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Efficacy and safety of TMC278 in antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial
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2 January 2010
Pozniak, Anton L; Morales-Ramirez, Javier; Katabira, Elly; Steyn, Dewald; Lupo, Sergio H; Santoscoy, Mario; Grinsztejn, Beatriz; Ruxrungtham, Kiat; Rimsky, Laurence T; Vanveggel, Simon; Boven, Katia; on behalf of the TMC278-C204 study group aChelsea and Westminster NHS Foundation Trust and PKR/SSR, London, UK bClinical Research Puerto Rico, Inc, San Juan, Puerto Rico cMakerere University, Kampala, Uganda dUniversity of the Free State, Bloemfontein, South Africa eUniversidad Nacional de Rosario, Santa Fe, Argentina fHospital Carlos Mac Gregor IMSS, Mexico City, Mexico gInstituto de Pesquisa Cl’nica Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil hHIV-NAT, Thai Red Cross AIDS Research Centre and Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand iTibotec BVBA, Mechelen, Belgium jTibotec Inc., Yardley, Pennsylvania, USA.
Objective: TMC278 is a next-generation nonnucleoside reverse transcriptase inhibitor highly active against wild-type and nonnucleoside reverse transcriptase inhibitor-resistant HIV-1 in vitro. The week 96 analysis of TMC278-C204, a large dose-ranging study of TMC278 in treatment-naive HIV-1-infected patients, is presented.
Design: Phase IIb randomized trial.
Methods: Three hundred sixty-eight patients were randomized and treated with three blinded once-daily TMC278 doses 25, 75 or 150 mg, or an open-label, active control, efavirenz 600 mg once daily, all with two nucleoside reverse transcriptase inhibitors. The primary analysis was at week 48.
Results: No TMC278 dose-response relationship for efficacy and safety was observed. TMC278 demonstrated potent antiviral efficacy comparable with efavirenz over 48 weeks that was sustained to week 96 (76.9-80.0% and 71.4-76.3% of TMC278-treated patients with confirmed viral load <50 copies/ml, respectively; time-to-loss of virological-response algorithm). Median increases from baseline in CD4 cell count with TMC278 at week 96 (138.0-149.0 cells/µl) were higher than at week 48 (108.0-123.0 cells/µl). All TMC278 doses were well tolerated. The incidences of the most commonly reported grade 2-4 adverse events at least possibly related to study medication, including nausea, dizziness, abnormal dreams/nightmare, dyspepsia, asthenia, rash, somnolence and vertigo, were low and lower with TMC278 than with efavirenz. Incidences of serious adverse events, grade 3 or 4 adverse events and discontinuations due to adverse events were similar among groups.
Conclusion: All TMC278 doses demonstrated potent and sustained efficacy comparable with efavirenz in treatment-naive patients over 96 weeks. TMC278 was well tolerated with lower incidences of neurological and psychiatric adverse events, rash and lower lipid elevations than those with efavirenz. TMC278 25 mg once daily was selected for further clinical development.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of highly active antiretroviral (ARV) therapy (HAART) in treatment-naive patients due to their good tolerability and long-term efficacy [1-5]. However, the first NNRTIs approved for treatment-naive patients, nevirapine (NVP) and efavirenz (EFV), have a low genetic barrier to the development of drug resistance, as well as substantial cross-resistance [6-11]. Furthermore, though they are generally well tolerated, they also have a number of associated safety concerns, including hepatotoxicity, neuropsychiatric disorders and rash [12-16]. Therefore, new, potent NNRTIs with activity against NNRTI-resistant viruses and better tolerability are needed. The next-generation NNRTI, etravirine (ETR, TMC125, INTELENCE) has recently been approved for use in combination with other ARV agents in treatment-experienced adult patients with HIV resistant to first-generation NNRTIs [17,18].
TMC278 is a next-generation NNRTI with potent in-vitro anti-HIV activity against wild-type and NNRTI-resistant isolates [19]. This potency is likely to be related to the structural flexibility of TMC278 [20-21]. TMC278 monotherapy 25, 50, 100 or 150 mg once daily (q.d.) demonstrated potent ARV activity and favourable safety in a 7-day randomized, double-blinded, placebo-controlled, proof-of-principle trial in treatment-naive patients [22].
