Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Austell Pharmaceuticals (Pty) Ltd, 1 Sherborne Road, Parktown, JOHANNESBURG, 2193, South Africa Tel: 0860287835 Manufactured by Lupin Ltd, imported and distributed by Austell Pharmaceuticals (Pty) Ltd. ...
Pharmacological Classification/Category and Class: A.20.2.8 Antiviral agents
Dolutegravir:
Direct acting antivirals, other antivirals
ATC code: J05AX12
Lamivudine and tenofovir disoproxil:
Direct acting antivirals, Antivirals for treatment of HIV infections, combinations
ATC code: J05AR12
Lamivudine, a nucleoside reverse transcriptase inhibitor (NRTI), is a selective inhibitor of HIV1 and HIV-2 replication in vitro.
Lamivudine is metabolised intracellularly to the active 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 DNA 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 and in combination with certain antiretroviral medicines.
In treatment naïve patients treated with tenofovir + lamivudine + efavirenz, viral isolates from 17% of 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 selected by tenofovir is also selected in some HIV-1 infected patients treated with 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 reported.
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 (t½ 71 hours).
Isolation from wild-type HIV-1 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 S135Y 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.
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 wild-type strain.
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. Integrase Inhibitor-Resistant HIV-2 Strains Site directed mutant HIV-2 viruses were constructed based on patients 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 naïve 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-naïve studies.
The effect of dolutegravir on serum creatinine clearance (CrCl), glomerular filtration rate (GFR) using iohexol as the probe and effective renal plasma flow (ERPF) using paraaminohippurate (PAH) as the probe was evaluated. A small decrease of 10-14 % in mean serum creatinine clearance (CrCl) 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 increase 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% and 85%. 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. 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.
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 an 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.
Tenofovir disoproxil fumarate is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate 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.
Administration of tenofovir following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of tenofovir with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the medicine. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 326 ± 119 ng/mL and 3324 ± 1370 ng h/mL following multiple doses of tenofovir 300 mg once daily in the fed state, when meal content was not controlled.
The mean volume of distribution is 1,3 L/kg and the mean terminal half-life of elimination is 5 to 7 hours.
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 medicine-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 patients, approximately 0,4 to 0,5% in patients with moderate hepatic impairment and 0,8 to 1,0% in patients with severe renal impairment and 0,5% in HIV-1 infected patients. Dolutegravir is present in cerebrospinal fluid (CSF). In 13 treatment-naïve patients on a stable dolutegravir plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable to unbound plasma concentration, and above the IC50); CSF: plasma concentration ratio of dolutegravir ranged from 0,11 to 0,66%.
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 section 5.1).
In vitro binding of tenofovir to human plasma or serum proteins 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.
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 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 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.
Dolutegravir has a terminal half-life of ~14 hours and an apparent clearance (Cl/F) of 0,56 L/hr.
In vitro studies reported that neither tenofovir disoproxil nor tenofovir are substrates of CYP450 enzymes. 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.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin.
Dolutegravir pharmacokinetics are reported as similar between healthy and HIV-infected patients. The PK variability of dolutegravir is between low to moderate.
The pharmacokinetics of tenofovir are dose proportional over a dose range of 75 to 600 mg and are not affected by repeated dosing.
Dolutegravir is primarily metabolised and eliminated by the liver. In a study comparing 8 patients 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.
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.
Lamivudine elimination will be affected by renal impairment, whether it is disease- or agerelated.
Renal clearance of unchanged medicine is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in patients with severe renal impairment (CLcr <30 mL/min). No clinically important pharmacokinetic differences between patients with severe renal impairment (CLcr <30 mL/min) and matching healthy patients were observed, AUC, Cmax and C24 of dolutegravir were decreased by 40%, 23% and 43% respectively, compared with those in matched healthy patients. 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.
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). 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.
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 patients, patients with UGT1A1 (n=7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with patients 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 patients with hepatitis B coinfection.
Lamivudine:
Lamivudine pharmacokinetics in late-pregnancy were similar to non-pregnant adults. Administration of lamivudine in reported 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 as 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:
Pharmacokinetic studies have not been performed in children (<18 years)
Dolutegravir:
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 9. Adolescent pharmacokinetic parameters:
| Dolutegravir Pharmacokinetic Parameter Estimates Geometric Mean (CV %) | ||||
|---|---|---|---|---|
| Age/Weight Dolutegravir dose | Age/Weight Dolutegravir dose | 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 patient weighing 37 kg received 35 mg once daily.
Tenofovir:
Pharmacokinetic studies have not been or in the elderly (>65 years).
Dolutegravir:
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 patients >65 years old are limited.
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