Absence of a pharmacokinetic interaction of rilpivirine with the P‐glycoprotein substrate digoxin in healthy volunteers
Authors: Crauwels H , Deckx H , Enweonye I , Stevens M , Hoetelmans R 
Published: November 2012

Rilpivirine (RPV, TMC278, Edurant®) is a next‐generation non‐nucleoside reverse transcriptase inhibitor (NNRTI), which demonstrated high virologic response rates and non‐inferiority versus efavirenz in two Phase III trials in HIV‐infected patients through 96 weeks [1,2]. RPV has been shown to inhibit P‐glycoprotein (P‐gp) in vitro with an apparent IC50 of 9.2 µM (3.4 µg/mL). This study evaluated the in‐vivo effect of steady‐state RPV 25 mg once daily (qd) on the single‐dose pharmacokinetics of the probe P‐gp substrate digoxin. This was a Phase I, open‐label, randomised, crossover trial in 22 HIV‐negative volunteers. Participants received in one session a single 0.5 mg dose of digoxin, and in another session RPV 25 mg qd for 16 days with a single 0.5 mg dose of digoxin in the morning of Day 11. All study drugs were taken with a breakfast. Pharmacokinetic profiles of digoxin in plasma and urine were determined over 144 hours after dosing in each session. Steady‐state RPV 24‐hour pharmacokinetic profiles in plasma were determined on Day 11. Plasma and urine samples were analysed using validated LC‐MS/MS methods. Pharmacokinetic parameters were calculated with non‐compartmental methods. The least square (LS) means and associated 90% confidence intervals (CI) of treatment ratios were calculated based on log‐transformed pharmacokinetic parameters. Safety and tolerability were assessed throughout the trial. Digoxin pharmacokinetic parameters and statistical results are summarised in Table 1.

Single dose pharmacokinetic parameters of digoxin in the absense and presence of steady‐state RPV

Parameter
digoxin 0.5 mg alone (reference)
digoxin 0.5 mg + RPV 25 mg qd (test)

N
21
22

AUC4h ng.h/mL
4.44±1.21
4.46±1.31

AUClast ng.h/mL
26.6±7.38
26.0±7.86

Cmax, ng/mL
1.93±0.637
2.05±0.678

tmax, h
1.50 (0.68–3.00)
1.74 (0.65–3.02)

t½, h
38.8±6.30
38.3±8.17

Durine total, %
47.7±9.51
55.7±12.2

CLR, L/h
9.46±2.54
11.2±2.66

LS means (90% CI) of digoxin pharmacokinetic parameter ratios*

AUClast

0.98 (0.93–1.04)a

Cmax

1.06 (0.97–1.17)a

CLR

1.16 (1.07–1.25)b

Ratios presented as test/reference, calculated based on log‐transformed pharmacokinetic parameters.
N=21 for test and N=22 for reference.
N=18 for test and N=22 for reference.

The plasma and urine digoxin pharmacokinetics were unaffected by co‐administration of steady‐state RPV. The 90% CIs of the LS means ratios of the main pharmacokinetic parameters were contained within the 0.80‐1.25 boundaries of no effect. The terminal elimination half‐life of digoxin was similar in the absence or the presence of steady‐state RPV. RPV pharmacokinetic parameters were comparable to those in previous clinical trials in healthy volunteers. Administration of digoxin and RPV was generally safe and well tolerated. There were no discontinuations due to adverse events. In conclusion, RPV does not affect the pharmacokinetics of the probe P‐gp substrate digoxin. In vivo, at the recommended RPV dose of 25mg qd, the observed in‐vitro inhibition of P‐gp by RPV is not clinically relevant.