Here we present data from the week 48 and 96 analyses of TMC278-C204, a large dose-ranging study in treatment-naive patients.
Data from this phase IIb, randomized study demonstrate the potent and sustained efficacy of q.d. oral TMC278 25, 75 and 150 mg through 96 weeks in treatment-naive-HIV-1-infected patients. The proportion of patients with viral load less than 50 copies/ml at 48 weeks was high (>75%) and well maintained to week 96, as was the plasma viral load reduction, with no clear differentiation between TMC278 doses. Importantly, rates of virological failures were similarly low for the EFV and TMC278 groups. CD4 cell count further increased at week 96 compared with week 48. No statistically significant differences in efficacy were observed between TMC278 and EFV at weeks 48 or 96.
Although comparisons across studies are difficult due to differences in selection criteria and baseline characteristics, efficacy data for TMC278 in this study compare favourably with week 96 data from historical studies of EFV in treatment-naive patients [27,28]. In the GS903 [27] and GS934 studies [28], 68-73% and 61-67% of EFV-treated patients, respectively, in the ITT populations achieved a viral load less than 50 copies/ml after 96 weeks.
The number of patients failing TMC278 and developing RAMs was limited; therefore, definitive conclusions about the resistance profile of TMC278 could not be drawn from this study. The virological findings are being explored further in the phase III trials.
All TMC278 doses were generally safe and well tolerated, and the overall incidence of grade 2-4 adverse events at least possibly related to treatment was lower with TMC278 than with EFV. The most common grade 2-4 adverse events at least possibly associated with TMC278 included nausea and dizziness, as is the case with currently available NNRTIs approved for use in treatment-naive patients [12-16]. Although first-generation NNRTIs approved for use in treatment-naive patients are generally well tolerated, they are associated with some safety concerns, including rash, most commonly with NVP [13,14], nervous system and psychiatric effects, as well as increases in cholesterol and triglyceride levels more common with EFV [12-14,16]. Rash, neurological and psychiatric adverse events occurred less frequently with TMC278 than with EFV in this study and in comparison with historical data on EFV [16]. Furthermore, increases in total and LDL-C and triglycerides were either not, or only minimally, observed with TMC278. In contrast, there were increases in these lipid parameters in the EFV group. Anaemia and haemoglobin abnormalities were more common with TMC278 than with EFV. Haemoglobin decreases, however, were primarily observed in patients using AZT/3TC as the NRTI backbone. Haemoglobin levels returned to baseline values for all groups.
Female patients of childbearing potential are not ideal candidates for EFV because it is potentially teratogenic in pregnant women [16]. Pregnancy was an exclusion criterion in this study. Two women in the EFV group and one woman in the TMC278 25 mg group became pregnant during the trial and discontinued. Prior to Food and Drug Administration ruling in 2000, recruiting women with HIV-related and AIDS-related disease to clinical trials has been challenging because such patients were often excluded due to the potential for reproductive toxicity. Therefore, another important success of this trial was the high female recruitment, with 33% of the total patients being women.
One limitation of the study was that it was open-label with respect to EFV administration. However, the ongoing phase III trials of TMC278 vs. EFV in treatment-naive patients are randomized, double-blind, double-dummy trials. Also, the size of the treatment groups in this phase II trial was relatively small in comparison with that in the phase III trial. Nevertheless, this was a large phase IIb study in which 279 patients received TMC278, and results demonstrate that TMC278 is a well tolerated and potent ARV, with the potential to offer significant clinical benefits to treatment-naive HIV-1-infected patients. All doses of q.d. oral TMC278 demonstrated high and sustained efficacy similar to that of EFV over 96 weeks. TMC278 was associated with lower incidences of neurological and psychiatric adverse events, rash and smaller increases in lipids than EFV. The TMC278 25 mg dose offers the best benefit-risk balance for further development in treatment-naive, HIV-1-infected patients.
Baseline characteristics and patient disposition

Patients were recruited between 1 June and 19 October 2005. In total, 515 patients were screened, of whom 373 were randomized. Of those, 368 patients were treated (ITT population) and included in this week 96 analysis (Fig. 1).
