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8-oa-0292_hoetelmans.qxp 13/6/07 17:16 Page 509 Antiviral Therapy 12:509–514 Pharmacokinetic interaction between TMC114/r and efavirenz in healthy volunteers Vanitha J Sekar1*, Martine De Pauw2, Kris Mariën2, Monika Peeters2, Eric Lefebvre1 and Richard MW Hoetelmans2 1 Tibotec, Inc., Yardley, PA, USA Tibotec BVBA, Mechelen, Belgium 2 *Corresponding author: Tel: +1 609 730 7500; Fax: +1 609 730 7501; E-mail: [email protected] Background: This open-label, crossover study investigated the pharmacokinetic interaction between TMC114 (darunavir [Prezista™]), administered with low-dose ritonavir (TMC114/r) and efavirenz (EFV) in HIV-negative, healthy volunteers. Methods: Volunteers received TMC114/r 300/100 mg twice daily for 6 days, and once daily on day 7 (session 1). After a 7-day washout period volunteers received EFV 600 mg once daily for 18 days (session 2), with coadministration of TMC114/r 300/100 mg twice daily from day 11–day 16 and TMC114/r once daily on day 17. Results: When coadministered with TMC114/r, plasma concentrations of EFV were slightly increased. In the presence of TMC114/r, EFV minimum (Cmin) and maximum (Cmax) plasma concentrations increased by 15–17%, and by 21% for EFV area under the curve (AUC24h). TMC114/r and EFV coadministration resulted in TMC114 Cmin, Cmax and AUC12h decreases of 31%, 15% and 13%, respectively. No serious adverse events (AEs) or AEs leading to withdrawal were reported in this trial. Overall, TMC114/r and EFV coadministration was well tolerated. Conclusions: The clinical significance of the changes in AUC and Cmin seen with TMC114/r and EFV coadministration has not been established; this combination should be used with caution. Similar findings are expected with the approved TMC114/r 600/100 mg twice daily dose. Introduction Guidelines for the treatment of HIV-infected individuals recommend the first-line use of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a protease inhibitor (PI, generally boosted) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in antiretroviral-naive patients [1–3]. The two most widely used NNRTIs are efavirenz (EFV) and nevirapine, which showed comparable antiviral efficacy in a large open-label, randomized trial in treatment-naive patients with chronic HIV infection [4]. Treatmentexperienced patients who have failed to respond to first-line PI therapy due to the emergence of virological resistance may require optimized regimens including both NNRTIs and PIs. Combining a PI with an NNRTI has been successful in nucleoside-experienced patients. Thus, in the AIDS Clinical Trials Group (ACTG) 364 study a quadruple regimen including nelfinavir and EFV and two NRTIs provided a greater likelihood of achieving virological suppression at 144 weeks than a triple antiretroviral regimen including either nelfinavir or EFV [5]. However, the benefits observed with such a quadruple regimen, containing both a PI and an NNRTI, must be balanced with the potential tolerability issues observed with this combination [6]. The combined use of NNRTIs and PIs has © 2007 International Medical Press 1359-6535 also been confirmed as a promising strategy in singlePI-experienced patients, although direct comparative studies with other optimized regimens are lacking [7]. Data (24-week) from the noncomparative Bitherapy Kaletra Sustiva (BIKS) study, which includes both treatment-experienced and treatment-naive patients, have suggested that the NRTI-sparing regimen of boosted lopinavir/EFV may provide effective antiviral and immunological activity with acceptable tolerability [8]. ACTG 5142 compared EFV plus NRTIs with a lopinavir/ritonavir (LPV/r) plus NRTIs regimen, and it also compared these two regimens to a regimen of only LPV/r and EFV (without NRTIs) [9]. Compared with a regimen of EFV + NRTIs, LPV/r + NRTIs had a significantly shorter time to virological failure. At 96 weeks, the NRTI-sparing regimen of LPV/r + EFV had similar virological efficacy and similar time to treatment-limiting toxicity as EFV + NRTIs. In general, PIs are rapidly absorbed and extensively metabolized primarily via cytochrome P450 (CYP) 3A4 pathways. NNRTIs lower the plasma concentrations of PIs [10–12] mainly by induction of CYP3A4 metabolism; this induction can be reversed by coadministration of low-dose ritonavir (RTV) [13,14]. Interactions with NNRTIs differ considerably amongst 509 8-oa-0292_hoetelmans.qxp 13/6/07 17:16 Page 510 VJ Sekar et al. PIs and predicting the direction or size of potential interactions a priori can be difficult. TMC114 (darunavir, [Prezista™]) is a novel PI, highly active against both wild-type and resistant HIV1 strains in vitro, including a broad range of over 4,000 clinical isolates [15,16]. TMC114 has received its first regulatory approvals for the treatment of HIV infection in treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one PI [17]. TMC114 is a substrate for CYP3A4 metabolism [18], and an inhibitor of this enzyme. In HIV-negative, healthy volunteers, coadministration of TMC114 as a polyethylene glycol (PEG) 400-containing oral solution with low-dose RTV (TMC114/r) resulted in an improved pharmacokinetic profile compared with TMC114 alone [19]. An interaction with NNRTIs may significantly lower the exposure to TMC114, and thereby lower the efficacy of TMC114/r. Given the possible future use of TMC114/r in combination with EFV in clinical practice, the present study was performed to assess the potential for a pharmacokinetic interaction and to determine whether dose adjustments may be required during coadministration. Short-term safety and tolerability of the coadministration of TMC114/r with EFV was also assessed. Materials and methods Study population and study design This was an open-label, crossover study to investigate the pharmacokinetic interaction between TMC114, coadministered with low-dose RTV (TMC114/r), and EFV. The study participants were 12 HIV-negative, healthy volunteers aged 18–55 years. During session 1, volunteers received 300 mg TMC114 and 100 mg RTV (TMC114/r 300/100 mg) twice daily for 6 days with an additional dose in the morning of day 7. Following a 7-day washout period, volunteers received 600 mg EFV once daily in the morning for 18 days (session 2). TMC114/r 300/100 mg twice daily was coadministered with EFV 600 mg once daily from day 11 until day 16, with an additional single dose of TMC114/r 300/100 mg given on day 17. In this study, EFV was taken with or without food and TMC114/r was taken with food. TMC114 was formulated as an oral aqueous solution (20 mg/ml TMC114 containing D-α-tocopheryl polyethylene glycol 1000 succinate and PEG 400 as main solubilizing agents), while RTV (100 mg) and EFV (3× 200 mg) were given as commercially available capsules. Dosing of study medication by the volunteers at home was performed according to a predefined schedule; times of study drug administration and meal times were recorded in a diary. On day 7 of session 1 and days 10 and 17 of session 2, when samples were taken for 510 pharmacokinetic analysis, study drugs had to be taken within 15 min of completing a standard breakfast. The study protocol was reviewed and approved by the appropriate institutional ethics committee(s) and health authorities, and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all volunteers. Pharmacokinetic assessments Serial venous blood samples were drawn over the dosing interval for TMC114, RTV and EFV. Plasma concentrations of TMC114, RTV and EFV were determined using validated liquid chromatography tandem mass spectrometry methods. The lower limit of quantification was 10.1 ng/ml for TMC114, 5.0 ng/ml for RTV and 50.0 ng/ml for EFV. On days 12, 14 and 16 of session 2 both TMC114/r and EFV predose concentrations were determined. On days 17, 18 and 19 of session 2, TMC114 and RTV plasma concentrations were determined in samples taken predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 36 and 48 h postdose. On day 17 of session 2, EFV concentrations were determined in samples taken predose and at 1, 2, 3, 4, 5, 6, 9, 12 and 24 h postdose. Safety evaluations Volunteers were monitored regularly throughout the study for cardiovascular parameters and biochemical characteristics of blood and urine. In addition, fasted blood lipid values were evaluated. The investigator scored the severity of adverse events (AEs) as mild, moderate, severe, or (potentially) life-threatening. Laboratory safety blood samples were obtained on days 1, 4 and 7 of session 1 and days 1, 4, 7, 10, 12, 14, 17 and 19 of session 2. All safety evaluations were graded according to the ACTG severity grading scales. Statistical methods Descriptive statistics were