Rilpivirine clinical pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
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 (5.0) 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 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of EDURANT 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax 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.
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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 (8.6)].
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 also Contraindications and Drug Interactions.]
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 Cmax, AUC, and Cmin values of rilpivirine are summarized in Table 6 (effect of other drugs on EDURANT). The effect of co-administration of EDURANT on the Cmax, AUC, and Cmin values of other drugs are summarized in Table 7 (effect of EDURANT on other drugs). For information regarding clinical recommendations, see Drug Interactions .[1]
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References
Adapted from the FDA Package Insert.