Source: Health Products Regulatory Authority (ZA) Publisher: GlaxoSmithKline South Africa (Pty) Ltd, 39 Hawkins Avenue, Epping Industria 1, 7460
A 20.2.8 Antiviral agents
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. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2,7 nM and 12,6 nM in vitro, dolutegravir dissociates slowly from the active site of the wild type integrase-DNA complex (t½ 71 hours).
Abacavir and lamivudine are nucleoside reverse transcriptase inhibitors (NRTIs) and are selective inhibitors of HIV-1 and HIV-2. Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the respective triphosphate (TP) which are the active moieties with extended intracellular half-lives supporting once daily dosing (see Pharmacokinetic properties, Elimination). Lamivudine-TP and carbovir-TP (the active triphosphate form of abacavir) are substrates for and competitive inhibitors of HIV reverse transcriptase (RT). However, their main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Abacavir and lamivudine triphosphates show significantly less affinity for host cell DNA polymerases.
No integrase inhibitor-resistant mutations or treatment emergent resistance to the NRTI backbone therapy were isolated with dolutegravir 50 mg once daily in treatment-naïve studies (SPRING-1, SPRING-2 and SINGLE studies). In the SAILING study for treatment experienced (and integrase naïve) patients (n=354 in the dolutegravir arm), treatment emergent integrase resistance was observed in 2 of 9 subjects with virologic failure. In both cases, a unique R263K integrase substitution was observed, with a maximum FC of 1,93.
Abacavir-resistant isolates of HIV-1 have been selected in vitro and in vivo and are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115F). During in vitro abacavir selection the M184V mutation occurred first and resulted in about a two-fold increase in IC50, below the abacavir clinical cut-off of 4,5-FC. Continued passage in increasing concentrations of medicine resulted in selection for double RT mutants 65R/184V and 74V/184V or triple RT mutant 74V/115Y/184V. Two mutations conferred a 7- to 8-FC in abacavir susceptibility and combinations of three mutations were required to confer more than an 8-FC in susceptibility.
HIV-1 resistance to lamivudine involves the development of a M184I or M184V amino acid change close to the active site of the viral RT. This variant arises both in vitro and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. M184V is associated with a low level increase in abacavir resistance but does not confer clinical resistance for abacavir. Isolates resistant to abacavir may also show reduced sensitivity to lamivudine. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the substitutions K65R with or without the M184V/I substitution, and to viruses with L74V plus the M184V/I substitution.
A 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 the glomerular filtration rate (GFR) or the effective renal plasma flow (ERPF). In vitro studies suggest that the increases in serum creatinine observed in clinical studies are due to the nonpathologic inhibition of the organic cation transporter 2 (OCT2) in the proximal renal tubules, which mediates the tubular secretion of creatinine.
The TRELAVUE tablet has been shown to be bioequivalent to dolutegravir single entity tablet with abacavir/lamivudine fixed dose combination tablet administered separately. There was no clinically significant effect of a high fat meal on the exposure of abacavir or lamivudine with dolutegravir; a high fat meal increased the Cmax by 37% and the AUC by 48%. These results indicate that TRELAVUE can be taken with or without food. The pharmacokinetic properties of dolutegravir, lamivudine and abacavir are described below.
Dolutegravir, abacavir and lamivudine are absorbed following oral administration. The absolute bioavailability of dolutegravir has not been established. The absolute bioavailability of oral abacavir and lamivudine in adults is 83% and 80 to 85% respectively. The mean time to maximal serum concentrations (tmax) is about 2 to 3 hours (post dose for tablet formulation) for dolutegravir, 1,5 hours for abacavir and 1,0 hours for lamivudine.
Following multiple oral doses of dolutegravir 50 mg once daily, the geometric mean steady state pharmacokinetic parameter estimates are 53,6 μg.h/ml for AUC24, 3,67 μg/ml for Cmax, and 1,11 μg/ml for C24. Following a single oral dose of 600 mg of abacavir, the mean Cmax is 4,26 μg/ml and the mean AUC∞ is 11,95 μg.h/ml. Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days the mean steady-state Cmax is 2,04 μg/ml and the mean AUC24 is 8,87 μg.h/ml.
