Pharmacodynamics
Mechanism of Action
Dolutegravir inhibits HIV integrase by binding to the active site of integrase and blocking the chain transfer step during integration of retroviral deoxyribonucleic acid (DNA), which is necessary for the HIV replication cycle.
In a biochemical chain transfer assay using purified HIV-1 integrase and pretreated DNA substrate, IC50 (concentration that inhibits replication by 50%) values of 2.7 nM and 12.6 nM were obtained. In vitro, dolutegravir dissociates slowly from the active center of the wild-type DNA integrase complex (t1/2 71 hours).
Pharmacodynamic effects
. In a randomized trial to determine the optimal dose in HIV-1-infected patients who received dolutegravir monotherapy (ING111521), rapid and dose-dependent antiviral effects were observed, with mean HIV-1 RNA reduction at day 11 compared with baseline of 1.5, 2.0 and 2.5 log10 for 2mg, 10mg, and 50mg of dolutegravir when taken once daily, respectively.
This antiviral response was maintained for 3-4 days from the last dose in the group of patients taking 50 mg of dolutegravir.
Antiviral activity in cell culture
In peripheral blood mononuclear cells (PBMCs) infected with HIV-1 strain Bal or HIV-1 strain NL432, IC50 0.51 nM 0.53 nM were obtained for dolutegravir, respectively. In MT-4 cells infected with strain 1MB HIV-1 and incubated with dolutegravir for 4 or 5 days, IC50 0.71 and 2.1 nM were obtained.
In a viral integrase sensitivity assay using the integrase coding site of 13 clinically distinct subtype B isolates, dolutegravir demonstrated antiviral activity similar to that against laboratory strains, with an average IC50 of 0.52 nM.
In an ICRP analysis of a panel consisting of 24 clinical HIV-1 isolates [group M (subtypes A, B. C, D, E, F, and G) and group O] and 3 clinical HIV-2 isolates, the geometric mean IC50 was 0.20 nM, and IC50 values ranged from 0.02 to 2.14 nM for HIV-1, whereas for HIV-2 isolates the geometric mean IC50 was 0.18 nM. and IC50 values ranged from 0.09 to 0.61 nM.
Antiviral activity in combination with other antiviral drugs
None of the drugs with typical antiviral activity against HIV exhibited antagonism to dolutegravir [in vivo assessments were performed in combination with stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir and raltegravir, selected in staggered order].
In addition, antiviral drugs without typical HIV activity (ribavirin) had no apparent effect on dolutegravir activity
The effects of human serum and serum proteins
In-vitro studies confirmed a 75-fold change (CI) of IC50 of dolutegravir in the presence of 100% human serum (extrapolation method), and IC90, adjusted for protein binding (PA-IC90), in ICPC was 64 ng/mL.
The minimum concentration of dolutegravir after a single dose of 50 mg in patients who had not previously taken integrase inhibitors (INIs) was 1.20 µg/mL, 9 times the established PA-IC90.
In vitro resistance
HIV-1 wild-type isolates: no viruses with high resistance to dolutegravir were detected during the 112-day passages of strain IIIB. The maximum 4.1-fold change was observed in resistant virus groups obtained in passages with SI53Y and S153F replacements in conserved positions of the integrase gene.
Passage of wild-type HIV-1 strain HL432 in the presence of dolutegravir resulted in selection of the 92Q (crossed virus group with CI = 3.1) and G193B (crossed virus group with CI 3.2) replacements at day 56. Additional passaging of B. C and A/G subtypes of wild-type virus in the Presence of dolutegravir resulted in selection of R263K. Gl 18R and S153T.
Antiviral activity against resistant strains: strains resistant to reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs): Aolutegravir showed equal activity against 2 non-nucleoside (NN)-IOT-resistant, 3 nucleoside (H)-IOT-resistant, and 2 AI-resistant mutant HIV-1 clones (1 with triple and 1 with sixfold resistance) compared with the wild-type strain.
Ipi-resistant HIV-1 strains: 60 IP-resistant mutant HIV-1 isolates (28 with one substitution and 32 with 2 or more substitutions) were derived from wild-type BL432 virus by site-directed mutagenesis.
Dolutegravir demonstrated antiviral activity (sensitivity) against HIV with KI < 5 against 27 of 8 mutant AI-resistant viruses with one substitution, including T66A/I/K. E92Q/V, 43C/M/R. Q148H/K/R and N15511, while for raltegravir and elvitegravir, sgivability was evident against 17/28 and 11/21 mutant viruses tested with CI < 5. respectively.
In addition, of the 32 mutant viruses resistant to AI with 2 or more substitutions, 23 of 32 demonstrated CI < 5 for dolutegravir compared with CI < 5 for 4 of 32 for raltegravir and CI < 5 for 2 of 25 tested viruses for titegravir.
