Singapore Drugs Database

Indication

Elvitegravir in combination with an HIV protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s) is indicated for the treatment of HIV-1 infection in antiretroviral treatment-experienced adults.

Mechanism of Action

Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.

Pharmacokinetics

Absorption

Following oral administration of elvitegravir and ritonavir with food, in HIV-1 infected subjects, peak elvitegravir plasma concentrations were observed approximately 4 hours post-dose.

Distribution

Metabolism

Elvitegravir undergoes primarily oxidative metabolism via CYP3A, and is secondarily glucuronidated via UGT1A1/3 enzymes. Metabolites are found in the plasma at very low concentrations, displayed considerably lower anti-HIV activity, and did not contribute to the overall antiviral activity of elvitegravir.

Elimination

Toxicity

The most common adverse reactions reported for elvitegravir use during clinical trials include nausea, vomiting, and diarrhea. Less common side effects occurring in

Active Ingredient/Synonyms

6-(3-chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid | elvitégravir | EVG | GS 9137 | Elvitegravir |

Indication

Indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults and for postexposure prophylaxis of HIV infection in health care workers and others exposed occupationally or nonoccupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with risk for transmission of the virus.

Mechanism of Action

Emtricitabine works by inhibiting reverse transcriptase, the enzyme that copies HIV RNA into new viral DNA. Emtricitabine is a synthetic nucleoside analogue of cytidine. It is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate, which is responsible for the inhibition of HIV-1 reverse transcriptase. It competes with the natural substrate deoxycytidine 5'-triphosphate and incorporates into nascent viral DNA, resulting in early chain termination. Therefore emtricitabine inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate deoxycytidine 5'-triphosphate and by its incorporation into viral DNA. By inhibiting HIV-1 reverse transcriptase, emtricitabine can help to lower the amount of HIV, or "viral load", in a patient's body and can indirectly increase the number of immune system cells (called T cells or CD4+ T-cells). Both of these changes are associated with healthier immune systems and decreased likelihood of serious illness.

Pharmacokinetics

Absorption

Rapidly absorbed (mean absolute bioavailability of 93% for capsules, and 75% for solution). Food does not effect absorption.

Distribution

Metabolism

Minimally transformed (13%), most appears unchanged in urine (86%). The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3′-sulfoxide diastereomers (~ 9% of dose) and conjugation with glucuronic acid to form 2′-O-glucuronide (~ 4% of dose). In vitro studies indicate emtricitabine is not an inhibitor or cytochrome P450 enzymes.

Elimination

Clearance

* 302 +/- 94 mL/min [Renal Function Creatinine Clearance>80 ml/min] * 168 +/- 10 mL/min [Renal Function Creatinine Clearance 50-80 ml/min] * 138 +/- 28 mL/min [Renal Function Creatinine Clearance 30-49 ml/min] * 99 +/- 6 mL/min [Renal Function Creatinine Clearance

Toxicity

Symptoms of overdose include serious liver problems (hepatotoxicity, with liver enlargement and fat in the liver called steatosis) or a lactic acidosis (buildup of an acid in the blood).

Active Ingredient/Synonyms

(−)-(2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine | (−)-2'-deoxy-5-fluoro-3'-thiacytidine | (−)-cis-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one | (−)-FTC | (−)-β-2',3'-dideoxy-5-fluoro-3'-thiacytidine | (2R-cis)-4-amino-5-fluoro-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-2(1H)-pyrimidinone | 4-amino-5-fluoro-1-((2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl)pyrimidin-2(1H)-one | 4-Amino-5-fluoro-1-((2R,5S)-2-hydroxymethyl-[1,3]oxathiolan-5-yl)-1H-pyrimidin-2-one | 5-fluoro-1-((2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl)cytosine | Emtricitabin | Emtricitabina | Emtricitabine | Emtricitabinum | Emtricitabine |

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 |