AMBULATORY PERITONEAL DIALYSIS--PHARMACOKINETICS OF LAMIVUDINE IN HIV

Duke University, Durham NC

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Abstract

Lamivudine is a potent HIV reverse transcriptase inhibitor and is commonly used in combination with other drugs to treat patients infected with HIV. A growing number of HIV-infected patients also have severe renal failure and are undergoing continuous ambulatory peritoneal dialysis (CAPD) or hemodialysis. The purpose of this study is to evaluate steady-state levels of lamivudine in HIV-infected patients with severe renal failure who are undergoing dialysis in order to make dosage recommendations. Understanding the steady-state pharmocokinetics of lamivudine is important to ensure safe and effective therapy in patients with severe renal failure who are undergoing dialysis. Giving patients a dosage that is too low may result in subtherapeutic serum concentrations leading to the development of viral resistance mutations and treatment failure, whereas a dosage that is too high may lead to more frequent and perhaps more dangerous side effects of lamivudine necessitating discontinuation of therapy. HIV-infected patients already receiving lamivudine who also have severe renal impairment and are undergoing CAPD or hemodialysis will be enrolled in the study. Fourteen days prior to their admission to the Duke Clinical Research Unit, each patient will begin taking lamivudine at a dose of 150 mg per day. During this period, patients will continue their dialysis regimen and all other medications as usual. The patients will then be admitted to the Duke Clinical Research Unit. For each patient, a pre-dose lamivudine serum sample will be drawn and then 150 mg of lamivudine will be given orally. Post-dose serum lamivudine samples will be obtained at frequent time points for a 24 hour period. This procedure will be performed for each patient in the presence and absence of dialysis. Lamivudine levels in serum samples will be determined using a validated HPLC assay by personnel from Glaxo Wellcome Inc. Lamivudine serum concentrations determined pre-dose and at various times post-dose will be used to determine pharmacokinetic paramaters including the minimum serum concentration (C-min), maximum serum concentration (C-max), area under the the serum concentration versus time curve (AUC), and terminal elimination half life (t-1/2). These parameters will be calculated for each patient in the presence and absence of dialysis and may be used to determine whether or not dialysis significantly influences elimination of lamivudine. Finally, the C-min and C-max levels around each dose of lamivudine would be expected to represent steady state levels in patients undergoing dialysis. These levels can be compared to the 50% inhibitory concentration of lamivudine and may be useful for making dosage recommendations.