The HIV-2 strains resistant to AI: viruses were obtained by site-directed mutagenesis of HIV-2 isolates isolated from HIV-2-infected patients who were receiving raltegravir and who had virologic treatment failure.
In general, the CIs in HIV-2 were similar to those of HIV-1, which were observed with a similar set of mutations. The CI of dolutegravir was < 5 against 4 HIV-2 viruses (S163D, G140A/Q148R, A153G/N155H/S163G, and I292Q/T97A/N155H/S163D); for E92Q/N155II the CI of dolutegravir was 8.5, and for G140S/QI48R the CI of dolutegravir was 17.
Dolutegravir, raltegravir, and elvitegravir showed similar activity against HIV-2 with a site-directed mutation with SI63D as against the wild type, and for the remaining mutant HIV-2 viruses, the CI ranges of raltegravir were 6.4-420 and the CI ranges of elvitegravir were 22-640.
Clinical isolates in patients with virologic ineffectiveness of raltegravir treatment: 30 clinical isolates with genotypic and phenotypic resistance to raltegravir (median CI >81) were tested for sensitivity to olutegravir (median CI 1.5) by analysis with Monogram Biosciences PlienoSense.
The median CI of dolutegravir for isolates with substitutions at positions 140S-I-Q148II was 3.75: G140S + Q148R was 13.3: T97A + Y143R – 1.05 and 15511 – 1.37. 705 raltegravir-resistant isolates obtained from patients receiving raltegravir were analyzed for sensitivity to dolutegravir by analysis with Monogram Biosciences PhenoSense.
Dolutegravir exhibited KI<10 against 93.9% of 705 clinical isolates, with 16 (9%) of 184 QI48 + 1 substituted isolates with resistance to AI and 25 (27%) of 92 clinical isolates with Q148 +>2 substituted isolates with resistance to AI showing more than a 10-fold change.
In vivo resistance: Patients who did not take InI
No mutations of InI resistance or treatment-associated resistance to nucleoside reverse transcriptase inhibitors (NRTIs) basis therapy were observed in previously untreated patients who were taking 50 mg of dolutegravir once daily ( SPRING-1, SPRING-2, SINGLE and FLAMINGO studies).
In the SAILINGy study of patients receiving dolutegravir who had not previously received InI (n = 354 in the delutegravir group), treatment-related replacements in integrase were observed at 48 weeks in 4 of 17 patients with virologic ineffectiveness receiving dolutegravir.
Two of 4 patients had a unique R263K substitution in the integrase gene with a maximum FC of 1.93, 1 patient had a polymorphic V151V/I integrase substitution with a maximum FC of 0.92, and 1 patient had an initial integrase mutation and was thought to have previously received an AI or had been infected with an AI-resistant virus.
In vivo resistance: InI-resistant patients
The VIKING-3 study examined dolutegravir (plus optimized baseline therapy) in patients with existing resistance to InI. Up to 24 weeks, 36 of 183 patients had protocol-established virologic ineffectiveness (RDVF).
Of these, 32 patients had paired baseline and PDVF resistance for analysis. and 17/32 (53%) had treatment-associated mutations, the following treatment-associated mutations or mutation combinations were observed: L74L/M (n = 1), E92Q (n = 2), T97A (n = 9), E138K/A/T (n = 8), G140S (n = 2), Y143H (n = 1). S147G (n=l), Q148H/K/R (n = 4). N155II (n=1) and E157E/Q (n=1).
14 of 17 patients with treatment-associated viral mutations had a C 148 mutation at baseline or in the history. Five other patients had PDVF between weeks 24 and 48 and 2 of these 5 patients had mutations that occurred during treatment. The observed mutations that occurred during treatment or combinations of mutations were L74I (n = 1), M55H(n = 2).
The VIKING-4 study examined dolutegravir (plus optimized baseline therapy) in 30 patients with primary genotypic resistance to Ini identified at screening. The mutations arising during treatment were consistent with those observed in the VIKING-3 study.
Effects on electrocardiogram (ECG)
In a randomized, crossover, placebo-controlled clinical trial, 42 healthy volunteers received a single dose of placebo, dolutegravir 250 mg suspension (approximately 3 times the exposure to 50 mg once daily in equilibrium) and moxifloxacin (400 mg, active control) in a randomized order.
Dolutegravir did not cause prolongation of the corrected interval (QTc) within 24 hours of drug administration. After correction by baseline ECG readings and placebo administration, the maximum mean change in QTc based on correction by the Frederick formula (QTcF) was 1.99 msec (upper limit of the 1-way 95% confidence interval, 4.53 msec).
Impact on renal function
. The effects of dolutegravir on serum creatinine clearance (CK), cystic filtration rate (CFR) in the yogxsol assay and effective renal plasma flow (EPP) in the para-aminogipiurate assay were evaluated in an open randomized, placebo-controlled, 3-group study involving 37 healthy volunteers, who took 50 mg of dolutegravir once daily (n = 12), 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days.
