Lamivudine/Zidovudine as a Combined Formulation Tablet: Bioequivalence Compared with Lamivudine and Zidovudine Administered Concurrently and the Effect of Food on Absorption

To establish whether a feline model can predict nucleoside analogue behavior in human semen, zidovudine (ZDV) and lamivudine (3TC) pharmacokinetic parameters (PKs) were determined in the blood and seminal plasma of healthy cats. Our results show considerable similarity in ZDV and 3TC PKs between cats and humans. As in humans, ZDV and 3TC tend to accumulate in feline seminal plasma. Area under the blood plasma concentration-time curve was predictive of seminal plasma excretion. The felid model offers a unique in vivo experimental alternative for investigating the pharmacokinetics of nucleoside analogues in the male genital tract.

supporting

confidence: 84%

Domestic Cat Model for Predicting Human Nucleoside Analogue Pharmacokinetics in Blood and Seminal Plasma

Jordan¹,

Pereira²,

Cohen³

et al. 2001

“…Both plasma 3TC concentrations and intracellular 3TC-TP concentrations were measured. A study population consisting of healthy subjects was deemed appropriate, since there are no reports of differences in 3TC pharmacokinetics between healthy and HIV-infected populations (19,20,28). Importantly, it is not possible to conduct a study with monotherapy lamivudine in HIV-infected subjects because of the high likelihood of HIV drug resistance in this setting.…”

Section: Discussionmentioning

confidence: 99%

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

Else

Jackson

Puls

et al. 2012

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 (...

“…We felt that a study population consisting of healthy subjects was appropriate, because earlier studies showed no differences in lamivudine pharmacokinetic parameters in healthy males and females from those reported in patients with HIV infection (11,21). Furthermore, because a population pharmacokinetics study showed that lamivudine pharmacokinetics are unaffected by surrogate markers of HIV disease (CD4 ϩ counts, HIV-1 RNA PCR, and Centers for Disease Control and Prevention Classification), it is unlikely that lamivudine biodispositions would differ between healthy and HIV-infected populations (12).…”

Section: Discussionmentioning

confidence: 99%

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

Yuen¹,

Lou²,

Bumgarner³

et al. 2004

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 twicedaily 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.Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) that is frequently used as a core component of highly active antiretroviral therapy (HAART) regimens in the treatment of human immunodeficiency virus (HIV) infection (13). In clinical trials conducted over 48 weeks, twice-daily regimens combining lamivudine at 150 mg with the NRTIs zidovudine (300 mg) and abacavir (300 mg) have proved equivalent to lamivudine-zidovudine-protease inhibitor combinations in reducing HIV-1 RNA levels and elevating CD4 cell counts (19;