calculated for the plasma concentrations of TMC114, RTV and EFV, and the urinary concentrations of TMC114. WinNonlin Professional™ (version 3.3; Pharsight Corp., Mountain View, CA, USA) was used for pharmacokinetic analysis. The pharmacokinetic parameters were determined by noncompartmental methods and included the area under the curve over the dose interval (AUC12h or AUC24h), minimum (Cmin) and maximum (Cmax) plasma concentrations, time to maximum plasma concentration (tmax), terminal elimination half-life defined as 0.693/λz (t1/2term), and elimination rate constant (λz). Comparison of the pharmacokinetic parameters Cmin, Cmax and AUC12h of TMC114/r with and without concomitant EFV and comparison of the pharmacokinetic parameters of Cmin, Cmax and AUC24h of EFV with and without concomitant TMC114/r were © 2007 International Medical Press 8-oa-0292_hoetelmans.qxp 13/6/07 17:16 Page 511 PK interaction of TMC114/r and efavirenz Of the 22 volunteers screened, 12 were assigned to treatment and completed the study. The median age was 42 years (range: 20–54) and four of the volunteers were female. The median (range) in body weight was 71.5 (64–90) kg and median (range) body mass index was 24.6 (20–29) kg/m2. One volunteer received 10 mg domperidone on day 10 of session 2 during treatment with EFV alone, and was included in the pharmacokinetic analysis. Pharmacokinetic data Mean plasma concentration–time curves of TMC114 and EFV are shown in Figures 1A and B, respectively. Mean TMC114 plasma concentrations were decreased while those of EFV were increased following coadministration of EFV and TMC114/r. However, median TMC114 or EFV tmax was not influenced by coadministration of the two compounds. Mean pharmacokinetic parameters determined for TMC114 are shown in Table 1. Predose plasma concentrations of TMC114 were comparable between days 4, 6 and 7 of session 1 and between days 14, 16 and 17 of session 2, showing achievement of steady-state prior to pharmacokinetic assessments. The mean t1/2term of TMC114 was decreased by approximately 50% after coadministration of EFV, from 12.5 ±4.8 to 5.0 ±1.1 h. Mean TMC114 Cmax and AUC12h were decreased by 15% (LS means ratio, 90% CI: 0.85, 0.72–1.00) and 13% (LS means ratio, 90% CI: 0.87, 0.75–1.01), respectively, and mean Cmin was decreased by 31% (LS means ratio, 90% CI: 0.69, 0.54–0.87), respectively (Table 1). EFV AUC24h was increased by 21% (LS means ratio, 90% CI: 1.21, 1.08–1.36), Cmin by 17% (LS means ratio, 90% CI: 1.17, 1.01–1.36) and Cmax by 15% (LS means ratio, 90% CI: 1.15, 0.97–1.35) after coadministration of TMC114/r (Table 2). Systemic exposure to low-dose RTV coadministered with TMC114 was decreased in the presence of EFV. Based on the LS means ratio, there was a decrease of 28% in RTV AUC12h (LS means ratio, 90% CI: 0.72, 0.61–0.84), a decrease of 32% in RTV Cmax (LS means ratio, 90% CI: 0.68, 0.58–0.81) and a decrease of 40% in RTV Cmin (LS means ratio, 90% CI: 0.60, 0.47–0.77) in the presence of EFV. Antiviral Therapy 12:4 A Plasma concentration of TMC114, ng/ml Results Figure 1. Mean plasma concentration–time profiles of TMC114 and EFV 3,500 3,000 2,500 2,000 1,500 1,000 without EFV with EFV 500 0 0 2 4 6 8 10 12 10 12 Scheduled time, h B Plasma concentration of EFV, ng/ml performed using linear mixed effect modelling. The least square (LS) means ratio and 90% confidence intervals (CI) around the LS means ratio were reported with treatment of TMC114/r alone or treatment of EFV alone as reference. The nonparametric t-test (Koch) was used for tmax. No statistical analysis was performed for other pharmacokinetic parameters. 5,000 4,000 3,000 2,000 without TMC114/r with TCMC114/r 1,000 0 0 2 4 6 8 Scheduled time, h (A) TMC114 administered as TMC114/r 300/100 mg twice daily without or with steady-state concentrations of efavirenz (EFV) 600 mg daily on day 7 of session 1 and day 17 of session 2, respectively. (B) EFV administered as 600 mg daily without or with TMC114/r 300/100 mg twice daily on day 10 and 17 of session 2, respectively. TMC114/r, darunavir with low-dose ritonavir. Safety and tolerability All 12 volunteers reported at least one AE during the trial. Of all AEs reported, 63%, 34% and 3% were classified by the investigator as mild, moderate and severe, respectively. All severe events were reported during treatment with EFV. The most commonly