Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: Viatris Healthcare (Pty) Ltd, 4 Brewery Street, Isando, Kempton Park, 1600, Republic of South Africa
A 20.2.8 Antimicrobial (Chemotherapeutic) Agents. Antiviral agents.
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, ß and mitochondrial DNA polymerase Ɣ.
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-naïve 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 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 O (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.
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 (t~½~ 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 wildtype subtype B, C, and A/G viruses in the presence of dolutegravir selected for R263K, G118R and S153T.
Reverse Transcriptase Inhibitor-and Protease Inhibitor-Resistant Strains: Dolutegravir demonstrated equivalent potency against 2 non-nucleoside (NN)-RTI-resistant, 3 nucleoside (N)-RTI-resistant and 2 PI-resistant HIV-1 mutant clones (1 triple and 1 sextuple) compared to the wildtype 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.
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 – naïve studies.
The effect of dolutegravir on serum creatinine clearance (CLcr), 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 (CLcr) 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.
Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral lamivudine in adults is normally between 80 to 85%. Following oral administration, the mean time (Tmax) to maximum serum concentration (Cmax) is about an hour. At therapeutic dose levels, i.e. 4 mg/kg/day (as two 12-hourly doses), Cmax is in the order of 1-1,5 μg/ml.
From intravenous studies, the mean volume of distribution is 1,3 l/kg and the mean terminal half-life of elimination is 5 to 7 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 observed. 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. The likelihood of adverse drug interactions with lamivudine is low due to the limited metabolism and plasma protein binding and almost complete renal clearance.
Limited data shows lamivudine penetrates somewhat to 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.
The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
Tenofovir disoproxil fumarate is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir in fasted patients is approximately 25%. Following oral administration of a single dose of tenofovir 300 mg to HIV-1 infected patients in the fasted state, maximum serum concentrations (Cmax) are achieved in 1,0 ± 0,4 hrs. Cmax and AUC values are 296 ± 90 ng/ml and 2287 ± 685 ng*h/ml, respectively. The pharmacokinetics of tenofovir are dose proportional over a tenofovir dose range of 75 to 600 mg and are not affected by repeated dosing.
Administration of tenofovir disoproxil fumarate with a high fat meal enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax by approximately 14%. However, administration of tenofovir disoproxil fumarate with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the substance. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 326 ± 119 ng/ml and 3324 ±1 370 ng*h/ml following multiple doses of tenofovir 300 mg once daily in the fed state, when meal content was not controlled.
In vitro binding of tenofovir to human plasma or serum protein is less than 0,7% and 7,2%, respectively, over the tenofovir concentration range 0,01 to 25 μg/ml. The volume of distribution at steady-state is 1,3 ± 0,6 l/kg and 1,2 ± 0,4 l/kg, following intravenous administration of tenofovir 1,0 mg/kg and 3,0 mg/kg.
In vitro studies have determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for the CYP450 enzymes. Following IV administration of tenofovir, approximately 70-80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of tenofovir, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of tenofovir 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
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. It is recommended that the dosing interval for tenofovir be modified in patients with creatinine clearance <50 ml/min or in patients with ESRD who require dialysis (see section 4.2 Posology and method of administration). 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 pharmacokinetics are similar between healthy and HIV-infected subjects. The PK variability of dolutegravir is between low to moderate. In Phase 1 studies in healthy subjects, between-subject CVb% for AUC and Cmax ranged from ~20 to 40% and CƮ from 30 to 65% across studies. The between-subject PK variability of dolutegravir was higher in HIV-infected subjects than healthy subjects. Within-subject variability (CVw%) is lower than between-subject variability.
Dolutegravir is absorbed following oral administration, with median Tmax at 2 to 3 hours post dose for the tablet formulation. The linearity of dolutegravir pharmacokinetics is dependent on dose and formulation. Following oral administration of tablet formulations, dolutegravir exhibited 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. Food increased the extent and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravir depends on meal content: low, moderate and high fat meals increased dolutegravir AUC(0-∞) by 34%, 41%, and 66%, increased Cmax by 46%, 52%, and 67%, prolonged Tmax to 3, 4 and 5 hours from 2 hours under fasted conditions, respectively. These increases are not clinically significant. 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 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 concentrations in CSF exceeded the IC50, supporting the median reduction from baseline in CSF HIV-1 RNA of 2,1 log after 2 weeks of therapy (see 5.1 Pharmacodynamic properties).
Dolutegravir is primarily metabolised via UGT1A1 with a 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 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. Thirty-one percent of the total oral dose is excreted in the urine, represented by ether 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).
Dolutegravir has a terminal half-life of ~14 hours and an apparent clearance (CL/F) of 0,56 l/hr.
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 B 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 NR1l2 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.
© 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.