There was a moderate decrease in CK with dolutegravir during the first week of treatment, consistent with the decrease seen in clinical trials.
In both doses, dolutegravir had no significant effect on GFR or EPP these findings are supported by in vitro studies, which suggest that the small increases in creatinine seen in clinical trials are due to nonpathological inhibition of the organic cation transporter (OCT2) in proximal renal tubules, which accounts for the tubular secretion of creatinine.
Pharmacokinetics
The pharmacokinetics of dolutegravir are similar in healthy volunteers and HIV-infected patients. The variability in the pharmacokinetics of dolutegravir was low to moderate.
In Phase 1 studies involving healthy volunteers, the coefficient of variation (KB) among participants for the area under the pharmacokinetic concentration-time curve (AUC) and for maximum concentration (C mah) ranged from 20 to 40%, and the end-of-dosing interval concentration (Cmax) ranged from 30 to 65%. Individual variability in dolutegravir pharmacokinetics between participants was higher in HIV-infected patients than in healthy volunteers. Individual variability in pharmacokinetics was lower than variability between individuals.
Introduction
Dolutegravir is rapidly absorbed after oral administration, with a median time to reach maximum concentration (Tmax) after a dose in tablet form of 2-3 hours. The linearity of the pharmacokinetics of dolutegravir depends on the dose and the dosage form.
After oral administration, dolutegravir in tablet form generally exhibited nonlinear pharmacokinetics, with a less than dose-dependent increase in plasma exposure from 2 to 100 mg, but the increase in dolutegravir exposure was proportional to the dose from 25 mg to 50 mg.
Dolutegravir can be taken regardless of food intake. Food increases the degree and decreases the rate of absorption of dolutegravir. The bioavailability of dolutegravir is dependent on the lean content: low-, moderate- and high-fat AUQ0-∞) dolutegravir was increased by 33 %, 41 % and 66 %, Cmax was increased by 46 %, 52 % and 67 %, Tmax was prolonged to 3, 4 and 5 hours compared to 2 hours when taken on an empty stomach, respectively. These increases have no clinical significance. The absolute bioavailability of dolutegravir has not been established.
Distribution
According to the data obtained in vitro, dolutegravir is significantly (99.3%) bound to human plasma proteins.
The apparent volume of distribution (after oral administration in the form of suspension, Vd/F) is approximately 12.5 l. The binding of dolutegravir to plasma proteins was independent of the concentration. The ratios of the total concentration of the radioactively labeled drug in blood to plasma were 0.441-0.535, indicating minimal binding of the radioactively labeled drug to cellular components of the blood.
The free plasma fraction of dolutegravir was approximately 0.2-1.1% in healthy volunteers, approximately 0.4-0.5% in patients with moderate hepatic impairment, 0.8-1.0% in patients with severe renal impairment, and 0.5% in patients infected with HIV-1.
Dolutegravir penetrates cerebrospinal fluid (CSF). In 12 previously untreated patients who received dolutegravir and abacavir/lamivudine II for 16 weeks, the mean concentration of dolutegravir in CSF was 15.4 ng/mL at week 2 and 12.6 ng/mL at week 16, with a range of 3.7 to 23.2 ng/mL (comparable to the pretreatment plasma concentration).
The ratio of dolutegravir concentration in CSF to plasma concentration ranged from 0.11 to 2.04%. Concentrations of dolutegravir in CSF exceeded IC50, confirming a median decrease in HIV-1 RNA concentration in CSF compared with baseline concentration at 2.2 log tcl 2 weeks of therapy and 3.4 log after 16 weeks of therapy (see subsection Pharmacodynamics).
Delutegravir is detectable in the male and female genital tracts. The AUC in cervico-vaginal fluid, cervical and vaginal tissues was 6-10% of that in plasma in equilibrium. AUC in seminal fluid was 7% and in rectal tissues 17% of that in blood plasma at equilibrium concentration.
Metabolism
Dolutegravir is primarily metabolized by uridine diphosphate-glucoronosyltransferase UDF-GT1A1 with a minor component of the CYP3A isoenzyme (9.7% of total dose taken in a mass balance study in humans).
Dolutegravir is the major compound circulating in plasma, and is slightly excreted unchanged through the uterus (<1% of the dose). 53% of the total dose taken internally is excreted unchanged through the intestine.
It is unknown whether this is due to incomplete absorption of the drug or to excretion with the bile of the glucuronide conjugate, which may further break down to form related compounds in the intestinal lumen. 31% of the total dose taken orally is excreted through the kidneys in the form of doluguegravir glucuronide ester (18.9% of the total dose). N-dealkylated metabolite (3.6% of total dose) and metabolite formed by benzyl carbon acidification (3.0% of total dose).
Elimination
The final half-life of doluguegravir is approximately 14 hours and apparent clearance (CL/F) is 0.56 L/h.
