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 population pharmacokinetic properties of rilpivirine have been evaluated in healthy and HIV-1 infected adults.

Table 1. Pharmacokinetic parameters of rilpivirine following once daily oral dosing, and after initial, monthly, or every two months intramuscular injections of rilpivirine in adults:

^a Based on individual post-hoc estimates from rilpivirine IM population pharmacokinetic model (pooled data FLAIR, ATLAS and ATLAS-2M).
^b tau is dosing interval: 24 hours for oral; 1 or 2 months for monthly or every 2 months IM injections.
^c For oral rilpivirine, C_tau represents observed pooled data FLAIR, ATLAS and ATLAS-2M, AUC_(0-tau) and C_max represent pharmacokinetic data from oral rilpivirine Phase 3 studies
^d When administered with oral lead-in, initial injection C_max primarily reflects oral dosing because the initial injection was administered on the same day as the last oral dose. When administered without oral lead-in (direct to injection, n=110), the rilpivirine observed geometric mean (5^th, 95^th percentile) C_max (1 week post initial injection) was 68.0 ng/mL (27.5, 220) and the C_tau was 48.9 ng/mL (17.7, 138).
^e Week 48 data.

Absorption

Rilpivirine prolonged-release injection exhibits absorption rate-limited kinetics (i.e., flip-flop pharmacokinetics) resulting from slow absorption from the gluteal muscle into the systemic circulation resulting in sustained rilpivirine plasma concentrations.

Following a single intramuscular dose, rilpivirine plasma concentrations are detectable the first day and gradually rise to reach maximum plasma concentrations after a median of 3-4 days. Rilpivirine has been detected in plasma up to 52 weeks or longer after administration of a single dose of rilpivirine. After 1 year of monthly or every 2 months injections, approximately 80% of the rilpivirine pharmacokinetic steady-state exposure is reached.

Plasma rilpivirine exposure increases in proportion or slightly less than in proportion to dose following single and repeat IM injections of doses ranging from 300 to 1200 mg.

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. Based on population pharmacokinetics analysis, the typical apparent volume of the central compartment (Vc/F) for rilpivirine after IM administration was estimated to be 132 L, reflecting a moderate distribution to peripheral tissues.

Rilpivirine is present in cerebrospinal fluid (CSF). In HIV-1-infected subjects receiving a regimen of rilpivirine injection plus cabotegravir injection, the median rilpivirine CSF to plasma concentration ratio (n=16) was 1.07 to 1.32% (range: not quantifiable to 1.69%). Consistent with therapeutic rilpivirine concentrations in the CSF, CSF HIV-1 RNA (n=16) was <50 c/mL in 100% and <2 c/mL in 15/16 (94%) of subjects. At the same time point, plasma HIV-1 RNA (n=18) was <50 c/mL in 100% and <2 c/mL in 12/18 (66.7%) of subjects.

Biotransformation

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

Elimination

The mean apparent half-life of rilpivirine following rilpivirine administration is absorption rate-limited and was estimated to be 13-28 weeks.

The apparent plasma clearance (CL/F) of rilpivirine was estimated to be 5.08 L/h.

After single dose administration of oral 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.

Special patient populations

Gender

No clinically relevant differences in the rilpivirine exposure after intramuscular (IM) administration have been observed between men and women.

Race

No clinically relevant effect of race on the rilpivirine exposure after intramuscular administration has been observed.

BMI

No clinically relevant effect of BMI on the rilpivirine exposure after intramuscular administration has been observed.

Elderly

No clinically relevant effect of age on the rilpivirine exposure after intramuscular administration has been observed. Pharmacokinetic data for rilpivirine in subjects of >65 years old are limited.

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.

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 oral 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.

HBV/HCV Co-infected Patients

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

Paediatric Patients

The pharmacokinetics of rilpivirine in children less than 12 years of age and adolescents weighing less than 35 kg have not been established with rilpivirine.

Adolescents

Population pharmacokinetic analyses revealed no clinically relevant differences in exposure between adolescent participants (at least 12 years of age and weighing 35 kg or more) and HIV-1 infected and uninfected adult participants. Therefore, no dosage adjustment is needed for adolescents weighing ≥35 kg.

Table 2. Pharmacokinetic parameters of rilpivirine following once daily oral dosing, and after initial, monthly, or every two months intramuscular injections of rilpivirine in adolescents (aged 12 to less than 18 years and weighing ≥35 kg):

|/2<>_.Population |/2<>_.Dosing phase |/2<>_.Dose
regimen|\3<>_.Geometric mean (5^th; 95^th Percentile) |

^a Based on individual post-hoc estimates from rilpivirine IM population pharmacokinetic model (MOCHA, IMPAACT 2017).
^b tau is dosing interval: 24 hours for oral; 1 or 2 months for monthly or every 2 months IM injections.
^c OLI PK parameter values represent steady state.
^d When administered with oral lead-in, initial injection C_max primarily reflects oral dosing because the initial injection was administered on the same day as the last oral dose; however, the AUC_tau and the C_tau value at Week 4 reflect the initial injection.
^e Every month injection: 11th RPV LA IM Injection (40-44 weeks after initiation injection).
^f Every 2 months injection: 6th RPV LA IM Injection (36-44 weeks after initiation injection).

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 4). 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.

Table 4. 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:

All studies were performed with rilpivirine for oral use except for the studies on local tolerance with rilpivirine injections.

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 oral rilpivirine in rats and rabbits. The exposures at the embryo-foetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively ≥12 times and ≥57 times the exposure in humans at the maximum recommended human daily dose of 25 mg once daily in HIV-1 infected patients or 600 mg or 900 mg intramuscular injection dose of rilpivirine long-acting injectable suspension.

Carcinogenesis and mutagenesis

Oral 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 ≥17 times (mice) and ≥2 times (rats) the exposure in humans at the maximum recommended human daily dose of 25 mg once daily in HIV-1 infected patients or 600 mg or 900 mg intramuscular injection dose of rilpivirine long-acting injectable suspension. 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.

Local tolerance for rilpivirine injection

After long-term repeated IM administration of rilpivirine in dogs and minipigs, slight, short-lasting (i.e., 1-4 days in minipigs) erythema was observed, and white deposits were noted at the injection sites at necropsy, accompanied by swelling and discolouration of draining lymph nodes. Microscopic examination showed macrophage infiltration and eosinophilic deposits at the injection sites. A macrophage infiltration response was also noted in the draining/regional lymph nodes. These findings were considered to be a reaction to the deposited material rather than a manifestation of local irritation.