Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: CIPLA MEDPRO MANUFACTURING (PTY) LTD., 1474 South Coast Road, Mobeni, Durban, 4052, Customer care: 080 222 6662
Pharmacological classification: A 20.2.8
Pharmacotherapeutic group: antivirals for systemic use
ATC Code: J05AR25
Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI) which inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration, which is essential for the HIV replication cycle. In this process, the integrase inhibitor chelates with two Mg2+ ions in the integrase catalytic active site and prevents the integrase enzyme from completing the strand transfer. Accumulation of 2-long terminal repeat (2-LTR) circles in treated cells indicate the integrase strand transfer reaction inhibition by a lower DTG concentration in comparison with that which causes cell toxicity.
Lamivudine is a nucleoside analogue of 2'-deoxycytosine that exerts its antiviral effects by acting as a DNA chain terminator. The active anabolite of lamivudine, lamivudine 5'-triphosphate, is formed from phosphorylation by intracellular kinases and competes with naturally occurring cytidine triphosphate for incorporation into DNA. Lamivudine is a selective inhibitor of HIV-1 and HIV-2 replication. Lamivudine is a potent inhibitor of the reverse transcriptase (RT) enzymes of HIV-1, with in vitro IC50 in different cell lines with different HIV-1 strains ranging from 0,002 to 1,14 mM and IC50 against HBV of 0,1 mM with limited cell toxicity at concentrations ˃1000-fold those effective against HIV. It is also active against zidovudine resistant clinical isolates of HIV.
Lamivudine 5'-triphosphate is a weak inhibitor of the RNA and DNA dependent activities of HIV reverse transcriptase. Its mode of action is a chain terminator of HIV reverse transcription.
Lamivudine does not interfere with cellular deoxynucleotide metabolism and has little effect on mammalian cell and mitochondrial DNA content.
Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells.
Lamivudine resistance to HIV-1 is due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine residue to either isoleucine or valine.
Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentrations of drug necessary to effect viral replication by 50 percent (EC50) values of 0,5 nM (0,21 ng/mL) to 2,1 nM (0,85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a mean EC50 value of 0,52 nM in a viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates (3 in each group of M [clades A – G], and 3 in group O) with EC50 values ranging from 0,02 nM to 2,14 nM for HIV-1. Dolutegravir EC50 values against three HIV-2 clinical isolates in PBMC assays ranged from 0,09 nM to 0,61 nM.
The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 3 to 15,000 nM (1 nM = 230 ng/mL). The EC50 values of lamivudine against different HIV-1 clades (A – G) and group O viruses ranged from 1 to 120 nM, and against HIV-2 isolates from 3 to 120 nM in PBMCs.
Neither dolutegravir nor lamivudine were antagonistic to all tested anti-HIV medicines.
In 100% human serum, the mean fold shift for dolutegravir activity is 75 fold, resulting in protein adjusted IC90 of 0,064 μg/mL. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%).
In the first week of treatment, a small decrease (10 to 14%) in mean serum creatinine clearance may be observed. Dolutegravir has no significant impact on glomerular filtration rate (GFR) or the effective renal plasma flow (ERPF). The increases in creatinine are due to non-pathologic inhibition of the organic cation transporter 2 (OCT2) in the proximal renal tubules, which mediates the tubular secretion of creatinine.
There are no significant differences between dolutegravir pharmacokinetics in healthy subjects compared to those of HIV-infected patients.
The PK variability of dolutegravir is between low to moderate.
Dolutegravir is absorbed following oral administration, with median Tmax at 2 to 3 hours post dose. The linearity of dolutegravir pharmacokinetics is dependent on dose and formulation. Following oral administration of tablet formulations, dolutegravir exhibits non-linear pharmacokinetics with less than dose proportional increases in plasma exposure from 2 to 100 mg; however, dolutegravir exposure appears dose proportional from 25 to 50 mg.
The absolute bioavailability of dolutegravir has not been established.
Food increases the extent and slows the rate of the absorption of dolutegravir. Bioavailability of dolutegravir depends on the meal content: low, moderate and high fat meals increase dolutegravir AUC(0-∞) by 34%, 41% and 66%; increase Cmax by 46%, 52%, and 67%; prolong Tmax to 3, 4 and 5 hours from 2 hours under fasting conditions, respectively.
