Monika Schöller-Gyüre
No pharmacokinetic interaction between TMC125
Tibotec BVBA
Generaal de Wittelaan L11 B3
(etravirine; ETR) and paroxetine in HIV-negative volunteers
B2800, Mechelen
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
Objectives: TMC125 is a next-generation NNRTI with
Treatment A
Treatment B
demonstrated activity in treatment-experienced HIV- Paroxetine
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. Methods: 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.
PK analyses
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 Paroxetine
Paroxetine +
(Treatment B). Paroxetine 20mg qd was co-administered on Plasma concentrations of paroxetine were determined using a validated (reference)
LSM ratio
PK parameter
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 Results: 16 male volunteers participated (median age
PK and safety parameters and
29 years). Least square mean (LSM) ratios and 90% Safety summary
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 Demographics
paroxetine was generally safe and well tolerated; one All volunteers
Demographic parameter
volunteer discontinued due to grade 2 rash. The most • When co-administered with paroxetine, TMC125 common adverse event (AE) was grade 1 nausea, which Conclusions: 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 Introduction
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 References
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.
Study design
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, paroxetine
separated by a washout period of at least 14 days as shown in the study (reference)
LSM ratio
design scheme. Half of the volunteers were randomised to start with (test/reference)
Treatment A and half were randomised to start with Treatment B Acknowledgements
PK parameter
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
Presented at the 11th European AIDS Conference, Madrid, Spain, 24–27 October 2007.


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