Source: Health Products Regulatory Authority (ZA) Revision Year: 2025 Publisher: Emcure Pharmaceuticals SA (Pty) Ltd., Arizona House, First floor, South Wing, Aspen Business Park, 1 Madison Avenue, Aspen Lakes, Extension 13, Johannesburg South, 2190
Pharmacotherapeutic group: nucleoside analogue
ATC Code: J05AF05
Lamivudine, a nucleoside reverse transcriptase inhibitor (NRTI), is a selective inhibitor of HIV-1 and HIV-2 replication in vitro.
Lamivudine is metabolised intracellularly to the 5'-triphosphate which has an intracellular half-life of 16-19 hours. 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.
Reduced in vitro sensitivity to lamivudine has been reported for HIV isolates from patients who have received lamivudine therapy.
Lamivudine-resistant HIV-1 mutants are cross-resistant to didanosine and zalcitabine. In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, have emerged.
Lamivudine does not interfere with cellular deoxynucleotide metabolism and has little effect on mammalian cell and mitochondrial DNA content.
Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate and is converted in vivo to tenofovir. It is a nucleoside reverse transcriptase inhibitor.
Tenofovir is phosphorylated by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase, by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation in DNA, by chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β and mitochondrial DNA polymerase γ.
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro and a K65R mutation in reverse transcriptase have been selected in vitro and, in some patients, treated with tenofovir in combination with certain antiretroviral medicines. In treatment naϊve patients treated with tenofovir + lamivudine + efavirenz, viral isolates from 17% patients with virologic failure showed reduced susceptibility to tenofovir.
In treatment-experienced patients, some of the tenofovir-treated patients with virologic failure through week 96 showed reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 reverse transcriptase gene resulting in the K65R amino acid substitution.
Cross-resistance among certain reverse transcriptase inhibitors has been recognised. The K65R mutation can also be selected by abacavir, didanosine or zalcitabine and results in Page 33 of 43 reduced susceptibility to these medicines plus lamivudine, emtricitabine and tenofovir. Tenofovir disoproxil fumarate should be avoided in antiretroviral experienced patients with strains harbouring the K65R mutation. Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir disoproxil fumarate.
The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 has been assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) values for tenofovir were in the range of 0,04 μM to 8,5 μM. In medicine combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed.
Tenofovir displayed antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, G, and 0 (IC50 values ranged from 0,5 μM to 2,2 μM). The IC50 values of tenofovir against HIV-2 ranged from 1,6 μM to 4,9 μM.
Pharmacokinetic studies have not been performed in children (<18 years) or in the elderly (>65 years).
Tenofovir pharmacokinetics after a 300 mg single dose have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. Change in tenofovir dosing is not required in patients with hepatic impairment.
Tenofovir pharmacokinetics are altered in patients with renal impairment. In patients with creatinine clearance <50 ml/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-∞ of tenofovir were increased. Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir, a four-hour haemodialysis session removed approximately 10% of the administered tenofovir dose.
Dolutegravir 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 vitro, dolutegravir dissociates slowly from the active site of the wild-type integrase-DNA complex (t1/2 71 hours).
Viruses highly resistant to dolutegravir have not been observed during HIV-1 passage. During wild-type HIV-1 passage in the presence of dolutegravir integrase substitutions observed were S153Y and S153F with FCs ≤ 4,1 for strain IIIB, or E92Q with FC = 3,1 and G193E with FC = 3,2 for strain NL432. Additional passage of wild-type subtype B, C, and A/G viruses in the presence of dolutegravir selected for R263K, G118R and S153T.
Anti-HIV activity Against Resistant Strains: Reverse Transcriptase Inhibitor-and Protease Inhibitor-Resistant Strains: Dolutegravir demonstrated equivalent potency against 2 non-nucleoside (NN)-RTl-resistant, 3 nucleoside (N)-RTl-resistant and 2 Pl- resistant HIV-1 mutant clones (1 triple and 1 sextuple) compared to the wild-type strain.
