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.
Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Rilpivirine activity is mediated by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.
The IC50 for dolutegravir against various laboratory strains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7-2 nM. Similar IC50s were seen for clinical isolates without any major difference between subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC50 value was 0.2 nM (range 0.02-2.14). The mean IC50 for 3 HIV-2 isolates was 0.18 nM (range 0.09-0.61).
Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median IC50 value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated limited in vitro activity against HIV-2 with IC50 values ranging from 2 510 to 10 830 nM.
Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (clades A, B, C, D, F, G, H) primary isolates with IC50 values ranging from 0.07 to 1.01 nM and group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM.
In 100% human serum, the dolutegravir mean protein fold shift was 75 fold, resulting in protein adjusted IC90 of 0.064 µg/mL.
A reduction in the antiviral activity of rilpivirine was observed in the presence of 1 mg/mL alpha-1-acid glycoprotein, 45 mg/mL human serum albumin, and 50% human serum as demonstrated by median IC50 rates of 1.8, 39.2 and 18.5, respectively.
Dolutegravir/rilpivirine fixed-dose combination is bioequivalent to a dolutegravir tablet and a rilpivirine tablet administered together with a meal.
Dolutegravir pharmacokinetics are similar between healthy and HIV-infected subjects. The PK variability of dolutegravir is low to moderate. In Phase I studies in healthy subjects, between-subject CVb% for AUC and Cmax ranged from ~20 to 40% and Cτ 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-naïve HIV-1 infected patients. Systemic exposure to rilpivirine was generally lower in HIV-1 infected patients than in healthy subjects.
Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 2 to 3 hours post dose for tablet formulation. After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4-5 hours.
Dolutegravir/rilpivirine must be taken with a meal to obtain optimal absorption of rilpivirine. When dolutegravir/rilpivirine was taken with a meal, the absorption of both dolutegravir and rilpivirine was increased. Moderate and high fat meals increased the dolutegravir AUC(0-∞) by approximately 87% and Cmax by approximately 75%. Rilpivirine AUC(0-∞) was increased by 57% and 72% and Cmax by 89% and 117%, with moderate and high fat meals respectively, compared to fasted conditions. Taking dolutegravir/rilpivirine in fasted condition or with only a protein-rich nutritional drink may result in decreased plasma concentrations of rilpivirine, which could potentially reduce the therapeutic effect of dolutegravir/rilpivirine.
The absolute bioavailability of dolutegravir or rilpivirine has not been established.
Dolutegravir is highly bound (>99%) to human plasma proteins based on in vitro data. The apparent volume of distribution is 17 L to 20 L in HIV-infected patients, based on a population pharmacokinetic analysis. Binding of dolutegravir to plasma proteins is independent of dolutegravir 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. The unbound fraction of dolutegravir in plasma is increased at low levels of serum albumin (<35 g/L) as seen in subjects with moderate hepatic impairment.
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 IC50).
Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue and vaginal tissue were 6-10% of those in corresponding plasma at steady state. AUC in semen was 7% and 17% in rectal tissue of those in corresponding plasma at steady state.
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 through glucuronidation 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). 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 active substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-two percent of the total oral dose is excreted in the urine, mainly 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).
In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the CYP3A system.
In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2 or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Based on this data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters. In vitro, dolutegravir was not a substrate of human OATP 1B1, OATP 1B3 or OCT 1.
Dolutegravir has a terminal half-life of ~14 hours. The apparent oral clearance (CL/F) is approximately 1L/hr in HIV-infected patients based on a population pharmacokinetic analysis.
The terminal elimination half-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. In 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.
Neither dolutegravir/rilpivirine fixed-dose combination nor the combination dolutegravir and rilpivirine as single entities have been studied in children. Dose recommendations for paediatric patients cannot be made due to insufficient data.
The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected adolescents (12 to <18 years of age and weighing ≥40 kg) 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. The pharmacokinetics was evaluated in 11 children 6 to 12 years of age and showed that 25 mg once daily in patients weighing at least 20 kg and 35 mg once daily in patients weighing at least 30 kg resulted in dolutegravir exposure comparable to adults.
The pharmacokinetics of rilpivirine in 36 antiretroviral treatment-naïve HIV-1 infected adolescent subjects (12 to <18 years of age) receiving rilpivirine 25 mg once daily were comparable to those in treatment-naïve HIV-1 infected adults receiving rilpivirine 25 mg once daily. There was no impact of body weight on rilpivirine pharmacokinetics in paediatric subjects in study C213 (33 to 93 kg), similar to what was observed in adults.
