Single dose pharmacokinetics of lamivudine in subjects with impaired renal function and the effect of haemodialysis

Johnson, Mark; Verpooten, Gert A.; Daniel, M J; Plumb, Robert S.; Moss, Jonathan; Caesbroeck, D. Van; Broe, Marc E. De

doi:10.1046/j.1365-2125.1998.00044.x

Cited by 55 publications

(47 citation statements)

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“…Lamivudine has a short serum half-life (5-7 h), although much of the drug is transported intracellularly and phosphorylated, the active metabolite has a half-life of 12-18 h [23]. The dose of lamivudine should be adjusted in patients with renal impairment [24]. Active lamivudine metabolites are not concentrated in the mitochondria, which may account for the low incidence of mitochondrial toxicity of lamivudine.…”

Section: Lamivudine (3tc)mentioning

confidence: 99%

A Review of the Toxicity of HIV Medications

et al. 2013

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Antiretroviral therapy has changed human immunodeficiency virus (HIV) infection from a near-certainly fatal illness to one that can be managed chronically. More patients are taking antiretroviral drugs (ARVs) for longer periods of time, which naturally results in more observed toxicity. Overdose with ARVs is not commonly reported. The most serious overdose outcomes have been reported in neonates who were inadvertently administered supratherapeutic doses of HIV prophylaxis medications. Typical ARV regimens include a "backbone" of two nucleoside reverse transcriptase inhibitors (NRTI) and a "base" of either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor. New classes of drugs called entry inhibitors and integrase inhibitors have also emerged. Older NRTIs were associated with mitochondrial toxicity, but this is less common in the newer drugs, emtricitabine, lamivudine, and tenofovir. Mitochondrial toxicity results from NRTI inhibition of a mitochondrial DNA polymerase. Mitochondrial toxicity manifests as myopathy, neuropathy, hepatic failure, and lactic acidosis. Routine lactate assessment in asymptomatic patients is not indicated. Lactate concentration should be obtained in patients taking NRTIs who have fatigue, nausea, vomiting, or vague abdominal pain. Mitochondrial toxicity can be fatal and is treated by supportive care and discontinuing NRTIs. Metabolic cofactors like thiamine, carnitine, and riboflavin may be helpful in managing mitochondrial toxicity. Lipodystrophy describes changes in fat distribution and lipid metabolism that have been attributed to both PIs and NRTIs. Lipodystrophy consists of loss of fat around the face (lipoatrophy), increase in truncal fat, and hypertriglyceridemia. There is no specific treatment of lipodystrophy. Clinicians should be able to recognize effects of chronic toxicity of ARVs, especially mitochondrial toxicity.

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Section: Lamivudine (3tc)mentioning

confidence: 99%

A Review of the Toxicity of HIV Medications

et al. 2013

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“…We believed that it was important to perform our evaluations at steady state because single-dose studies may fail to recognize the contributions of the drug distribution in tissue or alternative routes of metabolism or elimination induced by prolonged exposure to a drug. For example, in addition to renal elimination, lamivudine is also metabolized through a hepatic pathway (12). Although in patients with normal renal function hepatic metabolism contributes little to the overall metabolism of the drug, this pathway becomes more important in patients with renal impairment (12).…”

Section: Discussionmentioning

confidence: 99%

“…where Q H is the blood flow rate through the dialysis filter, H is the hematocrit, K is the concentration of lamivudine in red blood cells/concentration of lamivudine in plasma reported previously (12), and C a and C v are as defined above. Since in vitro studies indicate that lamivudine partitions equally between red blood cells and plasma (12), a value of 1 was used for K. The amount of lamivudine removed during hemodialysis was estimated by the following formula:…”

Section: Methodsmentioning

confidence: 99%

“…Since in vitro studies indicate that lamivudine partitions equally between red blood cells and plasma (12), a value of 1 was used for K. The amount of lamivudine removed during hemodialysis was estimated by the following formula:…”

Section: Methodsmentioning

confidence: 99%

“…The low molecular weight, low level of protein binding, high degree of water solubility, and high degree of permeability exhibited by lamivudine suggest that it would be readily removed by dialysis (11,12). A single-dose pharmacokinetic study of lamivudine in HIV-negative subjects undergoing hemodialysis indicated that although hemodialysis removed up to 50% of dialyzed lamivudine, it did not reduce the concentrations in serum to a clinically significant extent because of a large apparent volume of distribution (12). Neither of these single-dose studies assessed the pharmacokinetics of lamivudine at steady state.…”