Integrase Inhibitor-Resistant HIV-1 Strains: Dolutegravir showed anti-HIV activity (susceptibility) with FC < 5 against 27 of 28 integrase inhibitor -resistant mutant viruses with single substitutions including T66A/I/K, E92Q/V, Y143C/H/R, Q148H/K/R, and N155H.
Site directed mutant HIV-2 viruses were constructed based on subjects infected with HIV-2 and treated with raltegravir who showed virologic failure. Overall, the HIV-2 FCs observed were similar to HIV-1 FCs observed for similar pathway mutations.
Integrase inhibitor naϊve patients: No integrase inhibitor (INI) resistant mutations or treatment emergent resistance to the NRTI backbone therapy were isolated with dolutegravir 50 mg once daily in treatment-naϊve studies.
The effect of dolutegravir on serum creatinine clearance (CrCI), glomerular filtration rate (GFR) using iohexol as the probe and effective renal plasma flow (ERPF) using para-aminohippurate (PAH) as the probe was evaluated.
A small decrease of 10-14% in mean serum creatinine clearance (CrCI) was observed with dolutegravir within the first week of treatment. Dolutegravir had no significant effect on glomerular filtration rate (GFR) or the effective renal plasma flow (ERPF). In vitro studies suggest that the increases in creatinine observed in clinical studies are due to the non-pathologic inhibition of the organic cation transporter 2 (OCT2) in the proximal renal tubules, which mediates the tubular secretion of creatinine.
The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected adolescents (12 to <18 years of age) showed that dolutegravir 50 mg once daily dosage resulted in dolutegravir exposure comparable to that observed in adults who received dolutegravir 50 mg once daily.
Table 1. Adolescent pharmacokinetic parameters:
| Age/weight | Dolutegravir Dose | Dolutegravir Pharmacokinetic Parameter Estimates Geometric Mean (CV %) | ||
|---|---|---|---|---|
| AUC(0-24) μg.hr/ml | Cmax μg/ml | C24 μg/ml | ||
| 12 to <18 years ≥40 kga | 50 mg once dailya | 46 (43) | 3,49 (38) | 0,90 (59) |
a one subject weighing 37 kg received 35 mg once daily.
Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir exposure. Pharmacokinetic data for dolutegravir in subjects of >65 years old are limited.
Renal clearance of unchanged medicine is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment (CLcr <30 mL/min). No clinically important pharmacokinetic differences between subjects with severe renal impairment (CLcr <30 mL/min) and matching healthy subjects were observed, AUC, Cmax, and C24 of dolutegravir were decreased by 40%, 23%, and 43%, respectively, compared with those in matched healthy subjects.
No dosage adjustment is necessary for patients with renal impairment. Dolutegravir has not been studied in patients on dialysis, though differences in exposure are not expected.
Dolutegravir is primarily metabolised and eliminated by the liver. In a study comparing 8 subjects with moderate hepatic impairment (Child-Pugh category 8 score 7 to 9) to 8 matched healthy adult controls, the single 50 mg dose exposure of dolutegravir was similar between the two groups. No dosage adjustment is necessary for patients with mild hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.
There is no evidence that common polymorphisms in metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samples collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n=41). Polymorphisms in CYP3A4, CYP3A5, and NR1I2 were not associated with differences in the pharmacokinetics of dolutegravir.
Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited data on subjects with hepatitis B co-infection.
Lamivudine is well absorbed from the gastrointestinal tract and the bioavailability of oral lamivudine in adults is normally between 80% and 85%. The mean Cmax for lamivudine in LAVEM is 2283,8279 ng/ml, the mean time (Tmax) to maximum serum concentration (Cmax) is 2,240 hours and the mean terminal half-life T1/2 is 4,2651 hours. 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. No dose adjustment is needed when co-administered with food as lamivudine bioavailability is not altered, although a delay in Tmax and reduction in Cmax have been reported.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin.
Lamivudine elimination will be affected by renal impairment, whether it is disease- or age-related. A recommended dosage regimen for patients with creatinine clearance below 50 ml/min is shown in the dosage section.