Indications
Treatment of HIV-1 infection in adults and children over 12 years of age and weighing 40 kg or more as part of combination antiretroviral therapy (APT).
Pharmacological effect
Pharmacodynamics
Mechanism of action
Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step during retroviral deoxyribonucleic acid (DNA) integration, which is essential for the HIV replication cycle.
Biochemical strand transfer assays using purified HIV-1 integrase and pretreated DNA substrate yielded IC50 values of 2.7 nM and 12.6 nM. In vitro, dolutegravir slowly dissociates from the active site of the wild-type DNA integrase complex (t1/2 71 hours).
Pharmacodynamic effects
In a randomized trial to determine the optimal dose in HIV-1-infected patients who received dolutegravir monotherapy (ING111521), rapid and dose-dependent antiviral effects were observed, with mean reductions in HIV-1 RNA at day 11 compared with baseline of 1.5, 2.0, and 2.5 log10 for 2 mg, 10 mg, and 50 mg dolutegravir. when taken once a day, respectively.
This antiviral response was maintained for 3-4 days after the last dose in the group of patients taking 50 mg dolutegravir.
Antiviral activity in cell culture
In peripheral blood mononuclear cells (PBMCs) infected with HIV-1 strain Bal or HIV-1 strain NL432, an IC50 of 0.51 nM and 0.53 nM was obtained for dolutegravir. respectively. IC50s of 0.71 and 2.1 nM were obtained in MT-4 cells infected with HIV-1 strain 1MB and incubated with dolutegravir for 4 or 5 days.
In a viral integrase sensitivity assay using the integrase coding region from 13 clinically distinct subtype B isolates, dolutegravir demonstrated antiviral activity similar to that against laboratory strains, with a mean IC50 of 0.52 nM.
In the analysis of PBMCs of a panel consisting of 24 clinical isolates of HIV-1 [group M (subtypes A, B.C, D, E, F and G) and group O] and 3 clinical isolates of HIV-2, the geometric mean IC50 was 0.20 nM, and IC50 values ranged from 0.02 to 2.14 nM for HIV-1, while for HIV-2 isolates the geometric mean IC50 was 0.18 nM. and IC50 values ranged from 0.09 to 0.61 nM.
Antiviral activity in combination with other antiviral drugs
None of the drugs with typical antiviral activity against HIV showed antagonism to dolutegravir [in vitro evaluations were carried out in combination with stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir and raltegravir, selected in a checkerboard order).
In addition, antiviral drugs without typical activity against HIV (ribavirin) had no apparent effect on the activity of dolutegravir
Influence of blood serum and human serum proteins
In vitro studies confirmed a 75-fold change (CI) in the IC50 of dolutegravir in the presence of 100% human serum (by extrapolation), and the protein-adjusted IC90 (PA-IC90) in PBMC was 64 ng/mL.
The minimum concentration of dolutegravir after a single dose of 50 mg in patients who had not previously taken imtegrase inhibitors (InIs) was 1.20 μg/ml, 9 times higher than the established PA-IC90.
Stability in vitro
Wild-type HIV-1 isolates: No viruses highly resistant to dolutegravir were detected during the 112-day passage of strain IIIB. the maximum 4.1-fold change was observed in groups of resistant viruses obtained during passages with substitutions SI53Y and S153F in conservative positions of the integrase gene.
Passage of wild-type HIV-1 strain HL432 in the presence of dolutegravir resulted in selection of substitutions 92Q (subcultured virus group with CI = 3.1) and G193B (subcultured virus group with CI = 3.2) on day 56. Additional passage of wild-type virus subtypes B.C and A/G in the presence of dolutegravir led to selection of R263K. Gl 18R and S153T.
Antiviral activity against resistant strains: strains resistant to reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs): Aolutegravir demonstrated equal activity against 2 non-nucleoside (N)-RTI-resistant, 3 nucleoside (N)-RTI-resistant and 2 PI-resistant mutant clones of HIV-1 (1 triple-resistant and 1 six-fold resistant) compared to the wild strain.
InI-resistant HIV-1 strains: 60 InI-resistant HIV-1 mutant isolates (28 with one substitution and 32 with 2 or more substitutions) were obtained from wild-type virus BL432 by site-directed mutagenesis.
Dolutegravir demonstrated antiviral activity (sensitivity) against HIV with an CI < 5 against 27 of 8 single-substitution InI-resistant mutant viruses, including T66A/I/K. E92Q/V, 43C/M/R. Q148H/K/R and N15511, while for raltegravir and elvitegravir, susceptibility was observed in 17/28 and 11/21 tested mutant viruses with CI < 5, respectively.
In addition, of the 32 InI-resistant mutant viruses with 2 or more substitutions, 23 of 32 showed an CI < 5 for dolutegravir, compared with an CI < 5 for 4 of 32 for raltegravir and a CI < 5 for 2 of 25 viruses tested for titegravir.
