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Half-Dose Lamivudine Not Equivalent to Full Dose in Plasma or Cells
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12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami
Mark Mascolini
Lamivudine (3TC) taken at a dose of 150 mg once daily did not achieve concentrations equivalent to 300 mg once daily in plasma or peripheral blood mononuclear cells (PBMCs), according to results of a crossover trial in HIV-negative volunteers [1].
Interest in lower doses of often-used antiretrovirals reflects a desire to limit side effects, simplify dosing, and--especially in high-prevalence countries--lower cost. Because pharmacokinetic data to guide trial designs of this strategy are sparse, researchers in the UK and Australia planned this randomized crossover study of 150 versus 300 mg of 3TC in healthy HIV-negative volunteers.
The study involved 13 women and 11 men randomized to take 150 or 300 mg of 3TC daily for 10 days. Then, after 10 days taking no 3TC, volunteers switched to the other dose. The investigators measured 3TC concentrations in plasma and concentrations of 3TC triphosphate (3TC-TP), the active form of the drug, in PBMCs for 24 hours at the end of each dosing period. Before the trial began, the investigators determined that the different doses would be considered bioequivalent if the 90% confidence interval (CI) for geometric mean ratios (GMRs) of 3TC concentrations fell between 0.8 and 1.25.
Sixteen study participants (67%) were white, and 4 (17%) were black. Median age stood at 33.5 (range 27 to 57) and median weight at 72.2 kg (range 48.8 to 109.6). All 24 study participants completed both phases of the trial, and the researchers recorded no serious adverse events related to 3TC.
Geometric mean plasma 3TC concentrations stood considerably higher with the standard 300-mg daily dose than with 150 mg:
Area under the concentration-time curve for 24 hours (AUC24) (and 90% CI):
300 mg: 8354 ng x h/mL (7609 to 9172)
150 mg: 4773 ng x h/mL (4408 to 5169)
24-hour (trough) concentration (and 90% CI):
300 mg: 60.8 ng/mL (53.4 to 69.2)
150 mg: 38.1 ng/mL (34.0 to 42.7)
Maximum concentration (and 90% CI):
300 mg: 1344 ng/mL (1247 to 1448)
150 mg: 757 ng/mL (688 to 833)
GMRs (and 90% CI) of 150/300 mg showed that the lower dose was not bioequivalent to the higher dose in plasma: AUC24 0.57 (0.55 to 0.60), 24-hour concentration 0.63 (0.59 to 0.67), and maximum concentration 0.56 (0.53 to 0.60) (P < 0.001 for all).
Intracellular levels of 3TC-TP were also much lower with 150 mg daily than with 300 mg:
AUC24 (and 90% CI):
300 mg: 59.5 pmol x h/1 million cells (51.8 to 68.3)
150 mg: 44.0 pmol x h/1 million cells (38.0 to 51.0)
24-hour (trough) concentration (and 90% CI):
300 mg: 1.49 pmol/1 million cells (1.19 to 1.86)
150 mg: 1.23 pmol/1 million cells (1.0 to 1.52)
Maximum concentration (and 90% CI):
300 mg: 4.1 pmol/1 million cells (3.59 to 4.69)
150 mg: 2.95 pmol/1 million cells (2.47 to 3.51)
Once again, GMRs (and 90% CI) of 150/300 mg indicated that the lower dose was not bioequivalent to the higher dose in PMBCs: AUC24 0.73 (0.64 to 0.83) (P < 0.001), 24-hour concentration 0.82 (0.68 to 0.99) (P = 0.083), and maximum concentration 0.70 (0.61 to 0.82) (P < 0.001).
"For key pharmacokinetic parameters," the researchers concluded, "3TC at 150 mg is not bioequivalent to the standard regimen of 300 mg. This indicates that saturation of cytosine phosphorylation pathways is not achieved at a dose of 150 mg once daily." PMBC levels of 3TC-TP did not differ between men and women, a result reflecting another study at this workshop reviewed separately by NATAP [2].
References
1. Else L, Jackson A, Puls R, et al. Pharmacokinetics of plasma lamivudine (3TC), and its active intracellular anabolite 3TC-triphosphate (3TC-TP) over a 24 hour dosing interval following administration of 3TC 300 mg and 150 mg once daily to HIV-negative healthy volunteers. The ENCORE2 study. 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract O_05.
2. Anderson PI, Rower JE, Meditz A et al. The cellular pharmacology of zidovudine and lamivudine according to HIV-status and gender. 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract O_06.
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