This 2-part, phase 1, open-label, randomized, crossover study (NCT00752310) assessed ritonavir-boosted darunavir bioavailability (oral suspension vs. tablets), and steady-state darunavir pharmacokinetics (suspension). Part 1: 20 healthy adults randomly received 3 treatments with a >= 7-day washout between treatments; twice-daily ritonavir (100 mg, days 1-5) with darunavir (600 mg, day 3) as 2 x 300-mg tablets (fed, reference), or 6mL of a 100-mg/mL suspension (fed or fasted, test). Part 2: 18 healthy volunteers received twice-daily darunavir (suspension, 600 mg days 1-6, one dose day 7) with twice-daily ritonavir (100 mg, days 1-9). Darunavir pharmacokinetics were evaluated (part 1 day 3; part 2 day 7). Safety/tolerability were assessed. In part 1, 90% confidence intervals for darunavir C-max and AUC were all within 80-125% for suspension (fed or fasted) versus tablets (fed). Steady-state darunavir (suspension) pharmacokinetics in part 2 were similar to historic controls (tablets). No clinically relevant differences in adverse events or laboratory abnormalities occurred between treatments. Darunavir administered as an oral suspension or tablets (both with low-dose ritonavir) showed comparable bioavailability in healthy adults after a single dose. Steady-state darunavir pharmacokinetics (suspension, 600/100 mg twice daily) were consistent with historic controls; this formulation is considered suitable for pediatric use and for adults who cannot swallow tablets.

BACKGROUND & AIMS: Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in phase III trials for chronic hepatitis C virus (HCV) infection. We performed a phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-alpha 2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV. METHODS: We analyzed data from patients who did not respond (null response), had a partial response, or relapsed after treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n = 396), or placebo plus PegIFN and RBV for 48 weeks (n = 66). All patients were followed for 24 weeks after planned end of treatment; the primary end point was the proportion of patients with sustained virologic response (SVR; undetectable HCV RNA) at that time point. RESULTS: Overall, rates of SVR at 24 weeks were significantly higher in the groups given simeprevir than those given placebo (61%-80% vs 23%; P < .001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%-59% vs 19%; prior partial response, 48%-86% vs 9%; prior relapse, 77%-89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo. CONCLUSIONS: In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, and RBV and was generally well tolerated. ClinicalTrials.gov number: NCT00980330.

The phase IIb, double-blind, placebo-controlled PILLAR trial investigated the efficacy and safety of two different simeprevir (SMV) doses administered once-daily (QD) with pegylated interferon (Peg-IFN)--2a and ribavirin (RBV) in treatment-naive patients with HCV genotype 1 infection. Patients were randomized to one of five treatments: SMV (75 or 150 mg QD) for 12 or 24 weeks or placebo, plus Peg-IFN and RBV. Patients in the SMV arms stopped all treatment at week 24 if response-guided therapy (RGT) criteria were met; patients not meeting RGT continued with Peg-IFN and RBV until week 48, as did patients in the placebo control group. Sustained virologic response (SVR) rates measured 24 weeks after the planned end of treatment (SVR24) were 74.7%-86.1% in the SMV groups versus 64.9% in the control group (P < 0.05 for all comparisons [SMV versus placebo], except SMV 75 mg for 24 weeks). Rapid virologic response (HCV RNA <25 IU/mL undetectable at week 4) was achieved by 68.0%-75.6% of SMV-treated and 5.2% of placebo control patients. According to RGT criteria, 79.2%-86.1% of SMV-treated patients completed treatment by week 24; 85.2%-95.6% of these subsequently achieved SVR24. The adverse event profile was generally similar across the SMV and placebo control groups, with the exception of mild reversible hyperbilirubinemia, without serum aminotransferase abnormalities, associated with higher doses of SMV. Conclusion: SMV QD in combination with Peg-IFN and RBV significantly improves SVR rates, compared with Peg-IFN and RBV alone, and allows the majority of patients to shorten their therapy duration to 24 weeks. (Hepatology 2013; 58:1918-1929)