InI-resistant HIV-2 strains: Viruses were generated by site-directed mutagenesis of HIV-2 isolates isolated from HIV-2-infected patients who received raltegravir and experienced virological treatment failure.
In general, the CIs of HIV-2 were similar to those of HIV-1, which were observed with a similar set of mutations. The CI of dolutegravir was <5 against 4 HIV-2 viruses (S163D, G140A/Q148R, A153G/N155H/S163G and I292Q/T97A/N155H/S163D); for E92Q/N155II, the dolutegravir CI was 8.5, and for G140S/QI48R, the dolutegravir CI was 17.
Dolutegravir, raltegravir and elvitegravir showed similar activity against HIV-2 with a site-directed mutation with SI63D as against wild type, and for the remaining mutant HIV-2 viruses, the CI ranges for raltegravir were 6.4-420, and the CI ranges for elvitegravir were 22-640.
Clinical isolates from patients with virological failure of raltegravir treatment: 30 clinical isolates with genotypic and phenotypic resistance to raltegravir (median CI >81) were tested for susceptibility to olutegravir (median CI 1.5) by analysis using Monogram Biosciences PlienoSense.
The median CI of dolutegravir for isolates with substitutions at positions 140S-I-Q148II was 3.75: G140S + Q148R – 13.3: T97A + Y143R – 1.05 and 15511 – 1.37. 705 raltegravir-resistant isolates obtained from patients treated with raltegravir were analyzed for susceptibility to dolutegravir by the Monogram Biosciences PhenoSense assay.
Dolutegravir exhibited a CI of 2, with resistance to InI more than a 10-fold change observed.
In vivo resistance: patients not taking InI
There were no mutations of InI resistance or treatment-related resistance to the nucleoside reverse transcriptase inhibitor (NRTI) mainstay of therapy in treatment-naïve patients receiving dolutegravir 50 mg once daily (SPRING-1, SPRING-2, SINGLE and FLAMINGO studies).
In the SAILINGy study of dolutegravir-naïve patients (n = 354 in the delutegravir group), treatment-related integrase substitutions were observed at week 48 in 4 of 17 patients with virologic failure receiving dolutegravir.
2 of 4 patients had a unique R263K substitution in the integrase gene with a maximum FC of 1.93, 1 patient had a polymorphic V151V/I integrase substitution with a maximum FC of 0.92, and 1 patient had pre-existing integrase mutations and was presumed to have previously received InI or be infected with an InI-resistant virus.
In vivo resistance: patients with Ini resistance
The VIKING-3 trial examined dolutegravir (plus optimized background therapy) in patients with existing InI resistance. By week 24, 36 of 183 patients had protocol-defined virologic failure (PDVF).
Of these, 32 patients had paired data on baseline and PDVF resistance for analysis. and 17/32 (53%) had treatment-related mutations, the following treatment-related mutations or combinations of mutations were observed: L74L/M (n = 1), E92Q (n = 2), T97A (n = 9), E138K/A/T (n = 8), G140S (n = 2), Y143H (n = 1). S147G (n=l), Q148H/K/R (n = 4). N155II (n=1) and E157E/Q (n=1).
14 of 17 patients with treatment-related viral mutations had a C 148 mutation at baseline or a history. 5 other patients had PDVF between weeks 24 and 48, and 2 of these 5 patients had treatment-emergent mutations. Treatment-emergent mutations or combinations of mutations noted were L74I (n = 1), M55H (n = 2).
The VIKING-4 study examined dolutegravir (plus optimized background therapy) in 30 patients with primary genotypic resistance to InI detected by screening. The mutations that emerged during treatment were consistent with those observed in the VIKING-3 study.
Effect on electrocardiogram (ECG) parameters
In a randomized, crossover, placebo-controlled clinical trial, 42 healthy volunteers received a single dose of placebo, dolutegravir 250 mg suspension (approximately 3 times the effect of 50 mg once daily at steady state), and moxifloxacin (400 mg, active control) in random order.
Dolutegravir did not cause prolongation of the corrected interval (QTc) within 24 hours after dosing. After adjustment for baseline ECG measurements and placebo, the maximum mean change in QTc based on Frederick’s formula (QTcF) correction was 1.99 msec (upper limit of the 1-sided 95% confidence interval, 4.53 msec).
Effect on kidney function
The effect of dolutegravir on serum creatinine clearance (CC), cellular filtration rate (GFR) in a test with yogxsol, and effective renal plasma flow (ERP) in a test with para-aminohypiurate were assessed in an open-label, randomized, placebo-controlled study in 3 groups involving 37 healthy volunteers who took 50 mg of dolutegravir I once a day (n = 12), 50 mg – 2 times a day (n = 13) or placebo 1 time a day (n = 12) for 14 days.
There was a moderate decrease in creatinine clearance with dolutegravir during the first week of treatment, consistent with the decrease observed in clinical studies.
At both doses, dolutegravir did not have a significant effect on GFR or EPP. These data support in vitro studies that suggest that the small increases in creatinine observed in clinical studies are caused by nonpathologic inhibition of the organic cation transporter (OCT2) in the proximal renal tubule, which causes tubular secretion of creatinine.
Pharmacokinetics
The pharmacokinetics of dolutegravir in healthy volunteers and HIV-infected patients is the same. Variability in dolutegravir pharmacokinetics was low to moderate.
In Phase 1 studies in healthy volunteers, the coefficient of variation (CV) among participants for the area under the concentration-time curve (AUC) and maximum concentration (Cmax) ranged from 20 to 40%, and the concentration at the end of the dosing interval (Cmax) ranged from 30 to 65%. Inter-subject variability in dolutegravir pharmacokinetics was greater in HIV-infected patients than in healthy volunteers. Individual variability in pharmacokinetics was lower than interindividual variability.
Suction
Dolutegravir is rapidly absorbed after oral administration, the median time to reach maximum concentration (Tmax) after taking a dose in tablet form is 2-3 hours. The linearity of dolutegravir pharmacokinetics is dose and drug dependent.
Following oral administration, dolutegravir tablets exhibited generally nonlinear pharmacokinetics, with a less than dose-dependent increase in plasma exposure from 2 to 100 mg, but a dose-proportional increase in dolutegravir exposure from 25 mg to 50 mg.
Dolutegravir can be taken with or without food. Food increases the extent and reduces the rate of absorption of dolutegravir. The bioavailability of dolutegravir depends on the food content: when taking a meal with low, moderate and high fat content, AUQ0-∞) of dolutegravir increased by 33%, 41% and 66%, Cmax increased by 46%, 52% and 67%, Tmax extended to 3, 4 and 5 hours compared to 2 hours when taken on an empty stomach, accordingly. These increases are not clinically significant. The absolute bioavailability of dolutegravir has not been established.
Distribution
According to in vitro data, dolutegravir is highly (99.3%) bound to human plasma proteins.
The apparent volume of distribution (after oral administration in suspension form, Vd/F) is approximately 12.5 L. The binding of dolutegravir to plasma proteins was independent of concentration. The ratios of the total concentration of the radioactively labeled drug in the blood and plasma were 0.441-0.535, indicating minimal association of the radioactively treated drug with cellular components of the blood.
The free fraction of dolutegravir in plasma is approximately 0.2-1.1% in healthy volunteers, approximately 0.4-0.5% in patients with moderate hepatic impairment, 0.8-1.0% in patients with severe renal impairment, and 0.5% in patients infected with HIV-1.
Dolutegravir penetrates into the cerebrospinal fluid (CSF). In 12 treatment-naïve patients who received dolutegravir and abacavir/lamivudine II for 16 weeks, the mean dolutegravir CSF concentration was 15.4 ng/mL at week 2 and 12.6 ng/mL at week 16, with a range of 3.7 to 23.2 ng/mL (comparable to pre-adjuvant concentrations at plasma).
The ratio of dolutegravir concentrations in CSF to plasma concentrations ranged from 0.11 to 2.04%. CSF concentrations of dolugegravir exceeded the IC50, confirming a median reduction in CSF HIV-1 RNA concentration from baseline of 2.2 log cells after 2 weeks of therapy and 3.4 log after 16 weeks of therapy (see Pharmacodynamics subsection).
Delutegravir is found in the male and female genital tract. AUC in cervicovaginal fluid, cervical and vaginal tissues was 6-10% of that in plasma at steady state. AUC in seminal fluid was 7%, and in rectal tissue – 17% of that in blood plasma at steady state concentration.
Metabolism
Dolutegravir is primarily metabolized by uridine diphosphate glucoronosyltransferase UDP-GT1A1 with a minor component of the CYP3A isoenzyme (9.7% of the total dose administered in the human mass balance study).
Dolutegravir is the main compound circulating in the blood plasma and is excreted unchanged overnight (<1% of the dose). 53% of the total dose taken internally is excreted unchanged through the intestines.
It is unknown whether this is due to incomplete absorption of the drug or excretion of the glucuronide conjugate with bile, which can further degrade to form related compounds in the intestinal lumen. 31% of the total oral dose is excreted via the kidneys in the form of dolugegravir glucuronide ester (18.9% of the total dose). N-dealkylated metabolite (3.6% of the total dose) and a metabolite formed by oxidation of benzyl carbon (3.0% of the total dose).
Withdrawal
The terminal half-life of dolugegravir is approximately 14 hours and the apparent clearance (CL/F) is 0.56 L/h.
Special instructions
Hypersensitivity reactions
Hypersensitivity reactions, characterized by rash, systemic abnormalities, and, occasionally, organ dysfunction, including liver damage, have been reported with the use of InIs, including Tivicay.
If signs or symptoms of hypersensitivity occur (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint pain.
Bullous lesions, lesions of the oral mucosa, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema) the use of Tivicay and other drugs that could cause such reactions should be immediately discontinued.
It is necessary to monitor the clinical condition, including liver aminotransferase levels, and provide appropriate therapy.
Delay in stopping treatment with Tivicay* or other medicinal products that could cause similar reactions after hypersensitivity reactions have developed may result in life-threatening reactions.
Immune reconstitution syndrome
In HIV-infected patients who are severely immunocompromised at the time of initiation of APT, an inflammatory response to asymptomatic or residual opportunistic infections may occur, which can cause serious clinical conditions or worsening symptoms.
Typically, such reactions were observed within the first few weeks or months after starting APT. Typical examples of such conditions are cytomegalovirus retinitis, generalized and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (P. carinii).
Any inflammatory symptoms should be immediately assessed and treatment initiated if necessary. Autoimmune diseases (such as Graves’ disease, polymyositis and Guillain-Barre syndrome) have been observed in the setting of immune reconstitution, but the timing of initial manifestations varies and the disease may occur many months after the start of therapy and have an atypical course.
During the initiation of Tivicay therapy, some patients coinfected with hepatitis B and or C experienced elevated liver enzymes reflecting immune reconstitution syndrome. It is recommended to monitor the activity of liver enzymes in patients with coinfection with hepatitis B and/or C.
Particular monitoring is required for the initiation or continuation of hepatitis B therapy (according to current guidelines) in patients prescribed dolutegravir treatment (see section “Side effects”).
Opportunistic infections
Patients receiving Tivicay or other APTs may develop opportunistic infections or other complications of HIV infection. Therefore, patients should be under close clinical supervision by a physician experienced in treating HIV-related illnesses.
Transmission of infection
Patients should be advised that currently available APT has not been shown to prevent the risk of transmitting HIV to others through sexual contact or blood. including the drug Tivicay. You must continue to take the necessary precautions.
Interaction with other drugs
Caution should be exercised when used concomitantly with medicinal products (prescription and over-the-counter) that may alter the exposure of dolutegravir, or medicinal products whose exposure may be altered by dolutegravir (see section “Interactions with other medicinal products”).
The recommended dose of Tivicay is 50 mg 2 times a day when used concomitantly with etravirine (not boosted with protease inhibitors), efavirenz, nevirapine, tipranavir/ritonavir. rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s wort (see section on interactions with other drugs”).
Tivicay should not be co-administered with antacids containing pevalent cations. It is recommended to use Tivicay 2 hours before or 6 hours after using these drugs (see section “Interaction with other drugs”).
Tivicay is recommended to be taken 2 hours before or 6 hours after taking calcium or iron supplements, or alternatively taken with food (see Interactions with Other Drugs section).
The drug Tivicay increases concentrations of mstformin. It is necessary to consider the possibility of adjusting the dose of metformin at the beginning and when stopping the combined use of dolutegravir with metformin to maintain glycemic control (see section “Interaction with other drugs”).
Resistance to integrase inhibitors, of particular importance
When deciding on the use of dolutegravir in the presence of resistance to I&I, it should be taken into account that this significantly reduces the activity of dolutegravir against viral strains carrying secondary mutations Q148 + >2 in the G140A/C/S, E138A/K/T, L74I regions.
The extent to which dolutegravir provides additional efficacy in the presence of such InI resistance remains unclear.
Osteonecrosis
Although the etiology of this disease is multifactorial (including the use of corticosteroids, diphosphonates, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis most often occurred in patients at an advanced stage of HIV infection and/or long-term use of combined APT.
Patients should consult a doctor if they experience joint pain and stiffness or difficulty moving.
INFLUENCE ON THE ABILITY TO DRIVE VEHICLES, MECHANISMS
No studies have been conducted on the effect of Tivicay on the ability to drive vehicles and operate machinery. The patient’s clinical condition and the adverse event profile of Tivicay should be taken into account when considering the patient’s ability to drive or operate machinery.
Active ingredient
Dolutegravir
Composition
1 tab. contains:
Active substance:
dolutegravir sodium – 52.6 mg, which corresponds to the content of dolutegravir – 50 mg;
Excipients:
mannitol – q.s. up to 145.4 mg,
microcrystalline cellulose – 60 mg,
povidone K29/32 – 15 mg,
sodium carboxymethyl starch – 21 mg,
sodium stearyl fumarate – 6 mg;
Film shell composition: Opadry II yellow 85A92461 – 9 mg (hydrolyzed polyvinyl alcohol 40%, titanium dioxide 23.45%, macrogol (polyethylene glycol) 20.2%, talc 14.8%, yellow iron oxide 1.55%).
Pregnancy
Fertility
There is no data on the effect of Tivicay on fertility in men and women. Animal studies have shown no effect of dolutegravir on fertility in males or females.
Pregnancy
There have been no adequate and well-controlled studies of Tivicay in pregnant women.
The effect of Tivicay on pregnancy in women is unknown. Dolutegravir has been shown to cross the placenta in animal reproductive toxicity studies. Tivicay® can be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding period
HIV-infected patients are advised not to breastfeed their children to avoid vertical transmission of HIV infection.
Based on animal data, dolutegravir is expected to be excreted in women’s breast milk, although this has not been confirmed in humans.
Contraindications
Hypersensitivity to dolutegravir or any other component included in the drug. Concomitant use with dofetilide or pelsicainide, children under 12 years of age and body weight less than 40 kg.
WITH CAUTION
Severe liver failure (class C on the Child-Pugh scale);
When used concomitantly with medications (prescription and over-the-counter) that may alter the effect of Tivicay®, or medications whose effects may be altered by Tivicay®.
Side Effects
The adverse reactions presented below were identified through analysis of cumulative data from Phase IIb and III clinical trials and are listed according to organ system involvement and frequency of occurrence. The frequency of occurrence is defined as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000) and very rare (< 1/10,000, including isolated cases).
Frequency of occurrence of adverse reactions
Immune system disorders
Uncommon: hypersensitivity reaction, immune reconstitution syndrome.
Mental disorders
Common: insomnia, unusual dreams, depression.
Uncommon: suicidal ideation or suicide attempt (especially in patients with a history of depression or mental illness).
Nervous system disorders
Very common: headache, common: dizziness.
Gastrointestinal disorders
Very common: nausea, diarrhea,
Common: vomiting, flatulence, upper abdominal pain, abdominal pain, abdominal discomfort.
Disorders of the liver and biliary tract
Uncommon: hepatitis.
Skin and subcutaneous tissue disorders
Common: rash, itching.
General and administration site disorders
Common: fatigue.
Laboratory and instrumental data
Often: increased activity of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), creatine phosphokinase (CPK).
The safety profile was similar in the populations of treatment-naive patients, treated patients (and not taking integrase inhibitors), and patients with resistance to integrase inhibitors.
Description of individual side effects
Changes in laboratory parameters
During the first week of treatment with Tivicay®, an increase in serum creatinine concentration was observed, which persisted for 48 weeks. The average change in creatinine concentration at the time of 48 weeks of therapy was 9.96 μmol/L.
The increase in creatinine concentration was comparable for different background treatment regimens. These changes are not considered clinically significant because they do not reflect changes in glomerular filtration rate.
Immune reconstitution syndrome
At the time of initiation of combination antiretroviral therapy (cART), HIV-infected patients with severe immunodeficiency may develop an inflammatory reaction against the background of asymptomatic opportunistic infections or their residual effects.
Cases of the development of autoimmune diseases (for example, Graves’ disease) against the background of immune restoration have also been reported, but the time of initial manifestations varied, and the disease could occur many months after the start of therapy.
Use in children
Based on limited data from use in children and adolescents aged 12 to 18 years, it can be concluded that there are no additional types of adverse reactions beyond those observed in adults.
Coinfection with HIV and hepatitis B or C virus
Phase III studies were permitted to enroll patients coinfected with hepatitis B and/or C virus as long as baseline liver function laboratory results were no more than 5 times the upper limit of normal (ULN).
Overall, the safety profile in patients coinfected with hepatitis B and/or C virus was similar to that in patients without coinfection with hepatitis B or C virus, although the incidence of AST and ALT abnormalities was higher in the subgroup of patients coinfected with hepatitis B and/or C virus across all treatment groups.
Elevations of liver enzymes consistent with immune reconstitution syndrome have been observed in some patients coinfected with hepatitis B and/or C virus when initiating Tivicay therapy, particularly in those who have had hepatitis B treatment discontinued.
Post-registration data
Musculoskeletal and connective tissue disorders
Uncommon: arthralgia, myalgia.
Overdose
Symptoms
Data on overdose of Tivicay are limited.
Limited experience with higher single doses (up to 250 mg in healthy volunteers) has not revealed any special symptoms or signs other than those described in the section “Side effects”.
Treatment
Further treatment should be carried out in accordance with clinical indications or recommendations of the national poison control center, where applicable. There is no specific treatment for Tivicay overdose.
In case of overdose, supportive therapy and appropriate monitoring are necessary. Due to the high binding of dolutegravir to plasma proteins, it is unlikely that significant amounts can be eliminated by dialysis.
Storage conditions
Store at a temperature not exceeding 30°C. Keep out of the reach of children.
Shelf life
2 years.
Manufacturer
Glaxo Operations UK Ltd, UK
Shelf life | 2 years. |
---|---|
Conditions of storage | Store at a temperature not exceeding 30°C. Keep out of reach of children. |
Manufacturer | Glaxo Operations UK Ltd, United Kingdom |
Medication form | pills |
Brand | Glaxo Operations UK Ltd |
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