamivudine-TP concentration-time data. Regimens were considered bioequivalent if 90% confidence intervals (CI) for the ratio (once daily/twice daily) of geometric least-squares (GLS) means for lamivudine and lamivudine-TP pharmacokinetic values fell within the acceptance range of 0.8 to 1.25. Steady-state plasma lamivudine pharmacokinetics following the once- and twice-daily regimens were bioequivalent with respect to the area under the drug concentration-time curve from 0 to 24 h at steady state (AUC24,ss) (GLS mean ratio, 0.94; 90% CI, 0.92, 0.97) and average plasma lamivudine concentration over the dosing interval (Cave,ss) (GLS mean ratio, 0.94; 90% CI, 0.92, 0.97). Steady-state intracellular lamivudine-TP pharmacokinetics after the once- and twice-daily regimens were bioequivalent with respect to AUC24,ss (GLS mean ratio, 0.99; 90% CI, 0.88, 1.11), Cave,ss (GLS mean ratio, 0.99; 90% CI, 0.88, 1.11), and maximum lamivudine concentration (Cmax,ss) (GLS mean ratio, 0.93; 90% CI, 0.81, 1.07). Lamivudine-TP trough concentrations were modestly lower (by 18 to 24%) during the once-daily regimen; the clinical importance of this is unclear, given the large intersubject variability in values that was observed (coefficient of variation, 48 to 124%). Once-daily lamivudine was as well tolerated as the twice-daily regimen. Overall, the results of this study suggest that for key AUC-related parameters, lamivudine at 300 mg once daily is pharmacokinetically equivalent to lamivudine at 150 mg twice daily.

* Corresponding author. Mailing address: Clinical Pharmacology and Discovery Medicine, Full Development, GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC 27709. Phone: (919) 483-5676. Fax: (919) 483-6380. E-mail: gjy25826{at}glaxowellcome.com.

Antimicrobial Agents and Chemotherapy, January 2004, p. 176-182, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.176-182.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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