Rilpivirine

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.

Antiviral activity in vitro

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).

The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in antiretroviral treatment-naïve and virologically suppressed HIV-1 infected patients ≥6 years of age and weighing ≥16 kg. Exposure to rilpivirine was generally lower in HIV-1 infected patients than in healthy subjects.

Absorption

After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4-5 hours. The absolute bioavailability of rilpivirine is unknown.

Effect of food on absorption

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. 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.

Distribution

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.

Biotransformation

In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system.

Elimination

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.

Additional information on special populations

Paediatric population

The pharmacokinetics of rilpivirine in antiretroviral treatment-naïve or virologically suppressed HIV-1 infected paediatric patients aged 6 years to less than 18 years of age weighing at least 16 kg receiving the recommended weight-based dosing regimen of rilpivirine were comparable or higher (i.e., AUC is 39% higher, based on pharmacokinetic modeling) than those obtained in treatment-naïve HIV-1 infected adult patients.

The pharmacokinetics of rilpivirine in paediatric patients less than 6 years of age or weighing less than 16 kg have not been formally evaluated in patients.

Older people

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.

Gender

No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women.

Race

Population pharmacokinetic analysis of rilpivirine in HIV infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.

Hepatic impairment

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.

Hepatitis B and/or hepatitis C virus co-infection

Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine.

Renal impairment

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.

Pregnancy and Postpartum

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 2^nd and 3^rd trimester) compared with postpartum (see table). The decrease in unbound (i.e., 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 2^nd trimester of pregnancy, mean intra-individual values for total rilpivirine C_max, AUC_24h and C_min values were, respectively, 21%, 29% and 35% lower as compared to postpartum; during the 3^rd trimester of pregnancy, C_max, AUC_24h and C_min values were, respectively, 20%, 31% and 42% lower as compared to postpartum.

Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2^nd Trimester of Pregnancy, the 3^rd:

Repeated dose toxicity

Liver toxicity associated with liver enzyme induction was observed in rodents. In dogs, cholestasis-like effects were noted.

Reproductive toxicology studies

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 (based on AUC) 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 (minimum 12 years of age and weighing more than 32 kg) at the recommended dose of 25 mg once daily.

Carcinogenesis and mutagenesis

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 greater than 12-fold (mice) and greater than 1.4-fold (rats), relative to the expected exposure in humans at a dose of 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.