title: 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.
abstract: 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 (AUC(24,ss)) (GLS mean ratio, 0.94; 90% CI, 0.92, 0.97) and average plasma lamivudine concentration over the dosing interval (C(ave,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 AUC(24,ss) (GLS mean ratio, 0.99; 90% CI, 0.88, 1.11), C(ave,ss) (GLS mean ratio, 0.99; 90% CI, 0.88, 1.11), and maximum lamivudine concentration (C(max,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.
authors.affiliation: Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. gjy25826@glaxowellcome.com
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Yuen
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Bumgarner
authors.forename: Jim P
authors.initials: JP
authors.lastname: Bishop
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Smith
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Otto
authors.forename: David D
authors.initials: DD
authors.lastname: Hoelscher
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D019259:Lamivudine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D013810:Therapeutic Equivalency
chemical_list: D019380:Anti-HIV Agents; D019259:Lamivudine