reported AEs during the entire trial were nervous system disorders (12/12 volunteers), general disorders (which included fatigue, feeling hot, symptoms associated with excess alcohol consumption and loin pain; 9/12), gastrointestinal disorders (9/12) and psychiatric disorders (9/12). Nine volunteers experienced nervous system disorder-related AEs during combined treatment with EFV and TMC114/r, with headache, dizziness, somnolence and disturbance in attention occurring in 4/12, 7/12, 7/12 and 3/12 volunteers, respectively. Gastrointestinal disorders occurred in 9/12 volunteers during combined treatment with EFV and TMC114/r. Of these, three volunteers (3/12) each suffered from diarrhoea and vomiting and five volunteers (5/12) 511 8-oa-0292_hoetelmans.qxp 13/6/07 17:16 Page 512 VJ Sekar et al. Table 1. Statistical evaluation of the pharmacokinetic characteristics of TMC114 administered as TMC114/r 300/100 mg twice daily with or without coadministration of EFV 600 mg once daily LS means Parameter TMC114/r TMC114/r + EFV Ratio 90% CI n tmax, h Cmin, ng/ml Cmax, ng/ml AUC12h, ng•h/ml 12 0.75 [0.0–2.0] 1772 ±708 3,460 ±943 28,865 ±8,360 12 0.5 [0.5–3.0] 1,250 ±511 2,998 ±938 25,483 ±7,844 — 0.69 0.85 0.87 — 0.54–0.87 0.72–1.00 0.75–1.01 tmax value is median (range); all other values are mean ±SD. AUC, area under plasma concentration–time curve; Cmax, maximum plasma concentration; Cmin, minimum plasma concentration; CI, confidence interval; EFV, efavirenz; LS, least square; tmax, time to maximum plasma concentration; TMC114/r, darunavir with low-dose ritonavir. Table 2. Statistical evaluation of the pharmacokinetic characteristics of EFV 600 mg once daily with or without coadministration of TMC114/r 300/100 mg twice daily Session 2 Parameter Day 10 EFV LS means Day 17 EFV + TMC114/r Ratio 90% CI n tmax, h Cmin, ng/ml Cmax, ng/ml AUC24h, ng•h/ml 12 4.0 [2.0–5.0] 1,647 ±1,078 4,595 ±1,480 61,800 ±30,350 12 4.0 [3.0–5.0] 1,989 ±1,621 5,297 ±1,889 76,429 ±45,527 — 1.17 1.15 1.21 — 1.01–1.36 0.97–1.35 1.08–1.36 tmax value is median (range); all other values are mean ±SD. AUC, area under plasma concentration–time curve; Cmax, maximum plasma concentration; Cmin, minimum plasma concentration; CI, confidence interval; EFV, efavirenz; LS, least square; tmax, time to maximum plasma concentration; TMC114/r, darunavir with low-dose ritonavir. reported nausea. Three volunteers reported rash during treatment with EFV alone or during combined treatment with EFV and TMC114/r. No serious AEs or AEs leading to withdrawal were reported in this trial. In this study, EFV was administered in the presence of food; according to the US package insert for Sustiva (ie EFV), taking EFV with food increases EFV concentrations and may increase the frequency of adverse events. Most observed laboratory abnormalities were grade 1 in severity. Treatment-emergent grade 2 increases in cholesterol were observed during the following treatment phases: TMC114/r (2/12), EFV alone (3/12) and combined EFV and TMC114/r treatment (4/12). No grade 4 abnormalities were reported. One volunteer reported a treatment-emergent grade 3 elevation in cholesterol during combined EFV and TMC114/r treatment. One case of treatment-emergent grade 2 increase in alanine aminotransferase (ALT) was reported during combined EFV and TMC114/r treatment. No grade 3 or 512 4 elevations of ALT were observed and no abnormalities of aspartate aminotransferase were noted throughout the study. No abnormalities in vital signs or electrocardiograms leading to AEs were observed. Discussion The efficacy and safety of an antiretroviral regimen containing both TMC114/r and EFV may depend on the overall effect of the various pharmacokinetic interactions that may occur in the shared metabolic pathways. It is known that drug interactions mediated through the CYP3A4 isozyme can be clinically significant. EFV is an inducer of CYP3A4 and increases the rate of biotransformation of coadministered drugs that are CYP3A4 substrates [20,21]. EFV is a mixed inhibitor/inducer of other cytochrome isozymes, such as CYP2B6 and CYP3A. RTV inhibits CYP2B6 and is a potent inhibitor of CYP3A4 and, to a lesser extent, CYP2D6 [22–25]. RTV is also an inducer of certain other CYP isozymes [23]. TMC114 is both a substrate and an inhibitor of CYP3A4. Given the complex range of interactions of these three drugs