In general, demographic parameters and baseline disease characteristics were well balanced across groups (Table 1). However, there was an imbalance in the proportion of patients with very high viral loads (>300 000 copies/ml; 11.2% for EFV and 23.2-26.4% for TMC278). The patients' median age was 35 years, 45% were white and 33% were female patients.
The proportions of patients from each region were well balanced (region 1: 34%, region 2: 35%, and region 3: 31%). Overall, 75.5% of patients initiated ARV therapy with AZT/3TC, whereas 24.5% used TDF/FTC. A high proportion of patients in regions 1 (96.8%) and 3 (93.0%) started with AZT/3TC. In region 2, 60.8% started with TDF/FTC, reflecting ARV availability and the local standard of care.
Overall, 91 patients (25%) had discontinued the trial at the time of the 96-week analysis, with no differences among groups in the overall proportion of discontinuations. The most common reasons for discontinuation were adverse event/HIV-related event (11.1%), lost to follow-up (3.3%), virological failure (3.3%), withdrawal of consent (2.7%) and noncompliance (1.6%).
Safety and tolerability
The safety results include all information at the time of the week 96 analysis; a substantial number of patients were treated for longer than 96 weeks (Table 3; median treatment duration 100.4 weeks). In general, all TMC278 doses were safe and well tolerated, and there was no consistent association between safety assessments and TMC278 dose.
The incidence of any grade 2-4 adverse events at least possibly related to TMC278 or EFV was lower in the TMC278 combined group than in the EFV group (20.4 vs. 37.1%, respectively; P = 0.003). The most commonly reported grade 2-4 adverse events at least possibly related to study medication (occurring in ³2% of patients in the combined TMC278 group or EFV group), which included dizziness, vertigo, abnormal dreams/nightmare, somnolence and rash, were somewhat less frequent with TMC278 than with EFV (Table 3). The most frequently reported adverse events were nausea (3.6 vs. 5.6%) and dizziness (1.1 vs. 3.4%).
There was no dose relationship for TMC278 with the overall incidences of neurological adverse events of interest or psychiatric adverse events (Table 3). Neurological adverse events of interest (32.6 vs. 59.6%) and psychiatric adverse events (16.1 vs. 21.3%) irrespective of relatedness, any grade, as well as grades 2-4 (neurological: 6.5 vs. 14.6% and psychiatric: 7.9 vs. 11.2%), also occurred at a lower incidence in the TMC278 combined group than in the EFV group (P < 0.05 TMC278 vs. EFV for neurological adverse events; Table 3). The majority of these adverse events were grade 1 or 2.
The incidence of grade 2-4 rash, regardless of relationship to study medication, was also significantly lower in the TMC278 combined group (3.2%) or TMC278 25 mg group (2.2%) than in the EFV group (11.2%; P < 0.05 TMC278 vs. EFV). No grade 4 rashes were reported. All rashes in TMC278-treated patients were grade 1 or 2 and resolved with continued dosing, except for one case of grade 3 rash in the TMC278 75 mg group occurring at approximately 24 weeks on treatment. This was the only skin disorder in any of the TMC278 groups that led to treatment discontinuation, but was causally associated with dapsone. Two patients receiving EFV (2.2%) discontinued due to skin disorders; one patient with allergic dermatitis and one with drug eruption. Rashes of any grade, irrespective of relatedness, appeared more commonly in the TMC278 150 and 75 mg groups than in the 25 mg group (Table 3). Rashes resolved with continued dosing (median duration: TMC278 combined group 17 days vs. EFV group 15 days). There was no association between sex or CD4 cell count and rash for TMC278.
The incidence of serious adverse events (SAEs) was 12.2% (TMC278 combined group) vs. 14.6% (EFV group). There was no consistent pattern of SAEs and no TMC278-dose relationship with the incidence of SAEs. SAEs considered at least possibly related to study medication occurred in six patients: one receiving EFV (arthralgia) and five receiving TMC278 during the first 48 weeks of treatment (aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increase/cytolytic hepatitis, blood amylase increase, abdominal pain/constipation, suicide attempt and anaemia). There were two deaths in the TMC278 75 mg group considered not related to TMC278; one was a result of pneumonia, septic shock and cardiopulmonary arrest and the other caused by a car accident.