Population pharmacokinetic analysis using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir or rilpivirine exposures. Pharmacokinetic data in subjects >65 years old are very limited.
Renal clearance of unchanged active substance 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) and matched healthy controls. The exposure to dolutegravir was decreased by approximately 40% in subjects with severe renal impairment. The mechanism for the decrease is unknown. The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency.
Renal elimination of rilpivirine is negligible. No dose adjustment is needed for patients with mild or moderate renal impairment. In patients with severe renal impairment or end-stage renal disease, dolutegravir/rilpivirine should be used with caution, as rilpivirine plasma concentrations may be increased due to alteration of drug absorption, distribution and/or metabolism secondary to renal dysfunction. In patients with severe renal impairment or end-stage renal disease, the combination of dolutegravir/rilpivirine with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. Dolutegravir/rilpivirine has not been studied in patients on dialysis. As dolutegravir and rilpivirine are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.
Dolutegravir and rilpivirine are both primarily metabolised and eliminated by the liver. A single dose of 50 mg of dolutegravir was administered to 8 subjects with moderate hepatic impairment (Child-Pugh score B) and to 8 matched healthy adult controls. While the total dolutegravir concentration in plasma was similar, a 1.5- to 2-fold increase in unbound exposure to dolutegravir was observed in subjects with moderate hepatic impairment compared to healthy controls.
In a rilpivirine study comparing 8 patients with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 patients with moderate hepatic impairment (Child-Pugh score B) to 8 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. However, it may not be excluded that the pharmacologically active, unbound, rilpivirine exposure is significantly increased in moderate hepatic impairment.
No dose adjustment is considered necessary for patients with mild to moderate hepatic impairment (Child-Pugh score A or B). Dolutegravir/rilpivirine should be used with caution in patients with moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh score C) on the pharmacokinetics of dolutegravir or rilpivirine has not been studied, therefore dolutegravir/rilpivirine is not recommended in these patients.
Population pharmacokinetic analyses from studies with the individual components revealed that gender had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine.
No clinically important pharmacokinetic differences of dolutegravir or rilpivirine due to race have been identified.
Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir or rilpivirine. Subjects with hepatitis B co-infection or hepatitis C infection in need of anti-HCV therapy were excluded from studies with the dual combination of dolutegravir and rilpivirine.
No pharmacokinetic data are available for the combination of dolutegravir and rilpivirine in pregnancy. In limited data from small numbers of women in study IMPAACT P1026 who received dolutegravir 50 mg once daily during the 2nd trimester of pregnancy, mean intra-individual values for total dolutegravir Cmax, AUC24h and C24h values were, respectively, 26%, 37% and 51% lower as compared to postpartum; during the 3rd trimester of pregnancy, Cmax, AUC24h and Cmin values were, respectively, 25%, 29% and 34% lower as compared to postpartum.
In women receiving rilpivirine 25 mg once daily during the 2nd trimester of pregnancy, mean intraindividual values for total rilpivirine Cmax, AUC24h and Cmin values were, respectively, 21%, 29% and 35% lower as compared to postpartum; during the 3rd trimester of pregnancy, Cmax, AUC24h and Cmin values were, respectively, 20%, 31% and 42% lower as compared to postpartum.
Non-clinical data for dolutegravir and rilpivirine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. While dolutegravir was not carcinogenic in long-term animal studies, rilpivirine caused an increase in hepatocellular neoplasms in mice that may be species specific.
In reproductive toxicity studies in animals, dolutegravir was shown to cross the placenta.
Dolutegravir did not affect male or female fertility in rats at 33 times higher exposures than the AUCexposure at 50 mg human clinical dose.
Oral administration of dolutegravir to pregnant rats did not elicit maternal toxicity, developmental toxicity or teratogenicity (38 times the 50 mg human clinical exposure based on AUC).
Oral administration of dolutegravir to pregnant rabbits did not elicit developmental toxicity or teratogenicity (0.56 times the 50 mg human clinical exposure based on AUC).
Rilpivirine studies in rats and rabbits have shown no teratogenicity and no evidence of relevant embryonic or foetal toxicity or an effect on reproductive function at exposures respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily.
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