Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Adcock Ingram Limited, 1 New Road, Erand Gardens, Midrand, 1685 Customer Care: 0860 ADCOCK (232625)
Pharmacotherapeutic group: A 20.2.8 Antimicrobial (chemotherapeutic) agents. Antiviral agents. Antivirals for treatment of HIV infections, combinations
ATC code: J05AR27
NUVACO is an HIV-1 antiretroviral fixed-dose combination product containing lamivudine, tenofovir disoproxil fumarate and dolutegravir.
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 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-naїve 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 (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 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 nonnucleoside (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/l/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.
Resistance in vivo: integrase inhibitor-naїve 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 – naїve studies.
Lamivudine is absorbed following oral administration. Bioavailability is between 80-85% and is not affected by food. Following oral administration, the mean time (Tmax) to maximum serum concentration (Cmax) is approximately 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.
Intravenous studies with lamivudine showed that the mean apparent volume of distribution is 1,3 L/kg.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin.
The mean terminal half-life of elimination is 5 to 7 hours. Lamivudine elimination will be affected by renal impairment, whether it is disease- or age-related. 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 dosage 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.
Dose reduction is recommended for patients with creatinine clearance ≤80 mL/min.
Following oral administration of tenofovir disoproxil fumarate in HIV1- infected patients, tenofovir disoproxil fumarate is absorbed and converted to tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients is approximately 25%. 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%. Food delays the time to tenofovir Cmax by approximately 1 hour.
In vitro binding of tenofovir to human plasma or serum proteins is <0,7% and 7,2%, respectively, over the tenofovir concentration range 0,01 to 25 µg/mL.
Following single dose, oral administration of tenofovir disoproxil fumarate, the reported terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of tenofovir disoproxil fumarate 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.
Tenofovir pharmacokinetics are similar in male and female patients. Pharmacokinetic studies have not been performed in children (<18 years) or in the elderly (over 65 years).
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). 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 is absorbed following oral administration, with median Tmax at 2 to 3 hours post dose for 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 ln 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 (>99%) 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 is independent of dolutegravir concentration. Total blood and plasma medicine-related radioactivity concentration ratios averaged between 0,441-0,535; indicating minimal association of radioactivity with blood cellular components. It is reported that 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.
Dolutegravir is primarily metabolised via UGT1A1 with a minor CYP3A component. Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged active substance is low (<1% of the dose). 53% of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. 32% 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/h.
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 oral dosage resulted in dolutegravir exposure comparable to that observed in adults who received dolutegravir 50 mg orally once daily.
Table 1. Adolescent pharmacokinetic parameters:
| Age/weight | Dolutegravir dose | Dolutegravir pharmacokinetic parameter estimates Geometric mean (CV %) | ||
|---|---|---|---|---|
| AUC 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.
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 of age 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 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 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 for NUVACO alone, is necessary for patients with renal impairment. Dolutegravir has not been studied in patients on dialysis, though differences in exposure are not expected.
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 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.
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 considered 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 patients with hepatitis B co-infection.
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