Edurant (Rilpivirine Hydrochloride) - Description and Clinical Pharmacology

DESCRIPTION

EDURANT (rilpivirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). EDURANT is available as a white to off-white, film-coated, round, biconvex, 6.4 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine.

The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C₂₂H₁₈N₆ ∙ HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:

Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range.

Each EDURANT tablet also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin.

CLINICAL PHARMACOLOGY

Mechanism of Action

Rilpivirine is an antiviral drug [see Microbiology].

Pharmacodynamics

Effects on Electrocardiogram

The effect of EDURANT at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was 2.0 milliseconds (i.e., below the threshold of clinical concern).

When supratherapeutic doses of 75 mg once daily and 300 mg once daily of EDURANT 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 and 23.3 milliseconds, respectively. Steady-state administration of EDURANT 75 mg once daily and 300 mg once daily resulted in a mean steady-state C_max approximately 2.6-fold and 6.7-fold, respectively, higher than the mean C_max observed with the recommended 25 mg once daily dose of EDURANT [see Warnings and Precautions].

Pharmacokinetics

Pharmacokinetics in Adults

The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.

Table 5: Population Pharmacokinetic Estimates of Rilpivirine 25 mg once daily in Antiretroviral Treatment-Naïve HIV-1-Infected Subjects (Pooled Data from Phase 3 Trials through Week 96)

Parameter	Rilpivirine 25 mg once daily N = 679
AUC24h (ng∙h/mL)
Mean ± Standard Deviation	2235 ± 851
Median (Range)	2096 (198 – 7307)
C0h (ng/mL)
Mean ± Standard Deviation	79 ± 35
Median (Range)	73 (2 – 288)

Absorption and Bioavailability

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

Effects of Food on Oral Absorption

The exposure to rilpivirine was approximately 40% lower when EDURANT was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When EDURANT was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.

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.

Metabolism

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 50 hours. After single dose oral administration of ¹⁴C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, 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 Populations

Hepatic Impairment

Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. EDURANT has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations].

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

Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Use in Specific Populations].

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.

Pediatric Patients

The pharmacokinetics and dosing recommendations of rilpivirine in pediatric patients have not been established [see Use in Specific Populations].

Drug Interactions

[See Contraindications (4) and Drug Interactions (7) .]

Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of EDURANT and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance. Co-administration of EDURANT and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Co-administration of EDURANT with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine and to the class of NNRTIs.

EDURANT at a dose of 25 mg q.d. is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.

Drug interaction studies were performed with EDURANT and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the C_max, AUC, and C_min values of rilpivirine are summarized in Table 6 (effect of other drugs on EDURANT). The effect of co-administration of EDURANT on the C_max, AUC, and C_min values of other drugs are summarized in Table 7 (effect of EDURANT on other drugs). [For information regarding clinical recommendations, see Drug Interactions (7) .]

Table 6: Drug Interactions: Pharmacokinetic Parameters for Rilpivirine in the Presence of Co-administered Drugs