Background The Asian population, in general, has higher antiretroviral concentrations than those who are not Asian, but there are limited pharmacokinetic data for darunavir/ritonavir in Asian children. Methods Thai children aged ≥7 years and with body weight (BW)≥20 kg who were on darunavir/ritonavir for ≥2 weeks underwent 12-h pharmacokinetics with blood sampling before and at 1, 2, 4, 6, 8, 10 and 12 h post-dosing. Darunavir/ritonavir doses were 375/100 mg twice daily (BW 20 to <30 kg, n=12), 450/100 mg twice daily (BW 30 to <40 kg, n=2) or 600/100 mg twice daily (BW ≥40 kg, n=5). Ritonavir 100 mg soft gel capsules were used instead of solution. Results Of the 19 children, 8 were female, median age was 13 years (range 7-16) and median BW was 29.4 kg. The median duration of darunavir/ritonavir treatment was 11 months. The geometric mean values for darunavir were 60.3 hxmg/l for the area under the concentration–time curve at 0–12 h (AUC 0–12 ), 8.3 mg/l for the maximum concentration (C max ) and 3.1 for the concentration prior to the next dose (C 12 ) with no differences between dosing groups. All had C 12 above the protein binding adjusted 50% effective concentration (EC 50 ) of protease inhibitor-resistant virus (0.55 mg/l). The darunavir pharmacokinetic parameters were similar to those in non-Asian individuals from the DELPHI study, in which 13 of 20 with BW<40 kg used 50 or 60 mg ritonavir boosting. Conclusions Thai children aged ≥7 years who were on standard darunavir dosing with 100 mg ritonavir boosting had adequate and comparable darunavir AUC 0–12 , C max and C 12 to non-Asian children who mainly used lower doses of ritonavir boosting. A ritonavir boosting dose of 100 mg can be used for children weighing ≥20 kg, particularly when lower dose formulations are unavailable or if intolerant to the solution.

Objectives. Evaluation of pharmacokinetics and pharmacodynamics of darunavir and etravirine amongHIV-1-infected, treatmentexperienced adults from GRACE, by sex and race. Methods. Patients received darunavir/ritonavir 600/100mg twice daily plus other antiretrovirals, which could include etravirine 200mg twice daily. Population pharmacokinetics for darunavir and etravirine were determined over 48 weeks and relationships assessed with virologic response and safety. Rich sampling for darunavir, etravirine, and ritonavir was collected in a substudy at weeks 4, 24, and 48. Results. Pharmacokinetics were estimated in 376 patients for darunavir and 190 patients for etravirine. Median darunavir AUC(12h) and C-0h were 60,642ng.h/mL and 3624ng/mL, respectively; and for etravirine were 4183ng . h/mL and 280ng/mL, respectively. There were no differences in darunavir or etravirine AUC(12h) or C-0h by sex or race. Age, body weight, or use of etravirine did not affect darunavir exposure. No relationships were seen between darunavir pharmacokinetics and efficacy or safety. Patients with etravirine exposure in the lowest quartile generally had lower response rates. Rich sampling showed no time-dependent relationship for darunavir, etravirine, or ritonavir exposure over 48 weeks. Conclusions. Population pharmacokinetics showed no relevant differences in darunavir or etravirine exposure by assessed covariates. Lower etravirine exposures were associated with lower response rates.

Background & Aims: TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase Ill development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase ha study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naive patients infected with HCV genotypes 2-6.Methods: The study consisted of 7 days of monotherapy with TMC435 (200 mg once daily). Patients could begin treatment with pegylated interferon/ribavirin from day 8 with a follow-up period up to days 37-42.Results: Thirty-seven patients were enrolled in Germany, Belgium and Thailand. For the primary end point at day 8, the mean (+/- standard error) change in plasma HCV ribonucleic acid (log(10) IU/ml) from baseline was the greatest for genotypes 6 (-4.35 +/- 0.29) and 4 (-3.52 +/- 0.43), followed by genotypes 2 (-2.73 +/- 0.71) and 5 (-2.19 +/- 0.39). No antiviral activity was evident for genotype 3. Viral breakthrough occurred in six patients during the monotherapy phase and in six additional patients during PegIFN/RBV-only period. All adverse events were mild or moderate and there were no discontinuations during the TMC435 monotherapy period.Conclusions: The results of this phase ha proof-of-concept trial provide evidence that TMC435 has a spectrum of activity against multiple HCV genotypes, except for genotype 3. In this study, TMC435 was generally safe and well tolerated. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

1376 THE ASPIRE TRIAL: TMC435 IN TREATMENT-EXPERIENCED PATIENTS WITH GENOTYPE-1 HCV INFECTION WHO HAVE FAILED PREVIOUS PEGIFN/RBV TREATMENT S. Zeuzem, G.R. Foster, M.W. Fried, C. Hezode, G.M. Hirschfield, I. Nikitin, F. Poordad, O. Lenz, M. Peeters, V. Sekar, G. De Smedt. J.W. Goethe University Hospital, Frankfurt, Germany; Queen Mary, University of London, London, UK; University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Hopital Henri-Mondor, Universite Paris-Est Creteil, Creteil, France; Toronto Western Hospital Liver Centre, Toronto, ON, Canada; Russian State Medical University, Moscow, Russia; Cedars-Sinai Medical Center, Los Angeles, CA, USA; Tibotec BVBA, Mechelen, Belgium; Tibotec Inc, Yardley, PA, USA E-mail: zeuzem@em.uni-frankfurt.de