Co-administration of zidovudine results in a 13% increase in zidovudine exposure and a 28% increase in peak plasma levels. This is not considered to be of significance to patient safety and therefore no dosage adjustments are necessary. The likelihood of adverse drug interactions with lamivudine is low due to the limited metabolism and plasma protein binding and almost complete renal clearance.
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40% increase in lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment. Administration of co-trimoxazole with the lamivudine/zidovudine combination in patients with renal impairment should be carefully assessed. Limited data shows lamivudine penetrates the central nervous system and reaches the cerebrospinal fluid (CSF). The mean ratio CSF/serum lamivudine concentration 2-4 hours after oral administration was approximately 0,12. The true extent of penetration or relationship with any clinical efficacy is unknown.
In general, lamivudine pharmacokinetics in paediatric patients are similar to adults. However, absolute bioavailability of lamivudine (approximately 58-66%) was reduced in paediatric patients below 12 years of age.
In addition, systemic clearance values were greater in younger paediatric patients and decreased with age approaching adult values around 12 years of age. Recent findings indicate that exposure in children 2 to <6 years of age may be reduced by about 30% compared with other age groups. At present, the available data do not suggest that lamivudine is less efficacious in this group. There are limited pharmacokinetic data for patients less than three months of age. In neonates one week of age, lamivudine oral clearance was reduced when compared to paediatric patients and is likely to be due to immature renal function and variable absorption.
Following oral administration, lamivudine pharmacokinetics in late-pregnancy were similar to non-pregnant women. Administration of lamivudine in animal toxicity studies at very high doses was not associated with any major organ toxicity. The clinically relevant effects noted were a reduction in red blood cell count and neutropenia.
Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, showed activity in an in vitro cytogenic assay. Lamivudine was not genotoxic in vivo at doses that gave plasma concentrations around 30-40 times higher than the anticipated clinical plasma levels.
As the in vitro mutagenic activity of lamivudine could not be confirmed in in vivo tests it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing treatment. There is yet no information on the tumorigenic risk in animals, and therefore any potential risk to man must be balanced against the expected benefits of treatment.
Tenofovir DF has an oral bioavailability of 25%. A high-fat meal increases the oral bioavailability to 39%, but the medicine can be taken without food. Tenofovir is not bound significantly to plasma proteins. The mean Cmax for tenofovir in LAVEM is 354,7628 ng/ml, the mean time (Tmax) to maximum serum concentration (Cmax) is 1,317 hours and the mean terminal half-life T1/2 is 18,4231 hours.
Tenofovir undergoes both glomerular filtration and active tubular secretion. Between 70% and 80% of an intravenous dose is recovered unchanged in the urine.
The mean Cmax for dolutegravir in LAVEM is 3056,8828 ng/ml and the mean time (Tmax) to maximum serum concentration (Cmax) is 3,042 hours. 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, increase in dolutegravir exposure appears dose proportional from 25 mg to 50 mg.
Dolutegravir may be administered with or without food. The absolute bioavailability of dolutegravir has not been established.
Dolutegravir is highly bound (approximately 99,3%) to human plasma proteins based on in vitro data. The apparent volume of distribution (following oral administration of suspension formulation, Vd/F) is estimated at 12,5 L. Binding of dolutegravir to plasma proteins was independent of concentration. Total blood and plasma drug-related radioactivity concentration ratios averaged between 0,441 to 0,535 indicating minimal association of radioactivity with blood cellular components. Free fraction of dolutegravir in plasma 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 primarily metabolised via UGT1A1 with minor CYP3A component (9,7%) of total dose administered in a human mass balance study). Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged medicine is low (<1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in 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. Thirty-one percent of the total oral dose is excreted in the urine, represented by either glucuronide of dolutegravir (18, 9% of 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 terminal half-life T1/2 for dolutegravir in LAVEM is 17,2772 hours. Dolutegravir has an apparent clearance (CL/F) of 0,56 L/hr.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.