PHARMACOKINETICS OF LAMIVUDINE IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PATIENTS WITH RENAL DYSFUNCTION

The purpose of this study was to determine the safety and pharmacokine tics of lamivudine (3TC), a nucleoside analog that has shown potent in vitro and recent in vivo activity against human immunodeficiency viru s. Sixteen human immunodeficiency virus-infected patients, sh with nor mal renal function !creatinine clearance [CL(CR)], greater than or equ al to 60 ml/min), four with moderate renal impairment (CL(CR), 10 to 4 0 ml/min), and sis with severe renal impairment (CL(CR) <10 ml/min), w ere enrolled in the study. After an overnight fast, patients were admi nistered 300 mg of 3TC orally. Blood was obtained before 3TC administr ation acid 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, and 48 h afterward. Timed urine collections were performed for pa tients able to produce urine. Serum and urine were assayed for 3TC by reverse-phase high-performance liquid chromatography with UV detection . Pharmacokinetic parameters were calculated by using standard noncomp artmental techniques. The peak concentration of 3TC increased with dec reasing renal function; geometric means were 2,524, 3,538, and 5,684 n g/ml for patients with normal renal function, moderate renal impairmen t, and severe renal impairment, respectively. The terminal half-life a lso increased with decreasing renal function; geometric means were 11. 5, 14.1, and 20.7 h for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively, Both oral and renal clearances were linearly correlated with CL(CR). A 300-mg d ose of 3TC was well tolerated by all three patient groups. The pharmac okinetics of 3TC is profoundly affected by impaired renal function. Do sage adjustment, by either dose reduction or lengthening of the dosing interval, is warranted.