The Journal of Clinical PharmacologyVolume 51, Issue 2 p. 271-278 Pharmacokinetic Interactions Between Darunavir/Ritonavir and Opioid Maintenance Therapy Using Methadone or Buprenorphine/Naloxone Dr Vanitha Sekar PhD, Corresponding Author Dr Vanitha Sekar PhD Tibotec Inc, Yardley, PA Address for correspondence: Vanitha Sekar, PhD, Johnson & Johnson, 1125 Trenton Harbourton R, Titusville, NJ 08560-1504; e-mail: [email protected].Search for more papers by this authorDr Frank Tomaka MD, Dr Frank Tomaka MD Tibotec Inc, Yardley, PASearch for more papers by this authorDr Eric Lefebvre MD, Dr Eric Lefebvre MD Janssen-Cilag BV, Tilburg, The NetherlandsSearch for more papers by this authorDr Martine De Pauw PhD, Dr Martine De Pauw PhD Tibotec BVBA, Mechelen, BelgiumSearch for more papers by this authorDr Tony Vangeneugden PhD, Dr Tony Vangeneugden PhD Tibotec BVBA, Mechelen, BelgiumSearch for more papers by this authorDr Wim van den Brink MD, PhD, Dr Wim van den Brink MD, PhD Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorDr Richard Hoetelmans PharmD, PhD, Dr Richard Hoetelmans PharmD, PhD Tibotec BVBA, Mechelen, BelgiumSearch for more papers by this author Dr Vanitha Sekar PhD, Corresponding Author Dr Vanitha Sekar PhD Tibotec Inc, Yardley, PA Address for correspondence: Vanitha Sekar, PhD, Johnson & Johnson, 1125 Trenton Harbourton R, Titusville, NJ 08560-1504; e-mail: [email protected].Search for more papers by this authorDr Frank Tomaka MD, Dr Frank Tomaka MD Tibotec Inc, Yardley, PASearch for more papers by this authorDr Eric Lefebvre MD, Dr Eric Lefebvre MD Janssen-Cilag BV, Tilburg, The NetherlandsSearch for more papers by this authorDr Martine De Pauw PhD, Dr Martine De Pauw PhD Tibotec BVBA, Mechelen, BelgiumSearch for more papers by this authorDr Tony Vangeneugden PhD, Dr Tony Vangeneugden PhD Tibotec BVBA, Mechelen, BelgiumSearch for more papers by this authorDr Wim van den Brink MD, PhD, Dr Wim van den Brink MD, PhD Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorDr Richard Hoetelmans PharmD, PhD, Dr Richard Hoetelmans PharmD, PhD Tibotec BVBA, Mechelen, BelgiumSearch for more papers by this author First published: 07 March 2013 https://doi.org/10.1177/0091270010365558Citations: 18Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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This chapter contains sections titled: Introduction Discovery Synthesis Formulation Preclinical Development Clinical Development Future Directions Conclusions References

Methods and patients: 251 treatment naive HCV genotype 1 patients (all Caucasian, age: 44.2±11.4yrs [mean±SD], BMI: 25.4±3.7,male/female: 153/98) participating in two RCTs and one observational study have been included in this analysis.All were treated with 180 mcg peginterferon alpha-2a/week and 1000-1200 mg ribavirin/day.Whole blood was used for hemoglobin (Hb) determination at baseline and week 4.The SNP rs6051702 (A/A, A/C, C/C) was tested by the StepOnePlus Real time PCR System (Applied Biosystems, Foster City, USA).Results: 164/251 (65.3%) had a SVR, 44 (17.5%) were relapser and 43 (17.1%)non-responders.The majority of patients had the A/A (n = 174; 69.3%) followed by the A/C (n = 66; 26.3%) and the C/C (n = 11; 4.4%) genotype.SNP rs6051702 was not associated with SVR (A/A: 64.4%, C-allele carrier: 67.5%).Hb baseline levels were similar overall rs6051702 genotypes (A/A:14.8±1.4 g/dl, A/C:15.2±1.3,C/C:14.5±1.4 g/l; n.s.).The highest Hb drop at week 4 was observed in patients with the A/A genotype (2.7±1.5 g/dl) compared to C-allele carriers (1.7±1.2 g/dl; p < 0.001).31/35 (88.6%) patients with a Hb drop >4 g/dl had the A/A genotype, 4 the A/C genotype.Hb drop was higher in male (2.6±1.5 g/dl) compared to female (2.1±1.5 g/dl, p = 0.013) A/A patients.This effect is consistent, but not significant in C-allele carriers (male vs female:1.8±1.2 g/dl vs 1.4±1.3;p = 0.071).Data on ribavirin dose reduction and the use of erythropoietin will be available at the meeting.Conclusion: A C-allele in the rs6051702 region protects Caucasian HCV genotype 1 patients from anemia on HCV treatment with peginterferon alpha-2a and ribavirin.In A-allele homozygotes Hb drop till week 4 is higher in male than in female patients.However, there was no effect of SNP rs6051702 on treatment outcome.

The effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12 by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC12 3.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine.

Background Antiviral activity of TMC435, an oral, once-daily, HCV NS3/4A protease inhibitor, was evaluated with pegylated interferon-α2a/ribavirin (P/R) in HCV genotype-1 patients. Methods Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA-1; TMC435-C201; NCT00561353) is a Phase IIa, randomized, placebo-controlled study. Treatment-naive patients ( n=74) received 25, 75 or 200 mg TMC435 once daily, or placebo for 7 days followed by 21 days of triple therapy with P/R, or triple therapy for 28 days. Treatment-experienced patients ( n=37; 56.8% with cirrhosis) received 75, 150 or 200 mg TMC435 once daily, or placebo with P/R for 28 days. Patients continued P/R up to week 48. Results Treatment-naive patients who received initial monotherapy had a rapid decline in HCV RNA by day 3. At day 7, HCV RNA reductions were greatest for the 75 and 200 mg doses (0.02, -2.63, -3.43 and -4.13 log 10 IU/ml for placebo, and TMC435 25, 75 and 200 mg, respectively). At day 28, all patients who received triple therapy with TMC435 75 or 200 mg had HCV RNA<25 IU/ml versus 4/9 for placebo. In total, 18/28 treatment- experienced patients (9/9 prior relapsers, 9/19 non-responders) who received TMC435 had HCV RNA<25 IU/ml at day 28 versus 0/9 for placebo; similar results were observed for the 150 and 200 mg doses. Most adverse events were grade 1/2. No relevant changes in laboratory parameters occurred, except mild and reversible bilirubin elevations, mostly at the 200 mg dose. Conclusions Once-daily TMC435 with P/R showed potent, dose-dependent antiviral activity over 28 days, and had a favourable tolerability profile.

BACKGROUND AND OBJECTIVE:The pharmacokinetics of some HIV protease inhibitors are altered in patients with hepatic impairment. The TMC114-C134 study assessed the pharmacokinetics and safety of darunavir/ritonavir 600 mg/100 mg twice daily in HIV-negative subjects with hepatic impairment (defined according to Child-Pugh classification A [mild] or B [moderate]) compared with matched, HIV-negative, healthy subjects.METHODS:All subjects received darunavir/ritonavir 600 mg/100 mg twice daily for 6 days with a morning dose on day 7. Pharmacokinetic profiles were obtained up to 72 hours post-dose for darunavir and 12 hours post-dose for ritonavir on day 7. Safety and tolerability were also assessed.RESULTS:Darunavir pharmacokinetics in subjects with mild (n = 8) and moderate (n = 8) hepatic impairment were comparable to those in matched healthy control subjects (n = 16). In those with mild hepatic impairment, the least square mean ratios relative to healthy subjects for darunavir exposure (the area under the plasma concentration-time curve from 0 to 12 hours) and for maximum and minimum plasma concentrations were 0.94 (90% CI 0.75, 1.17), 0.88 (90% CI 0.73, 1.07) and 0.83 (90% CI 0.63, 1.10), respectively. In those with moderate hepatic impairment, these values were 1.20 (90% CI 0.90, 1.60), 1.22 (90% CI 0.95, 1.56) and 1.27 (90% CI 0.87, 1.85), respectively. Ritonavir pharmacokinetics were comparable between healthy subjects and those with mild hepatic impairment, but mean exposure was 50% higher in subjects with moderate hepatic impairment. Darunavir/ritonavir was generally well tolerated, regardless of hepatic impairment. All adverse events were grade 1-2 in severity, except for a grade 3 increase in alanine aminotransferase reported in one subject with mild hepatic impairment. No adverse events led to discontinuation.CONCLUSIONS:The results of this study show that the pharmacokinetics of darunavir/ritonavir 600 mg/100 mg are not affected by mild or moderate hepatic impairment. Therefore, it is recommended that dose adjustments of darunavir/ritonavir are not required in patients with mild or moderate hepatic impairment.