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Steady-State Pharmacokinetics of Lamivudine in Human Immunodeficiency Virus-Infected Patients with End-Stage Renal Disease Receiving Chronic Dialysis

Bohjanen

Johnson

Szczech³

et al. 2002

Antimicrob Agents Chemother

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The steady-state pharmacokinetics of lamivudine were evaluated in 11 subjects with human immunodeficiency virus infection and end-stage renal disease, 9 of whom were receiving hemodialysis and 2 of whom were receiving chronic ambulatory peritoneal dialysis (CAPD). All subjects received 150 mg of lamivudine daily for at least 2 weeks prior to sampling for determination of the pharmacokinetics of lamivudine over a 24-h period on 2 consecutive days. On the first day, subjects received 150 mg of oral lamivudine and underwent dialysis (hemodialysis or CAPD). On the second day, subjects received another 150 mg of oral lamivudine but dialysis was not performed. For the subjects undergoing hemodialysis, the geometric mean predose serum lamivudine concentration was 1.14 g/ml (95% confidence interval [CI], 0.83 to 1.58 g/ml), the geometric mean maximum concentration in serum (C max ) was 3.77 g/ml (95% CI, 3.01 to 4.71 g/ml), and the geometric mean area under the serum concentration-time curve from time zero to 24 h (AUC 0-24 ) was 49.8 g ⅐ h/ml (95% CI 39.1 to 63.6 g ⅐ h/ml). Hemodialysis removed approximately 28 mg of lamivudine but had no significant effect on C max or AUC 0-24 . In the absence of hemodialysis, the geometric mean lamivudine terminal elimination half-life was 17.2 h (95% CI, 10.5 to 28.1 h), whereas the geometric mean intradialysis half-life of lamivudine was 5.3 h (95% CI, 3.4 to 8.2 h). The pharmacokinetics of lamivudine in subjects undergoing CAPD were similar to those in subjects undergoing hemodialysis. CAPD removed 24 mg of lamivudine over a 24-h period but had no effect on C max or AUC 0-24 . Pharmacokinetic modeling suggests that a lamivudine dose of 25 mg daily in hemodialysis subjects would provide serum exposure similar to that provided by a dose of 150 mg twice daily in patients with normal renal function.

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Profound suppression of hepatitis B virus replication with lamivudine

Lai

Yuen

2000

J. Med. Virol.

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The therapeutic goals in chronic hepatitis B are to prevent or decrease cirrhosis and hepatocellular carcinoma in patients with pre-cirrhotic or early cirrhotic disease and to stabilise patients with end-stage cirrhosis. Lamivudine is an oral nucleoside analogue that suppresses hepatitis B virus (HBV) replication, and so may achieve both these treatment objectives. The active 5'-triphosphate metabolite of lamivudine has two modes of viral suppression. First, it mimics deoxycytidine triphosphate and is incorporated into newly synthesised HBV DNA to cause chain termination. Second, it demonstrates competitive inhibition of viral DNA-dependent and RNA-dependent DNA polymerase activity (i.e., reverse transcriptase activity). Lamivudine may, therefore, act at four possible stages during HBV replication: reverse transcription of pre-genomic mRNA into nascent minus-strand DNA; formation of plus strand DNA from nascent minus-strand DNA; completion of double-stranded DNA; and formation of covalently closed circular DNA. In clinical studies, lamivudine therapy reduced serum HBV DNA and this was associated with significant improvements in liver histology and significant and sustained enhancement of the proliferative CD4-mediated response to HBeAg and hepatitis B core antigen (HBcAg), and an increased frequency of HBeAg-specific T cells. HBV DNA concentrations often returned to pre-treatment values when therapy ended prior to the loss of hepatitis B e antigen (HBeAg). Although the emergence of HBV variants with a mutation in the YMDD (tyrosine-methionine-aspartate-aspartate) motif has been observed, such variants show reduced susceptibility to lamivudine due to limited replication competence, and their emergence is not a signal to cease lamivudine therapy. In conclusion, viral suppression with lamivudine offers a means of disease improvement and immunological control in chronic hepatitis B.

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Single dose pharmacokinetics of lamivudine in subjects with impaired renal function and the effect of haemodialysis

Cited by 55 publications

References 9 publications

A Review of the Toxicity of HIV Medications

A Review of the Toxicity of HIV Medications

Steady-State Pharmacokinetics of Lamivudine in Human Immunodeficiency Virus-Infected Patients with End-Stage Renal Disease Receiving Chronic Dialysis

Profound suppression of hepatitis B virus replication with lamivudine

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