Grade 3 or 4 adverse events at least possibly related to TMC278 or EFV occurred in 5.4% of patients in the TMC278 combined group and in 7.9% receiving EFV; this difference was not statistically significant. The most common grade 3 or 4 adverse events were related to laboratory abnormalities. The overall incidence of treatment-emergent grade 3 or 4 laboratory abnormalities was 26.8% (TMC278 combined group) vs. 24.4% (EFV; Table 3). Grade 3 or 4 laboratory abnormalities in haemoglobin occurred in 2.2% of patients, all in the TMC278 groups. However, haemoglobin levels declined for all groups and recovered throughout the course of the trial returning to baseline levels in all groups and even increasing above baseline at week 96. Haemoglobin abnormalities did not lead to treatment discontinuation. Overall decreases in haemoglobin levels and events of anaemia occurred predominantly in the subgroup of patients using AZT/3TC as the NRTI backbone. A higher number of patients receiving TMC278 than EFV [21 (10%) vs. 1 (1.5%), respectively] switched from AZT/3TC, mainly because of anaemia.
Adverse events leading to treatment discontinuation occurred in 11.5 vs. 9.0% of patients in the TMC278 combined group and EFV group, respectively, and more frequently in the TMC278 150 (14.3%) and 75 mg (11.6%) groups than in the 25 mg group (8.6%). For TMC278, the majority of these adverse events were related to laboratory test results, most commonly ALT and AST elevations. For EFV, the major reasons for treatment discontinuation were pregnancy, psychiatric disorders, and skin and subcutaneous tissue disorders.
Mean (SD) changes from baseline at week 96 in total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglycerides were significantly lower in the combined TMC278 group than in the EFV group (Table 3). Increases in high-density lipoprotein-cholesterol (HDL-C) occurred in both groups, though to a significantly lesser extent with TMC278 than with EFV. There was no difference in the change in ratio of total cholesterol/HDL-C in the combined TMC278 group compared with the EFV group.
There were no consistent or clinically relevant changes in vital signs with TMC278. There was a gradual mean increase from baseline in QT interval corrected according to Fridericia's formula (QTcF) up to week 48 only, which appeared slightly greater with EFV, TMC278 75 mg and 150 mg than with TMC278 25 mg, and then stabilized in all groups up to week 96. This increase was seen in patients receiving AZT/3TC but not with TDF/FTC. No clinically relevant changes in adrenal and thyroid parameters were observed.


Virological response
The proportion of patients with confirmed viral load less than 50 copies/ml (TLOVR) after 48 weeks was similar across TMC278 groups (76.9-80.0%) and comparable with that of EFV (80.9%; Table 2). Response rates were well maintained from week 48 to 96. At week 96, 71.4-76.3% of patients in the TMC278 groups and 70.8% in the EFV group had a viral load less than 50 copies/ml. No clear TMC278 dose-response relationships were observed. The logistic regression model showed no statistically significant differences among groups at weeks 48 or 96. From the logistic regression model at week 48, background NRTI was not statistically significantly related to virological response, but baseline viral load and region were marginally significant (P = 0.06 and P = 0.04, respectively). There was a 1.4-fold increase in the odds for virological response for every 10-fold decrease in baseline viral load. At week 96, neither baseline viral load nor region was significant predictor of response. At weeks 48 and 96, the proportion of virological failures was low and not statistically significantly different among groups (Table 2).
The proportion of patients with viral load less than 50 copies/ml over time was also similar across all TMC278 groups and the EFV group (Fig. 2a), as was the proportion of patients with viral load less than 400 copies/ml and the log10 reduction in viral load from baseline (Table 2 and Fig. 2b). There was no statistically significant difference in the log10 reduction in viral load at weeks 48 or 96 between groups.
Immunological response
The mean and median changes from baseline in CD4 cell count through weeks 48 and 96 were similar across groups (Table 2 and Fig. 2c) and showed a continuous increase over the duration of the trial.