Dolutegravir is highly bound to human plasma (approximately 99,3%). The apparent volume of distribution is estimated to be 12,5 L. Binding of dolutegravir to plasma proteins is independent of concentration. Dolutegravir has minimal association of radioactivity with blood cellular components.
Free fraction of dolutegravir is estimated at approximately 0,2 to 1,1% in healthy subjects, approximately 0,4 to 0,5% in subjects with moderate hepatic impairment, and 0,8 to 1,0% in subjects with severe renal impairment and 0,5% in HIV-1 infected patients.
Dolutegravir is present in cerebrospinal fluid (CSF).
Dolutegravir is present in the female and male genital tract.
Dolutegravir is primarily metabolised by UGT1A1 with a minor CYP3A component. Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged medicine is low (<1% of the dose). 53% of the total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed medicine or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. 31% of the total dose is excreted in urine, represented by ether glucuronide of dolutegravir (18,9% of the total dose), N-dealkylation metabolite (3,6% of total dose) and a metabolite formed by oxidation at the benzylic carbon (3,0% of total dose).
The mean elimination half-life of dolutegravir is approximately 7 hours.
Pharmacokinetic data for dolutegravir in subjects older than 65 years of age are limited.
Renal clearance of unchanged medicine is a minor pathway of elimination of dolutegravir. There are no clinically significant differences in the pharmacokinetics of patients with severe renal impairment and that of healthy subjects.
Dolutegravir is primarily metabolised and eliminated by the liver. While no dosage adjustment of dolutegravir is required in mild to moderate hepatic impairment, the effect of dolutegravir pharmacokinetics in patients with severe hepatic impairment has not been studied.
There is no evidence that common polymorphisms in metabolising enzymes alter dolutegravir pharmacokinetics to a clinically relevant extent.
Gender and race have no clinically relevant effects on the pharmacokinetics of dolutegravir.
Infection with hepatitis C has no clinically relevant effect on exposure to dolutegravir. Data on the effect of hepatitis B are limited.
The pharmacokinetics of dolutegravir in adolescents is comparable to that of adults. However, due to the lack of data, dolutegravir is not recommended in patients younger than 18 years of age.
Lamivudine is well absorbed from the gastrointestinal tract and the bioavailability in adults is normally between 80% and 85%. Following oral administration, the mean time (Tmax) to maximum serum concentrations (Cmax) is about an hour.
No dose adjustment is needed when lamivudine is co-administered with food as the bioavailability is not altered. There is, however, a delay in Tmax and a reduction in Cmax.
The mean volume of distribution of lamivudine is 1,3 L/kg.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin. Lamivudine penetrates the central nervous system and reaches the cerebrospinal fluid (CSF). The mean ratio of CSF to serum lamivudine concentration 2 to 4 hours after oral administration was approximately 0,12. The true extent of penetration or relationship with any clinical efficacy is unknown.
The mean systemic clearance of lamivudine is approximately 0,32 L/kg/h, with predominantly renal clearance (>70%) via active tubular secretion, but little (<10%) hepatic metabolism. The likelihood of metabolic medicine interactions with lamivudine is low due to the small extent of hepatic metabolism.
The mean terminal half-life of lamivudine is 5 to 7 hours.
Lamivudine elimination is affected by renal impairment, whether it is disease or age related. Plasma concentrations (AUC) of lamivudine are increased in patients with renal dysfunction due to decreased clearance.
Lamivudine pharmacokinetics are not significantly affected by hepatic impairment.
An interaction with trimethoprim, a component of co-trimoxazole, causes a 40% increase in lamivudine exposure at therapeutic doses. However, a dose adjustment is not required unless the patient also has renal impairment.
Gender and race have no clinically relevant effects on the pharmacokinetics of lamivudine. Co-infection with hepatitis B or C Data on the effect of hepatitis B are limited.
Following oral administration, lamivudine pharmacokinetics in pregnancy are similar to that of non-pregnant adults.
No data are available.
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