Co-administered Drug	Dose/Schedule		N	Mean Ratio of Rilpivirine Pharmacokinetic Parameters With/Without Co-administered Drug (90% CI); No Effect = 1.00
	Co-administered Drug	Rilpivirine		Cmax	AUC	Cmin
CI = Confidence Interval; N = maximum number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily; b.i.d. = twice daily
Co-Administration With HIV Protease Inhibitors (PIs)
Darunavir/ritonavir	800/100 mg q.d.	150 mg q.d. 1	14	1.79 (1.56–2.06)	2.30 (1.98–2.67)	2.78 (2.39–3.24)
Lopinavir/ritonavir (soft gel capsule)	400/100 mg b.i.d.	150 mg q.d.	15	1.29 (1.18–1.40)	1.52 (1.36–1.70)	1.74 (1.46–2.08)
Co-Administration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)
Didanosine	400 mg q.d. delayed release capsules taken 2 hours before rilpivirine	150 mg q.d.	21	1.00 (0.90–1.10)	1.00 (0.95–1.06)	1.00 (0.92–1.09)
Tenofovir disoproxil fumarate	300 mg q.d.	150 mg q.d.	16	0.96 (0.81–1.13)	1.01 (0.87–1.18)	0.99 (0.83–1.16)
Co-Administration With HIV Integrase Strand Transfer Inhibitors
Raltegravir	400 mg b.i.d.	25 mg q.d.	23	1.12 (1.04–1.20)	1.12 (1.05–1.19)	1.03 (0.96–1.12)
Co-Administration With other Antivirals
Telaprevir	750 mg q8h	25 mg q.d.	16	1.49 (1.20–1.84)	1.78 (1.44–2.20)	1.93 (1.55–2.41)
Co-Administration With Drugs other than Antiretrovirals
Acetaminophen	500 mg single dose	150 mg q.d.	16	1.09 (1.01–1.18)	1.16 (1.10–1.22)	1.26 (1.16–1.38)
Atorvastatin	40 mg q.d.	150 mg q.d.	16	0.91 (0.79–1.06)	0.90 (0.81–0.99)	0.90 (0.84–0.96)
Chlorzoxazone	500 mg single dose taken 2 hours after rilpivirine	150 mg q.d.	16	1.17 (1.08–1.27)	1.25 (1.16–1.35)	1.18 (1.09–1.28)
Ethinylestradiol/Norethindrone	0.035 mg q.d./ 1 mg q.d.	25 mg q.d.	15	↔ 2	↔	↔
Famotidine	40 mg single dose taken 12 hours before rilpivirine	150 mg single dose	24	0.99 (0.84–1.16)	0.91 (0.78–1.07)	N.A.
Famotidine	40 mg single dose taken 2 hours before rilpivirine	150 mg single dose	23	0.15 (0.12–0.19)	0.24 (0.20–0.28)	N.A.
Famotidine	40 mg single dose taken 4 hours after rilpivirine	150 mg single dose	24	1.21 (1.06–1.39)	1.13 (1.01–1.27)	N.A.
Ketoconazole	400 mg q.d.	150 mg q.d.	15	1.30 (1.13–1.48)	1.49 (1.31–1.70)	1.76 (1.57–1.97)
Methadone	60–100 mg q.d., individualised dose	25 mg q.d.	12	↔	↔	↔
Omeprazole	20 mg q.d.	150 mg q.d.	16	0.60 (0.48–0.73)	0.60 (0.51–0.71)	0.67 (0.58–0.78)
Rifabutin	300 mg q.d.	25 mg q.d.	18	0.69 (0.62–0.76)	0.58 (0.52–0.65)	0.52 (0.46–0.59)
Rifabutin	300 mg q.d.	50 mg q.d.	18	1.43 (1.30–1.56)	1.16 (1.06–1.26)	0.93 (0.85–1.01)
				(reference arm for comparison was 25 mg q.d. rilpivirine administered alone)
Rifampin	600 mg q.d.	150 mg q.d.	16	0.31 (0.27–0.36)	0.20 (0.18–0.23)	0.11 (0.10–0.13)
Sildenafil	50 mg single dose	75 mg q.d.	16	0.92 (0.85–0.99)	0.98 (0.92–1.05)	1.04 (0.98–1.09)

CLINICAL STUDIES

Treatment-Naïve Subjects

The evidence of efficacy of EDURANT is based on the analyses of 48- and 96-week data from 2 randomized, double-blinded, active controlled, Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve adults. Antiretroviral treatment-naïve HIV-1 infected subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA ≥ 5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI RAMs. The Phase 3 trials were identical in design, with the exception of the background regimen (BR). In TMC278-C209, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278-C215, randomization was also stratified by N(t)RTI BR.

In the pooled analysis for TMC278-C209 and TMC278-C215, demographics and baseline characteristics were balanced between the EDURANT arm and the efavirenz arm. Table 9 displays selected demographic and baseline disease characteristics of the subjects in the EDURANT and efavirenz arms.

