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No pharmacokinetic interaction between TMC125
Generaal de Wittelaan L11 B3
(etravirine; ETR) and paroxetine in HIV-negative volunteers
M Schöller-Gyüre,1 TN Kakuda,2 S Bollen,1 G De Smedt,1 B Woodfall,1 M Peeters,1 K Vandermeulen,1 RM Hoetelmans1
Tibotec BVBA, Mechelen, Belgium; 2Tibotec Inc., Yardley, PA, USA
Study design (cont’d)
Paroxetine plasma PK profile
TMC125 is a next-generation NNRTI with
demonstrated activity in treatment-experienced HIV-
infected patients, including those with NNRTI resistance.
TMC125 800mg bid
Paroxetine is widely used for the treatment of psychiatric
disorders and is primarily metabolised by CYP2D6.
TMC125 is a substrate of CYP3A4 and CYP2C and does
12-hour PK analysis of TMC125, determined on Day 7 and Day 14 of Treatment B
24-hour PK analysis of paroxetine, determined on Day 7 of Treatment A and Day 14 of Treatment B
not affect CYP2D6 in vitro. This study aimed to assess the
Safety and tolerability assessments were performed throughout the trial
pharmacokinetics of TMC125 and paroxetine when
until at least 30 days after the last trial medication intake
co-administered in HIV-negative volunteers.
This was an open-label, randomised, two-way,
two-period crossover trial in 16 HIV-negative volunteers. In
Treatment A, 20mg paroxetine qd was given for 7 days.
Paroxetine PK parameters
After 14 days washout, 800mg TMC125 bid (Phase II
Plasma concentrations of TMC125 were determined using a validated
formulation) was administered during Days 1–14
(Treatment B). Paroxetine 20mg qd was co-administered on
Plasma concentrations of paroxetine were determined using a validated
Days 8–14. Pharmacokinetics of TMC125 were assessed
PK and statistical PK analyses were performed using
SAS System for Windows® version 8.2 (SAS Institute Inc., Cary NC
over 12 hours on Day 7 and 14 of Treatment B; and of
paroxetine over 24 hours on Day 7 of Treatment A and
a non-compartmental model with extravascular input was used for the
Day 14 of Treatment B. Pharmacokinetic (PK) parameterswere obtained by non-compartmental analysis and
LC-MS/MS = liquid chromatography-tandem mass spectrometry;
summarised using a linear mixed effects model. Safety and
16 male volunteers participated (median age
PK and safety parameters and
29 years). Least square mean (LSM) ratios and 90%
confidence intervals (CI) for the primary PK parameters
The most frequently reported AE was grade 1 nausea in two
(area under the plasma concentration-time curve
volunteers, both reported during co-administration of TMC125 and
over 12- or 24-hour period, calculated by linear trapezoidal
All AEs reported were mild (grade 1) or moderate (grade 2) in
AEs, laboratory assessments, electrocardiogram (ECG), vital signs
summation), maximum plasma concentration (C ) and
assessment and physical examinations were evaluated throughout the study
severity and drug relationship of AEs to TMC125 and/or paroxetine were
One volunteer discontinued the trial on Day 9 of Treatment B
minimum plasma concentration (C ) obtained for TMC125
(TMC125 co-administered with paroxetine) due to grade 2 rash,
possibly related to TMC125 and paroxetine
during combined administration with paroxetine versus
descriptive statistics were calculated for the PK parameters of TMC125 and
There were no consistent or relevant changes in laboratory or
TMC125 treatment alone were all within the limits
cardiovascular safety parameters or physical examinations. One
LSM ratios and 90% CIs were estimated with a linear mixed effects model
volunteer had a grade 3 elevation of amylase during both TMC125
safety parameters were evaluated by descriptive statistics and frequency
0.80–1.25. When co-administered with TMC125,paroxetine LSM ratio for AUC
0.87 (90% CI: 0.75–1.02) compared to administrationalone. The concomitant administration of TMC125 and
paroxetine was generally safe and well tolerated; one
volunteer discontinued due to grade 2 rash. The most
• When co-administered with paroxetine, TMC125
common adverse event (AE) was grade 1 nausea, which
TMC125 and paroxetine pharmacokinetics
• TMC125 had no effect on the pharmacokinetics
are not affected when given concomitantly. TMC125 and
paroxetine can be co-administered without doseadjustments.
• Short-term co-administration of TMC125 with
paroxetine in HIV-negative volunteers was
TMC125 plasma PK profile
• TMC125 and paroxetine can be co-administered
TMC125 is a next-generation NNRTI with potent activity against both wild-type
HIV-1 and HIV-1 resistant to current NNRTIs1
Two Phase III trials (DUET-1 and DUET-2) demonstrated significant antiviral
benefit after 24 weeks of treatment with TMC125 in treatment-experienced
patients with resistance to currently approved NNRTIs. Except for a higher incidence of rash, patients treated with TMC125 had an AE profile similar to
TMC125 is predominantly metabolised by the cytochrome P450 enzymes
CYP3A4, CYP2C9 and CYP2C19, followed by glucuronidation; it is an inducer
of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19
Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is used in the
clinical management of depression and anxiety and is frequently administered
Paroxetine is primarily metabolised by CYP2D64,5 and partly by CYP3A4, and
subsequently conjugated into its pharmacologically inactive metabolites.
Paroxetine is also an inhibitor of CYP2D6
1. Vingerhoets J, et al. J Virol 2005;79:12773–82.
To support concomitant administration, an interaction study with paroxetine
2. Madruga JV, et al. Lancet 2007;370:29–38.
3. Lazzarin A, et al. Lancet 2007;370:39–48.
4. Basu S, et al. AIDS 2005;19:2057–67 .
5. Hemeryck, et al. Curr Drug Metab 2002;1:13–37.
TMC125 PK parameters
TMC125-C165 was a Phase I, open-label, two-way, two-period crossover trial in 16 HIV-negative volunteers
Two treatment sessions (A and B) were scheduled for all volunteers,
separated by a washout period of at least 14 days as shown in the study
design scheme. Half of the volunteers were randomised to start with
Treatment A and half were randomised to start with Treatment B
TMC125 was administered as 800mg bid of Phase II formulation (TF035), which provides comparable exposure to that obtained with 200mg bid of
The authors would like to express their gratitude to the volunteers.
All doses were taken within 10 minutes after a standardised meal
Post-treatment safety visits took place 7 days and 31 ( 1) days after the last
– MP Bouche, J&J Pharmaceutical Research and Development,
The trial protocol was reviewed and approved by the appropriate institutional ethics committee and health authorities; the trial was conducted
in accordance with the Declaration of Helsinki
– T Duvauchelle, Aster Clinical Unit, Paris, France.
Supported by Tibotec
This poster is available on-line at www.tibotec.com
Presented at the 11th European AIDS Conference, Madrid, Spain, 24–27 October 2007.
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