Resistance analysis
Very few patients failed virologically. Seventeen out of 279 patients (6%) and six of 89 patients (7%) met the definition of virological failure for resistance analysis (viral load >1000 copies/ml) in the TMC278 and EFV groups, respectively [sequence information not available for two virological failures (one in the TMC278 75 mg group and one in the EFV group)]. Among patients failing virologically, the proportion in whom treatment-emergent NNRTI resistance-associated mutations (RAMs) developed was similar between the TMC278 and EFV groups [53 (n = 9) vs. 50% (n = 3), respectively]. In the nine patients receiving TMC278, the following eight NNRTI RAMs were seen: L100I, K101E, K103N, V108I, E138K, E138R, Y181C and M230L, whereas in the three patients receiving EFV, the NNRTI RAMs K103N and V106M were observed. The most frequent NNRTI RAMs observed in patients receiving TMC278 and EFV were E138K and K103N, respectively. In three patients, the E138K mutation occurred alone. However, the role this mutation plays in TMC278 resistance remains unclear as the viral load in one patient receiving TMC278 with an E138K NNRTI RAM at baseline remained less than 50 copies/ml at week 96, and a site-directed mutant carrying the E138K mutation exhibited a low in-vitro fold change in 50% effective concentration against TMC278 (manuscript in preparation). The pattern of NNRTI RAMs was not associated with any specific viral subtype (AE, B or C).
Pharmacokinetics and relationships with pharmacodynamics
A nearly dose-proportional increase in TMC278 exposure was observed with increasing dose. The median TMC278 AUC24 h in the 25 mg (n = 89), 75 mg (n = 93) and 150 mg q.d. (n = 87) groups was, respectively, 2480, 5366 and 9779 ng h/ml.
Patients who discontinued treatment for reasons other than virological failure were excluded from the pharmacokinetic-efficacy analyses. A modest impact of TMC278 exposure on viral load less than 50 copies/ml was observed. Overall, 82.8% of patients with a TMC278 AUC24 h in the lowest quartile (²3023 ng h/ml) were responders at week 96, vs. 91.1-93.2% in the higher quartiles. While the majority of patients in the lowest quartile received TMC278 25 mg (>85%), some patients from the higher dose groups were in the lowest quartile possibly due to noncompliance or malabsorption. This included seven patients receiving TMC278 75 mg, of whom three were virological failures. Response rates in this subset of patients by dose group showed no clear difference across TMC278 groups (89.9, 88.3 and 91.5% in the TMC278 25, 75 and 150 mg q.d. groups, respectively, vs. 90.0% with EFV). This finding suggests that the pharmacokinetic parameters achieved with TMC278 25 mg q.d. resulted in similar efficacy to pharmacokinetic parameters achieved with higher dose groups.

The following inclusion criteria were applied: age at least 18 years, never previously treated with an ARV drug or therapeutic HIV-1 vaccine [or received ²2 weeks' treatment with a nucleoside reverse transcriptase inhibitor (NRTI) and/or protease inhibitor], genotypic sensitivity to the selected NRTIs and a plasma viral load more than 5000 copies/ml. The main exclusion criteria were any currently active AIDS-defining illness, prior use of NNRTIs or documented genotypic evidence of NNRTI resistance (i.e. the A098G, L100I, K101E/P/Q, K103H/N/S/T, V106A/M, V108I, Y181C/I/V, Y188C/H/L, G190A/E/S, P225H, M230L, P236L, K238N/T or Y318F reverse transcriptase mutations) [23].
The trial protocol was reviewed and approved by the local regulatory authorities and the Independent Ethics Committee/Institutional Review Board, and was conducted in accordance with the Declaration of Helsinki. All patients gave written, informed consent prior to study start. Details of the study were registered with (, trial identifier NCT00110305.
Study design and treatments
The present phase IIb, randomized trial was designed to evaluate the dose-response relationship for efficacy, tolerability and safety of three q.d. TMC278 doses over 96 weeks. Patients (N = 368) were randomized to TMC278 25, 75 or 150 mg q.d., or an open-label control EFV 600 mg q.d. in a 1: 1:1: 1 ratio. Investigators and patients were blinded to all TMC278 doses throughout, whereas the sponsor was fully unblinded at week 24. Comparisons with EFV were exploratory. Two TMC278 tablets were administered immediately after breakfast. One 600 mg EFV tablet was given in the evening.