Table 9: Demographic and Baseline Disease Characteristics of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects in the TMC278-C209 and TMC278-C215 Trials (Pooled Analysis)

	Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials
	EDURANT + BR N=686	Efavirenz + BR N=682
BR=background regimen
Demographic Characteristics
Median Age, years (range)	36 (18–78)	36 (19–69)
Sex
Male	76%	76%
Female	24%	24%
Race
White	61%	60%
Black/African American	24%	23%
Asian	11%	14%
Other	2%	2%
Not allowed to ask per local regulations	1%	1%
Baseline Disease Characteristics
Median Baseline Plasma HIV-1 RNA (range), log10 copies/mL	5.0 (2–7)	5.0 (3–7)
Percentage of Patients with Baseline Plasma Viral Load:
≤ 100,000	54%	48%
> 100,000 to ≤ 500,000	36%	40%
> 500,000	10%	12%
Median Baseline CD4+ Cell Count (range), cells/mm3	249 (1–888)	260 (1–1137)
Percentage of Subjects with:
Hepatitis B/C Virus Co-infection	7%	10%
Percentage of Patients with the following background regimens:
tenofovir disoproxil fumarate plus emtricitabine	80%	80%
zidovudine plus lamivudine	15%	15%
abacavir plus lamivudine	5%	5%

Week 96 efficacy outcomes for subjects treated with EDURANT 25 mg once daily from the pooled analysis are shown in Table 10. The incidence of virologic failure was higher in the EDURANT arm than the efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment.

Table 10: Virologic Outcome of Randomized Treatment of Studies TMC278-C209 and TMC278-C215 (Pooled Data) at Week 96

	EDURANT + BR N=686	Efavirenz + BR N=682
N = total number of subjects per treatment group; BR = background regimen.
Note: Analysis was based on the last observed viral load data within the Week 96 window (Week 90–103), respectively.
HIV-1 RNA < 50 copies/mLCI = Predicted difference (95% CI) of response rate is -0.2 (-4.7; 4.3) at Week 96.	76%	77%
HIV-1 RNA ≥ 50 copies/mL 1	16%	10%
No virologic data at Week 96 window    Reasons
Discontinued study due to adverse event or deathIncludes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window.	4%	8%
Discontinued study for other reasons and last available HIV-1 RNA < 50 copies/mL (or missing)Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.	4%	5%
Missing data during window but on study	< 1%	< 1%
HIV-1 RNA < 50 copies/mL by Baseline HIV-1 RNA (copies/mL)
≤ 100,000	82%	78%
> 100,000	70%	75%
HIV-1 RNA ≥ 50 copies/mL by Baseline HIV-1 RNA (copies/mL)
≤ 100,000	9%	8%
> 100,000	24%	11%
HIV-1 RNA < 50 copies/mL by CD4+ cell count (cells/mm3)
< 200	68%	74%
≥ 200	81%	77%
HIV-1 RNA ≥ 50 copies/mL by CD4+ cell count (cells/mm3)
< 200	27%	10%
≥ 200	10%	9%

At Week 96, the mean CD4+ cell count increase from baseline was 228 cells/mm³ for EDURANT-treated subjects and 219 cells/mm³ for efavirenz-treated subjects in the pooled analysis of the TMC278-C209 and TMC278-C215 trials.

Study TMC278-C204 was a randomized, active-controlled, Phase 2b trial in antiretroviral treatment-naïve HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-finding part [EDURANT doses blinded] followed by a long-term, open-label part. After Week 96, subjects randomized to one of the 3 doses of EDURANT were switched to EDURANT 25 mg once daily. Subjects in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine.

Study TMC278-C204 enrolled 368 HIV-1-infected treatment-naïve adult subjects who had a plasma HIV-1 RNA ≥ 5000 copies/ml, previously received ≤ 2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI RAMs.

At 96 weeks, the proportion of subjects with <50 HIV-1 RNA copies/ml receiving EDURANT 25 mg (N = 93) compared to subjects receiving efavirenz (N = 89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 cells/mm³ in subjects receiving EDURANT 25 mg and 160 cells/mm³ in subjects receiving efavirenz.

At 240 weeks, 60% (56/93) of subjects who originally received 25 mg once daily achieved HIV RNA < 50 copies/mL compared to 57% (51/89) of subjects in the control group.