with the P450 system, it is important to examine the effect of their coadministration in a clinical setting. In the ongoing POWER 1 (TMC114-C213) and POWER 2 (TMC114-C202) randomized controlled trials, designed to evaluate the efficacy and safety of TMC114/r in treatment-experienced HIV patients, four TMC114/r doses (400/100 mg once daily, 800/100 mg once daily, 400/100 mg twice daily and 600/100 mg twice daily) were compared with control PI regimens. An optimized background regimen consisting of NRTIs with or without enfuvirtide was used in each treatment arm. In pharmacokinetic analyses, there was no correlation with efficacy and TMC114 exposure at the recommended dose (600/100 mg twice daily), however, TMC114 fold change was a strong predictor of response [26,27]. EFV was not permitted in the POWER 1 or 2 studies as eligible subjects were required to be NNRTI-experienced; nevertheless, based on these analyses, the 13% decrease in TMC114 exposure due to EFV coadministration observed in this present study is not likely to be clinically relevant. The pharmacokinetic and pharmacodynamic relationships observed in the POWER studies support the selection of the TMC114/r 600/100 mg twice daily dose for the treatment of HIV-1 infected patients with prior treatment experience [25]. In this study, coadministration of EFV with TMC114/r resulted in a 21% increase in EFV exposure (AUC24h) and a 13% decrease in TMC114 exposure (AUC12h). When TMC114/r and EFV were administered concomitantly, Cmin of TMC114 was decreased by 31%. However, the mean TMC114 Cmin in the © 2007 International Medical Press 8-oa-0292_hoetelmans.qxp 13/6/07 17:16 Page 513 PK interaction of TMC114/r and efavirenz presence of EFV was 20-fold and sixfold greater than wild-type IC50 and IC90, respectively [17]. Concomitant administration of TMC114 300 mg with RTV 100 mg twice daily and EFV 600 mg once daily resulted in a decreased exposure to TMC114. Exposure to EFV was increased when administered with TMC114/r; the clinical significance of these changes has not been established. Exposure (AUC) to TMC114 has been found to increase less than dose proportionally. In HIV-infected patients receiving TMC114/r doses of 400/100 mg twice daily or 600/100 mg twice daily regimens, a considerable overlap in the exposure to TMC114 was obtained with these two dosing regimens. The 50% increase in dose between the 400/100 mg twice daily and 600/100 mg twice daily regimens resulted in only a 29% increase in median TMC114 exposure [26]. On this basis, the results of this study conducted with the TMC114/r 300/100 mg twice daily regimen is considered applicable to subjects receiving the recommended 600/100 mg twice daily dosing regimen. In conclusion, combinations of TMC114/r and EFV should be used with caution. Given the need to combine active antiretroviral drugs in the treatment of HIV infection, the coadministration of NNRTIs and TMC114/r is permitted and is currently being evaluated in an ongoing Phase III clinical trial in treatmentexperienced patients (TMC114-C214 or TITAN). 4. 5. 6. 7. 8. 9. 10. Acknowledgements Medical writing services were provided by Fiona Fernando of Gardiner-Caldwell Communications (GCC), Macclesfield, UK. This study was financially supported by Tibotec Pharmaceuticals Inc. Conflict of interest 11. 12. 13. All authors are employees of Tibotec. 14. Disclosure Some of the data shown in this article have previously been presented as a poster presentation at the 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20–22 April 2006, Lisbon, Portugal; poster 55. References 1. 2. 3. Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA Panel. JAMA 2006; 296:827–843. 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Eur J Clin Pharmacol 2005; 60:865–873. Sekar V, De Meyer S, Vangeneugden T, et al. Pharmacokinetic/pharmacodynamic (PK/PD) analyses of TMC114 in the POWER 1 and POWER 2 trials in treatment-experienced HIV-infected patients. 13th Conference on Retroviruses & Opportunistic Infections. 5–8 February 2006, Denver, CO, USA. Abstract 639b. Sekar V, De Meyer S, Vangeneugden T, et al. Absence of TMC114 exposure-efficacy and exposure-safety relationships in POWER 3. 16th International AIDS Conference. 13–18 August 2006, Toronto, Canada. Abstract TUPE0078. Accepted for publication 11th January 2007 514 © 2007 International Medical Press