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 highperformance liquid chromatography-tandem mass spectrometry. Within-subject changes in PK parameters ( L amivudine (3TC), a commonly used nucleoside reverse transcriptase inhibitor (NRTI), is an inactive prodrug that requires transport into the cell and stepwise phosphorylation by intracellular kinases to produce its active triphosphate form-lamivudine triphosphate (3TC-TP) (5). The active triphosphate competes with the corresponding endogenous nucleoside triphosphate, dCTP, for binding to the viral reverse transcriptase. Once incorporated into viral DNA, chain termination results due to absence of a 3=-hydroxy group to which 3=-5=-phosphodiester linkages are normally made (12).Studies conducted in HIV-infected patients have failed to establish clear pharmacokinetic-pharmacodynamic relationships between the plasma 3TC concentrations and antiviral efficacy and safety, whereas the concentrations of its intracellular triphosphate, 3TC-TP, have been shown to be the critical parameter to predict efficacy and toxicity in vivo (1, 8).The active nucleoside triphosphates are trapped intracellularly due to the presence of ionic phosphate groups and this confers the long intracellular half-lives compared to the respective parent compounds in plasma. Since 3TC-TP is characterized by a long intracellular half-life (ca. 15 to 16 h), active triphosphate concentrations persist in cells after plasma 3TC (half-life, ϳ5 h) concentrations have decreased, thus enabling less frequent dosing (18).3TC is currently approved at a dose of 150 mg twice daily (BID) or 300 mg once daily (QD). During the clinical development of 3TC, no clear correlation between its dose and reductions in HIV-RNA or other surrogate markers in HIV-infected individuals were demonstrated; including in the NUCB2001 trial, at doses of 35 to 1,400 mg/day (27). The NUCA3001 (treatment naive) and NUCA3002 (treatment experienced) trials reported no differences in reduction in HIV-RNA between patients taking 3TC at 300 mg BID versus 150 mg BID (4, 7) and, in a pharmacokinetic substudy of NUCA3001, only small elevations in 3TC triphosphate concentrations were found in patients receiving the 300-mg BID regimen (18). Similarly, a pharmacokinetic study found intracellular 3TC-TP exposures to be bioequivalent at 150-mg BID and 300-mg QD doses (28), and in a phase III (treatment naive) trial, no differences in efficacy were reported between these regimens (...

L1 drives IFN in senescent cells and promotes age-associated inflammation

“…For the 2 mg/ml cohort the concentration of 3TC in plasma averaged 7.2 μM. This dose of drug was chosen for further experiments to mimic the human HIV therapeutic dose (300 mg per day, 5–8 μM in plasma) 37 . For the experiments presented in this communication animals were aged in house until they reached 26 months of age.…”

Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy

“…Men were shown in previous studies to have lower nucleoside analog-triphosphate concentrations in PBMC, but the mechanism(s) was not elucidated (22)(23)(24). Comparatively, other studies did not reproduce these sex differences in PBMC (11,(25)(26)(27). There are a myriad of potential explanations, including differential expression of transporters or enzymes that influence tenofovir disposition, such as carboxylesterase 2, P-glycoprotein (ABCB1), and/or breast cancer resistance protein (BCRP) (28,29).…”

Viral Suppression Following Switch to Second-line Antiretroviral Therapy: Associations With Nucleoside Reverse Transcriptase Inhibitor Resistance and Subtherapeutic Drug Concentrations Prior to Switch

“…Because 3TC plasma concentrations do not correlate well with the active intracellular metabolite, no TDM targets exist. Using data from pharmacokinetic studies of 3TC (300 mg once daily) in plasma, we calculated the population standard deviation and found the lower limit of the 95% confidence interval (CI) for C trough to be approximately 20 ng/mL, the limit of quantification of the assay [ 31 , 32 ]. Drug concentrations were defined as subtherapeutic if they were greater than C trough (NNRTI and PI) or below the limit of quantification (BLQ) for the assay (3TC), and the regimen as subtherapeutic if either criterion was met.…”