Chemical formula: C₂₂H₁₈N₆ Molecular mass: 366.419 g/mol PubChem compound: 6451164
Rilpivirine is a diarylpyrimidine 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.
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-1/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 10,830 nM (920 to 3,970 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-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 resistance-associated mutations that emerged included L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I.
Resistance to rilpivirine was determined as a fold change in EC50 value (FC) above the biological cut-off (BCO) of the assay.
The effect of rilpivirine at the recommended dose of 25 mg once 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 once daily is not associated with a clinically relevant effect on QTc.
When supratherapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine were studied in healthy adults, 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 once daily and 300 mg once 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 once daily dose of rilpivirine.
The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in antiretroviral treatment-naïve HIV-1 infected patients 12 years of age and older. Exposure to rilpivirine was generally lower in HIV-1 infected patients than in healthy subjects.
After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4-5 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 ntic 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 moormal 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. Rilpivirine must be taken with a meal to obtain optimal absorption. Taking rilpivirine in fasted condition or with only a nutritional drink may result in decreased plasma concentrations of rilpivirine, which could potentially reduce the therapeutic effect of rilpivirine.
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.
In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system.
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.
The pharmacokinetics of rilpivirine in antiretroviral treatment-naïve HIV-1 infected adolescent subjects 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 trial TMC278-C213 (33 to 93 kg), similar to what was observed in adults.
The pharmacokinetics of rilpivirine in paediatric patients less than 12 years of age are under investigation. Dosing recommendations for paediatric patients less than 12 years of age cannot be made due to insufficient data.
Population pharmacokinetic analysis in HIV infected patients showed that rilpivirine pharmacokinetics are not different across the age range (18 to 78 years) evaluated, with only 3 subjects aged 65 years or older. No dose adjustment of rilpivirine is required in older patients. Rilpivirine should be used with caution in this population.
No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women.
Population pharmacokinetic analysis of rilpivirine in HIV infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.
Rilpivirine is primarily metabolised and eliminated by the liver. In a 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 suggested but caution is advised in patients with moderate hepatic impairment. Rilpivirine has not been studied in patients with severe hepatic impairment (Child-Pugh score C). Therefore, rilpivirine is not recommended in patients with severe hepatic impairment.
Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine.
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, rilpivirine should be used with caution, as 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 rilpivirine with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.
The exposure to total rilpivirine after intake of rilpivirine 25 mg once daily as part of an antiretroviral regimen was lower during pregnancy (similar for the 2nd and 3rd trimester) compared with postpartum (see table). The decrease in unbound (ie, active) rilpivirine pharmacokinetic parameters during pregnancy compared to postpartum was less pronounced than for total rilpivirine.
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.
Table 7. Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and Postpartum:
| Pharmacokinetics of total rilpivirine (mean ± SD, tmax: median [range]) | Postpartum (6-12 Weeks) (n=11) | 2nd Trimester of pregnancy (n=15) | 3rd Trimester of pregnancy (n=13) |
|---|---|---|---|
| Cmin, ng/ml | 84.0 ± 58.8 | 54.3 ± 25.8 | 52.9 ± 24.4 |
| Cmax, ng/ml | 167 ± 101 | 121 ± 45.9 | 123 ± 47.5 |
| tmax, h | 4.00 (2.03-25.08) | 4.00 (1.00-9.00) | 4.00 (2.00-24.93) |
| AUC24h, ng.h/ml | 2714 ± 1535 | 1792 ± 711 | 1762 ± 662 |
Liver toxicity associated with liver enzyme induction was observed in rodents. In dogs, cholestasis-like effects were noted.
Studies in animals have shown no evidence of relevant embryonic or foetal toxicity or an effect on reproductive function. There was no teratogenicity with rilpivirine in rats and rabbits. The exposures at the embryo-foetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily.
Rilpivirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to rilpivirine were 21-fold (mice) and 3-fold (rats), relative to those observed in humans at the recommended dose (25 mg once daily). In rats, there were no drug-related neoplasms. In mice, rilpivirine was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific.
Rilpivirine has tested negative in the absence and presence of a metabolic activation system in the in vitro Ames reverse mutation assay and the in vitro clastogenicity mouse lymphoma assay. Rilpivirine did not induce chromosomal damage in the in vivo micronucleus test in mice.
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