The apparent volume of distribution of dolutegravir (following oral administration of suspension formulation, Vd/F) is estimated at 12,5 l. Intravenous studies with abacavir and lamivudine showed that the mean apparent volume of distribution is 0,8 and 1,3 l/kg respectively.
Dolutegravir is highly bound (approximately 99,3%) to human plasma proteins based on in vitro data. 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 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. Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (approximately 49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%).
Dolutegravir, abacavir and lamivudine are present in cerebrospinal fluid (CSF). CSF:plasma concentration ratio of dolutegravir ranged from 0,11 to 2,04%. Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. The mean ratio of CSF/serum lamivudine concentrations 2 to 4 hours after oral administration was approximately 12%.
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).
Abacavir is primarily metabolised by the liver with less than 2% of the administered dose being renally excreted as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5'-carboxylic acid and 5'-glucuronide which account for about 66% of the administered dose. These metabolites are excreted in the urine.
Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic interactions with lamivudine is low due to the small extent of hepatic metabolism (less than 10%).
Dolutegravir has a terminal half-life of ~ 14 hours and an apparent clearance (CL/F) of 0,56 l/hr.
The mean half-life of abacavir is about 1,5 hours. The geometric mean terminal half-life of intracellular carbovir-TP at steady-state is 20,6 hours. Following multiple oral doses of abacavir 300 mg twice a day, there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces.
The observed lamivudine half-life of elimination is 5 to 7 hours. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was prolonged to 16 to 19 hours. The mean systemic clearance of lamivudine is approximately 0,32 l/h/kg, predominantly by renal clearance (greater than 70%) via the organic cationic transport system.
A paediatric study on 10 antiretroviral treatment-experienced HIV-1 infected adolescents aged 12 to 18 years of age, showed that dolutegravir 50 mg once daily resulted in dolutegravir exposure in adolescent subjects comparable to that observed in adults who received dolutegravir 50 mg once daily (Table 1).
Table 1. Adolescent pharmacokinetic parameters (n=10):
| 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.
Limited data are available in adolescents receiving a daily dose of 600 mg of abacavir and 300 mg of lamivudine. Pharmacokinetic parameters are comparable to those reported in adults.
Pharmacokinetic data for dolutegravir, abacavir and lamivudine in subjects of > 65 years old are limited.
Pharmacokinetic data have been obtained for dolutegravir, abacavir and lamivudine alone. TRELAVUE should not be used in patients with creatinine clearance of less than 50 ml/min because, whilst no dosage adjustment of dolutegravir or abacavir is necessary in patients with renal impairment, dose reduction is required for the lamivudine component. Therefore, the separate preparation of lamivudine should be used to treat these patients.
Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance.
Abacavir is primarily metabolised by the liver, with approximately 2% of abacavir excreted unchanged in the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar to patients with normal renal function.
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. Dolutegravir has not been studied in patients on dialysis, though differences in exposure are not expected.
Pharmacokinetic data has been obtained for dolutegravir, abacavir and lamivudine alone. Based on data obtained for abacavir, TRELAVUE is not recommended in patients with moderate and severe hepatic impairment.
Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5 to 6). The results showed that there was a mean increase of 1,89 fold in the abacavir AUC and 1,58 fold in the half-life of abacavir. The AUCs of the metabolites were not modified by the liver disease. However, the rates of formation and elimination of these were decreased. Dosage reduction of abacavir may be required in patients with mild hepatic impairment. The separate preparation of abacavir should therefore be used to treat these patients. The pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic impairment. Plasma concentrations of abacavir are expected to be variable and substantially increased in these patients. TRELAVUE is therefore not recommended in patients with moderate and severe hepatic impairment.
Data obtained for lamivudine in patients with moderate to severe hepatic impairment and for dolutegravir in patients with moderate hepatic impairment show that the pharmacokinetics are not significantly affected by hepatic dysfunction. Dolutegravir is primarily metabolised and eliminated by the liver. In a study comparing 8 subjects with moderate hepatic impairment (Child-Pugh category B) to 8 matched healthy adult controls, the single 50 mg dose exposure of dolutegravir was similar between the two groups. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.
There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent.
Population PK analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited pharmacokinetic data on subjects with hepatitis B co-infection (see WARNINGS AND SPECIAL PRECAUTIONS for the use of TRELAVUE in patients co-infected with hepatitis B).
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