The pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells from patients infected with HIV-1.
OBJECTIVE
To assess the pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells (PBMC) from patients infected with HIV-1.


METHODS
Single-center, open-label, randomized, two-period, cross-over study in 10 asymptomatic, antiretroviral-experienced, HIV-1-infected patients who had a CD4+ lymphocyte count of 200-500 x 10(6)/l and had received combination treatment with lamivudine 150 mg twice a day plus zidovudine 600 mg a day (divided into two or three doses) for > or = 16 weeks prior to study entry.


METHODS
Patients were randomly assigned to receive lamivudine 150 mg twice a day or lamivudine 300 mg twice a day for 14 days, with at least a 48-h washout period between treatments. Serial blood samples were collected over 36 h for determination of lamivudine serum concentrations using liquid chromatography/mass spectrometry and intracellular phosphate PBMC concentrations using high performance liquid chromatography/radioimmunoassay methods. Pharmacokinetic parameters were calculated based on lamivudine and lamivudine anabolite concentration-time data.


RESULTS
Intracellular pharmacokinetic parameters were highly variable between patients (coefficient of variations approximately 50%). The two regimens produced lamivudine-total phosphate (totP) values of a similar magnitude. Although the 300-mg regimen tended to produce higher lamivudine-monophosphate (MP) and -triphosphate (TP) values, differences from values produced by the 150-mg regimen were not statistically significant. As lamivudine diphosphate (DP) was the predominant anabolite, accounting for 50-55% of lamivudine-totP (compared with 30-35% for lamivudine-MP and 15-20% for lamivudine-TP), the conversion of lamivudine-DP to lamivudine-TP can be regarded as the rate-limiting step. The median lamivudine-TP intracellular half-life (t1/2) for the 150-mg and 300-mg regimens did not differ significantly (15.3 and 16.1 h, respectively). Serum lamivudine pharmacokinetic parameters were consistent with those observed in previous studies in HIV-1-infected patients. No apparent linear relationships were observed between lamivudine intracellular anabolite and serum data.


CONCLUSIONS
The intracellular pharmacokinetics of lamivudine phosphorylation in PBMC from asymptomatic HIV-1-infected patients are highly variable and do not differ statistically between the 150- and 300-mg twice a day regimens. The variations in intracellular lamivudine-TP concentrations following these two lamivudine dosage regimens are unlikely to result in differences in clinical effect. This was confirmed by the results of a large phase III study in HIV-1-infected patients which showed no differences in HIV-1 RNA or CD4+ lymphocyte counts between the 150- and 300-mg lamivudine regimens in combination with zidovudine.
Moore
K H
KH
Glaxo Wellcome Research and Development, Greenford, UK.
Barrett
J E
JE
Shaw
S
S
Pakes
G E
GE
Churchus
R
R
Kapoor
A
A
Lloyd
J
J
Barry
M G
MG
Back
D
D
D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D018592:Cross-Over Studies; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy; D015497:HIV-1; D006801:Humans; D019259:Lamivudine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D010766:Phosphorylation; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine