Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: CIPLA MEDPRO (PTY) LTD, Building 9, Parc du Cap, Mispel Street, Bellville, 7530 Phone: +27 21 943 4200 Customer Care: 080 222 6662 E-mail: info@cipla.co.za
Pharmacotherapeutic group: A 20.2.8 Antiviral medicines
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 HV replication cycle. In vitro, dolutegravir dissociates slowly from the active site of the wild type integrase–DNA complex (t1/2 71 hours).
Rilpivirine Is a diarylpyrimidine NNRTI of HIV. Rilpivirine activity is mediated by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.
Rilpivirine exhibited activity against laboratory strains of wild type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-M1/IIIB of 0,73 nM (0,27 ng/mL). Although rilpivirine demonstrated limited in vitro activity against HIV-2 with EC50 values ranging from 2 510 to 5 220 nM (920 to 1 910 ng/mL), treatment of HIV-2 infection with rilpivirine is not recommended in the absence of clinical data. Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B,C, D, F, G, H) primary isolates with EC50 values ranging from 0,07 to 1,01 nM (0,03 to 0,37 ng/mL) and group O primary isolates with EC50 values ranging from 2,88 to 8,45 nM (1,06 to 3,10 ng/mL).
Rilpivirine showed additive antiviral activity in combination with the N (t)RTIs abacavir, didanosine, emtricitabine, stavudine and tenofovir; the PIs amprenavir, atazanavir darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir; the NNRTIs efavirenz, etravirine and nevirapine; the fusion inhibitor enfuvirtide. Rilpivirine also shows additive to synergistic antiviral activity in combination with the NRTIs lamivudine and zidovudine, and the integrase inhibitor raltegravir.
Isolation from wild type HIV-1: Viruses highly resistant to dolutegravir were not observed during HIV-1 passage. during wild-HIV1 passage in the presence of dolutegravir integrase substitutions observed were S153Y and S153F with FCs ≤4,1 for strain IIIB, or E92Q with FC = 3,2 for strain NL 432. Additional passage of wildtype 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 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. (2: A8)
Integrase Inhibitor-Resistant HIV-2 Strains: Site directed mutant HIV-2 viruses were constructed based on subjects infected with HIV-2 and treated with raltegravir who showed virologic failure. Treatment of HIV-2 infections with rilpivirine is not recommended in the absence of clinical data.
Clinical Isolates from Raltegravir Treatment Virologic Failure Subjects: Seven hundred and five raltegravir resistant clinical isolates were analysed for susceptibility to dolutegravir using the Monogram Biosciences PhenoSense assay. Dolutegravir has a <10 FC against 93,9% of the 705 clinical isolates.
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 (SPRING-1, SPRING-2 and SINGLE studies). In a SAILING study for treatment experienced (and integrase naïve) patients (n=354 in 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.
The VIKING-3 study examined dolutegravir (plus optimised background therapy) in subjects with pre-existing INI resistance. Twenty-six subjects (26/114) experienced protocol defined virologic failure through to week 24. Of these, 25 had paired baseline and PDVF resistance data for analysis and 13/25 (52 %) had treatment emergent mutations. Treatment emergent mutations or mixtures of mutations observed were E92Q (n=2), T97A (n=6), E138K/A (n=4), G140S (n=2), Y143H (n=1), S147G (n=1), Q148H/K/R (n=3) and N155H (n=1). Eleven of the 13 subjects with virus exhibiting treatment emergent mutations harboured Q148 pathway virus present at baseline or historically.
Rilpivirine resistant strains were selected in cell culture starting from wild type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The most commonly observed amino acid substitutions that emerged included: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I.
A biological cut off (BCO) for rilpivirine was determined at the fold change In EC50 value (FC) of 3, 7 on the basis of the analysis of the susceptibility of a large panel of HIV-1 wild type recombinant clinical isolates.
Site-directed NNRTI mutant virus:
In a panel of 67 HIV-1 recombinant laboratory strains with one amino acid substitution at RT positions associated with NNRTI resistance, including the most commonly found K103N and Y181C, rilpivirine showed antiviral activity against 64 (96%) of these strains. The single amino acid substitutions associated with a loss of susceptibility to rilpivirine were: K101P, Y181I andY181V.
Recombinant clinical isolates:
Rilpivirine retained sensitivity (FC s BCO) against 62% of 4 786 HIV-1 recombinant clinical isolates resistant to efavirenz and/or nevirapine.
The effect of rilpivirine at the recommended dose of 25 mg daily on the QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady-state. rilpivirine, at the recommended dose of 25 mg daily, is not associated with a clinically relevant effect on QTc interval.
When supratherapeutic doses of 75 mg daily and 300 mg daily of rilpivirine were studied in healthy adults there was a dose related QTcF prolongation. The maximum mean time- matched (95 %upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10,7 (15,3) and 23,3 (28,4) ms, respectively. Steady-state administration of rilpivirine 75 mg daily and 300 mg daily resulted in a mean Cmax approximately 2,6-fold and 6,7-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 25 mg daily dose of rilpivirine.
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 CT 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.
The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naive HIV-1 infected patients. Exposure to rilpivirine was generally lower in HIV-1 infected patients than in healthy subjects
Dolutegravir is absorbed following oral administration, with median Tmax at 2 or 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 33%, 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 have not been established.
After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within four to five hours. The absolute bioavailability of rilpivirine is unknown.
The exposure to rilpivirine was approximately 40% lower when rilpivirine was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high fat high caloric meal (928 kcal). When rilpivirine was taken with only a protein rich nutritional drink, exposures were 50% lower than when taken with a meal.
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 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). In 13 treatment-naïve subjects on a stable dolutegravir plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable to unbound plasma concentration, and above the ICSO); CSF: plasma concentration ratio of dolutegravir ranged from 0,11 to 1 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 5.2.
Rilpivirine is approximately 99,7% bound to plasma proteins in vitro primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g. cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.
Dolutegravir is primarily metabolised via UGT1A 1 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).
In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP3A) system.
Dolutegravir has a terminal half-life of -14 hours and an apparent clearance (CUF) of 0,56 L/hr. 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).
The terminal elimination hail-life of rilpivirine is approximately 45 hours. After single-dose oral administration of 14C rilpivirine, on average 85% and 6,1% of the radioactivity could be retrieved in faeces and urine, respectively. ln faeces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (<1% of dose) were detected in urine.
Rilpivirine:
Dosing recommendations for paediatric patients cannot be made due to insufficient data. DALIDUO is not recommended for use in patients under 18 years of age, see section 4.2.
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 subjects of >65 years old are limited.
Rilpivirine:
Population pharmacokinetic analysis in HIV infected patients showed that rilpivirine Pharmacokinetics is not different across the age range (18 to 78 years) evaluated. No dose adjustment is required in elderly patients.
Dolutegravir:
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 heathy 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.
Rilpivirine:
The pharmacokinetics of rilpivirine has not been studied in patients with renal insufficiency. Renal elimination of rilpivirine is negligible. Therefore, the impact of renal impairment on rilpivirine elimination is expected to be minimal. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.
Dolutegravir:
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. 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.
Rilpivirine:
Rilpivirine is primarily metabolised and eliminated by the liver. ln a study comparing eight patients with mild hepatic impairment (Child-Pugh score A) to eight matched controls, and eight patients with moderate hepatic impairment (Child-Pugh score B) to eight matched controls, the multiple dose exposure of rilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher in patients with moderate hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh A or B). Rilpivirine has not been studied in patients with severe hepatic Iimpairment (Child-Pugh score C).
Dolutegravir:
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 NR112 were not associated with differences in the pharmacokinetics of dolutegravir. Rilpivirine pharmacokinetics are not anticipated to be impacted by polymorphisms in drug metabolising enzymes.
Dolutegravir:
Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir.
Rilpivirine:
Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine. Subjects with hepatitis B co-infections were excluded from studies with dolutegravir/rilpivirine tablet.
© 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.