The study was conducted in 54 centres across 14 countries, which were divided into three regions: region 1: Asia (China and Thailand), South Africa, Uganda; region 2: Europe (Austria, Germany, France and UK), USA, Russia, Puerto Rico; region 3: Latin America (Argentina, Brazil and Mexico).
Investigators selected one of two NRTI regimens as the backbone ARV combination [zidovudine/lamivudine (AZT/3TC) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)], administered as fixed-dose combinations wherever available. Randomization was stratified by region and NRTI backbone.
Randomization/stratification was handled through a central Interactive Voice Response System applying a dynamic randomization according to a minimization algorithm of Pocock and Simon [24].
Other NNRTIs, protease inhibitors, fusion inhibitors, cytochrome P4503A4 substrates/inducers/inhibitors and immunomodulators were not allowed during the treatment period. NRTI within-class substitutions and NRTI dose adjustments for tolerability reasons were allowed.
Study endpoints
The primary objective was to evaluate the TMC278 dose-efficacy relationship at week 48. Secondary objectives included evaluation of ARV activity over 96 weeks; safety and tolerability of TMC278; immunological changes; pharmacokinetics of TMC278; and resistance analysis of isolates from patients failing virologically. The safety and efficacy of TMC278 were also compared with those of EFV.
The primary efficacy parameter was the proportion of patients with confirmed viral load less than 50 copies/ml at 48 weeks (responders) according to the time to loss of virological response (TLOVR) algorithm [25]. In this algorithm, premature discontinuations for whatever reason are considered treatment failures. Secondary parameters included the proportion of patients with viral load less than 50 and less than 400 copies/ml at each time point, and changes in log10 viral load and CD4 cell count from baseline. For changes in log10 viral load and CD4 cell count from baseline, for patients who prematurely discontinued the study, subsequent time points were imputed with the baseline data; intermediate missing values were imputed using last observation carried forward.
Patients were seen at weeks 1, 2 and 4, then every 4 weeks through to week 24, and subsequently every 8 weeks. Adverse events were graded for severity using the Division of AIDS table [26]. Urine and blood samples were collected for urinalysis, biochemistry, haematology, coagulation, immunology (changes in CD4 cell counts), endocrinology, pharmacokinetics, resistance testing and plasma viral load determinations.
Plasma viral load was determined using the COBAS Amplicor HIV-1 Monitor assay (version 1.5 Roche Diagnostics, Basel, Switzerland), and viral phenotypic and genotypic resistance testing were performed by Virco BVBA using the Antivirogram and vircoTYPE HIV-1, respectively.
An independent Data and Safety Monitoring Board assessed the safety and efficacy data at regular time points.
Data analysis and statistics
Statistical testing was done at weeks 48 and 96. All analyses were performed on the intent-to-treat (ITT) population, regardless of their compliance with the protocol.
Based on previous studies, the percentage of patients with viral load less than 50 copies/ml (responders to EFV) was expected to be 70-80% at week 48 [27,28]. Power calculations to detect a significant dose response (at 5% level) based on the Cochran-Armitage trend test were done with 80 patients/group using 1000 simulations. With a 60, 70 and 80% expected response rate in the TMC278 25, 75 and 150 mg q.d. groups, respectively, the power was 83%. With 80 patients/group, the width of the 95% confidence interval (CI) around the percentage of responders would be at most ± 11%. The overall significance level was 5% (two-sided). The virological dose-response relationship between the TMC278 groups was evaluated using a logistic regression model, including terms for treatment, baseline viral load, region and background NRTIs.
Fisher's exact test was used to compare the incidence of adverse events between the combined TMC278 group (all patients treated with TMC278) and the EFV group. Treatment comparisons regarding changes from baseline in laboratory values were done applying a nonparametric Wilcoxon rank-sum test.
Individual estimates of the TMC278 area under the plasma concentration-time curve up to 24 h postdosing (AUC24 h) were determined by population pharmacokinetic modelling based on full pharmacokinetic profiles at weeks 4 and 24 and optionally at week 48 in a subset of patients participating in the pharmacokinetic substudy (n = 54), and sparse sampling in all patients (n = 269) at weeks 4 (two samples), 8 (two samples), 12 (one sample), 24 (two samples), 48 (one sample), 72 (one sample) and 96 (one sample).
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