title: Pharmacokinetics of lamivudine and lamivudine-triphosphate after administration of 300 milligrams and 150 milligrams once daily to healthy volunteers: results of the ENCORE 2 study.
abstract: There is interest in evaluating the efficacy of lower doses of certain antiretrovirals for clinical care. We determined here the bioequivalence of plasma lamivudine (3TC) and intracellular 3TC-triphosphate (3TC-TP) concentrations after the administration of two different doses. ENCORE 2 was a randomized crossover study. Subjects received 3TC at 300 and 150 mg once daily for 10 days (arm 1; n = 13) or vice versa (arm 2; n = 11), separated by a 10-day washout. Pharmacokinetic (PK) profiles (0 to 24 h) were assessed on days 10 and 30. Plasma 3TC and 3TC-TP levels in peripheral blood mononuclear cells were quantified by high-performance liquid chromatography-tandem mass spectrometry. Within-subject changes in PK parameters (the area under the concentration-time curve from 0 to 24 h [AUC(0-24)], the trough concentration of drug in plasma at 24 h [C(24)], and the maximum concentration of drug in plasma [C(max)]) were evaluated by determining the geometric mean ratios (GMRs) adjusted for study arm, period, and intra-individual variation. Regimens were considered bioequivalent if the 90% confidence interval (90% CI) fell within the range of 0.8 to 1.25. A total of 24 subjects completed the study. The GM (90% CI) 3TC AUC(0-24)), expressed as ng·h/ml, for the 300- and 150-mg doses were 8,354 (7,609 to 9,172) and 4,773 (4,408 to 5,169), respectively. Bioequivalence in 3TC PK following the administration of 300 and 150 mg was not demonstrated: the GMRs for AUC(0-24), C(24), and C(max) were 0.57 (0.55 to 0.60), 0.63 (0.59 to 0.67), and 0.56 (0.53 to 0.60), respectively. The GM (90% CI) 3TC-TP AUC(0-24) values (pmol·h/10(6) cells) for the 300- and 150-mg doses were 59.5 (51.8 to 68.3) and 44.0 (38.0 to 51.0), respectively. Bioequivalence in 3TC-TP PK following the administration of 300 and 150 mg was not demonstrated: the GMRs for AUC(0-24), C(24), and C(max) were 0.73 (0.64 to 0.83), 0.82 (0.68 to 0.99), and 0.70 (0.61 to 0.82), respectively. We found that 3TC at 150 mg is not bioequivalent to the standard regimen of 300 mg, indicating that saturation of cytosine phosphorylation pathways is not achieved at a dose of 150 mg.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom. l.j.else@liv.ac.uk
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Else
authors.forename: Akil
authors.initials: A
authors.lastname: Jackson
authors.forename: Rebekah
authors.initials: R
authors.lastname: Puls
authors.forename: Andrew
authors.initials: A
authors.lastname: Hill
authors.forename: Paul
authors.initials: P
authors.lastname: Fahey
authors.forename: Enmoore
authors.initials: E
authors.lastname: Lin
authors.forename: Alieu
authors.initials: A
authors.lastname: Amara
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.forename: Victoria
authors.initials: V
authors.lastname: Watson
authors.forename: John
authors.initials: J
authors.lastname: Tjia
authors.forename: Sean
authors.initials: S
authors.lastname: Emery
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D054306:Dideoxynucleotides / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D019259:Lamivudine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency; D006113:United Kingdom; D055815:Young Adult
chemical_list: D054306:Dideoxynucleotides; D018894:Reverse Transcriptase Inhibitors; C417268:lamivudine triphosphate; D019259:Lamivudine; D003570:Cytidine Triphosphate