Singapore Drugs Database

Indication

For the treatment of HIV infection and chronic hepatitis B (HBV).

Mechanism of Action

Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination.

Pharmacokinetics

Absorption

Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. The peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL when an oral dose of 2 mg/kg twice a day was given to HIV-1 patients. When given with food, absorption is slower, compared to the fasted state.

Distribution

Apparent volume of distribution, IV administration = 1.3 ± 0.4 L/kg. Volume of distribution was independent of dose and did not correlate with body weight.

Metabolism

Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. This biotransformation is catalyzed by sulfotransferases.

Elimination

Clearance

* Renal clearance = 199.7 ± 56.9 mL/min [300 mg oral dose, healthy subjects] * Renal clearance = 280.4 ± 75.2 mL/min [single IV dose, HIV-1-infected patients] * Total clearance = 398.5 ± 69.1 mL/min [HIV-1-infected patients]

Toxicity

The most common reported adverse reactions (incidence ≥15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.

Active Ingredient/Synonyms

(-)-1-((2R,5S)-2-(Hydroxymethyl)-1,3-oxathiolan-5-yl)cytosine | (-)-2'-Deoxy-3'-thiacytidine | 2',3'-Dideoxy-3'-thiacytidine | 3'-Thia-2',3'-dideoxycytidine | 3TC | beta-L-2',3'-Dideoxy-3'-thiacytidine | beta-L-3'-Thia-2',3'-dideoxycytidine | Lamivudin | Lamivudina | Lamivudine | Lamivudinum | Lamivudine |

Indication

Tenofovir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older. It is also indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older.

Mechanism of Action

Tenofovir inhibits the activity of HIV reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Specifically, the drugs are analogues of the naturally occurring deoxynucleotides needed to synthesize the viral DNA and they compete with the natural deoxynucleotides for incorporation into the growing viral DNA chain. However, unlike the natural deoxynucleotides substrates, NRTIs and NTRTIs (nucleoside/tide reverse transcriptase inhibitors) lack a 3'-hydroxyl group on the deoxyribose moiety. As a result, following incorporation of an NRTI or an NtRTI, the next incoming deoxynucleotide cannot form the next 5'-3' phosphodiester bond needed to extend the DNA chain. Thus, when an NRTI or NtRTI is incorporated, viral DNA synthesis is halted, a process known as chain termination. All NRTIs and NtRTIs are classified as competitive substrate inhibitors.

Pharmacokinetics

Absorption

Tenofovir disoproxil fumarate is the water soluble diester prodrug of the active ingredient tenofoir. The oral bioavailability in fasted patients is approximately 25%. When a single oral dose (300 mg) is given to HIV-1 infected subjects in the fasted state, the maximum serum concentration was achieved in 1.0 ± 0.4 hours (Tmax). Cmax and AUC values are 0.30 ± 0.09 µg/mL and 2.29 ± 0.69 µg∙hr/mL. Administration of food (high fat meal containing 40 to 50% fat) increases the oral bioavailability, with an increase in the AUC of approximately 40%. Cmax is lower in the oral powder, compared to the tablet formulation. However, the mean AUC is similar between the two formulations.

Distribution

* 1.3 ± 0.6 L/kg [tenofovir 1.0 mg/kg IV] * 1.2 ± 0.4 L/kg [tenofovir 3.0 mg/kg IV]

Metabolism

The cytochrome P450 enzyme system is not involved with the metabolism of tenofovir disoproxil or tenofovir.

Elimination

Clearance

The following are renal clearance (CL renal) parameters for subjects with varying degrees of renal function: * 243.5 ± 33.3 mL/min [baseline creatinine clearance >80 mL/min] * 168.6 ± 27.5 mL/min [baseline creatinine clearance 50-80 mL/min] * 100.6 ± 27.5 mL/min [baseline creatinine clearance 30-49 mL/min] * 43.0 ± 31.2 mL/min [baseline creatinine clearance 12-29 mL/min] The following are clearance (CL/F) parameters for subjects with varying degrees of renal function: * 1043.7 ± 115.4 [baseline creatinine clearance >80 mL/min] * 807.7 ± 279.2 [baseline creatinine clearance 50-80 mL/min] * 444.4 ± 209.8 [baseline creatinine clearance 30-49 mL/min] * 177.0 ± 97.1 [baseline creatinine clearance 12-29 mL/min]

Toxicity

Limited clinical experience at doses higher than the therapeutic dose of tenofovir 300 mg is available. In Study 901 tenofovir disoproxil fumarate 600 mg was administered to 8 patients orally for 28 days. No severe adverse reactions were reported. The effects of higher doses are not known.

Active Ingredient/Synonyms

Bis(POC)PMPA | Tenofovir bis(isopropyloxycarbonyloxymethyl) ester | Tenofovir disoproxil |