Vanitha Sekar

Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis.

Objective:Present 96-week data from ongoing ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In Naive Subjects) trial. Methods:Randomized, open-label, phase III trial of antiretroviral-naive patients with HIV-1 RNA at least 5000 copies/ml (stratified by HIV-1 RNA and CD4 cell count) receiving darunavir/ritonavir (DRV/r) 800/100 mg once daily or lopinavir/ritonavir (LPV/r) 800/200 mg total daily dose (twice daily or once daily) and fixed-dose tenofovir/emtricitabine. Primary outcome measure was noninferiority of DRV/r vs. LPV/r in virologic response (<50 copies/ml, time-to-loss of virologic response) at 96 weeks (secondary outcome: superiority). Results:Six hundred eighty-nine patients were enrolled. At week 96, significantly more DRV/r (79%) than LPV/r patients (71%) had viral load less than 50 copies/ml, confirming statistical noninferiority (estimated difference: 8.4%; 95% confidence interval 1.9–14.8; P < 0.001; per-protocol) and superiority (P = 0.012; intent-to-treat) in virologic response. Median CD4 cell count increases from baseline were 171 and 188 cells/μl for DRV/r and LPV/r, respectively (P = 0.57; noncompleter=failure). Overall, 4% of DRV/r patients and 9% of LPV/r patients discontinued treatment due to adverse events. Lower rates of grade 2–4 treatment-related diarrhea were seen with DRV/r (4%) vs. LPV/r (11%; P < 0.001), whereas grade 2–4 treatment-related rash occurred infrequently in both arms (3 vs. 1%, respectively; P = 0.273). DRV/r patients had smaller median increases in triglycerides (0.1 and 0.6 mmol/l, respectively, P < 0.0001) and total cholesterol (0.6 and 0.9 mmol/l, respectively; P < 0.0001) than LPV/r patients; levels remained below National Cholesterol Education Program cut-offs for DRV/r. Conclusion:At week 96, once-daily DRV/r was both statistically noninferior and superior in virologic response to LPV/r, with a more favorable gastrointestinal and lipid profile, confirming DRV/r as an effective, well tolerated, and durable option for antiretroviral-naive patients.

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6: TMC435-C202, a phase IIa, open-label study

BACKGROUND & AIMS TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III 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 IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naїve patients infected with HCV genotypes 2-6. METHODS The study consisted of 7 days of monotherapy with TMC435 (200mg 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 IIa 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.

The Effect of Different Meal Types on the Pharmacokinetics of Darunavir (TMC114)/Ritonavir in HIV‐Negative Healthy Volunteers

This open‐label, randomized, crossover study investigated the bioavailability, short‐term safety, and tolerability of darunavir (TMC114) coadministered with low‐dose ritonavir under fasted conditions and after different meal types in HIV‐negative healthy volunteers. All volunteers received ritonavir 100 mg twice daily on days 1 to 5, with a single darunavir 400‐mg tablet given on day 3 (darunavir/rtv). Pharmacokinetic parameters for darunavir and ritonavir were determined under fasted conditions and following a standard breakfast, a high‐fat breakfast, a nutritional protein‐rich drink, or a croissant with coffee. Administration of darunavir/rtv in a fasting state resulted in a decrease in darunavir Cmax and AUClast of approximately 30% compared with administration after a standard meal. No significant differences in darunavir plasma concentrations were observed between different fed states. Darunavir/rtv should therefore be administered with food, but exposure to darunavir is not affected by the type of meal.

Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial

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.

Pharmacokinetics, safety and efficacy of darunavir/ ritonavir in treatment-experienced children and adolescents

Objective:To assess pharmacokinetics, safety and efficacy of darunavir/ritonavir (DRV/r) and optimized background regimen in treatment-experienced patients (6–17 years). Design:Forty-eight-week, open-label, two-part, phase II study. Methods:In part I, 44 patients were randomized (1: 1 ratio) to receive a body weight-adjusted, adult-equivalent dose (group A) or a 20–33% higher DRV/r twice daily (b.i.d.) dose (group B). Pharmacokinetics, safety and efficacy were assessed following 2-week dosing (part I), which determined dosing for part II (evaluated 48-week safety and efficacy). Results:In part I, both groups met the protocol-specified criteria for pharmacokinetics and showed favorable tolerability and efficacy. The following body-weight doses were selected: DRV/r 375/50 mg b.i.d. (20–<30 kg), 450/60 mg b.i.d. (30–<40 kg) and 600/100 mg b.i.d. (≥40 kg); these gave an AUC24h, C0h and Cmax of 102, 114 and 112%, respectively, versus the corresponding mean adult pharmacokinetic parameter. In part II, 80 patients received DRV/r (median age: 14 years, mean baseline HIV-1 RNA: 4.64 log10copies/ml). One patient (1%) discontinued (treatment-unrelated grade 3 anxiety). An abnormal mean baseline triglyceride level was normalized at 48 weeks (P < 0.01). At week 48, 65% had at least 1.0 log10HIV-1 RNA reduction; 59 and 48% achieved HIV-1 RNA less than 400 and less than 50 copies/ml, respectively (time-to-loss-of-virologic response). Mean age-adjusted weight z-score increased by 0.2 (P = 0.003). Conclusion:In treatment-experienced children and adolescents, DRV/r showed comparable exposure to adults with appropriate dose selection, favorable safety and tolerability, improved body weight and significant virologic response. DRV/r is a valuable therapeutic option for this population.

Effects of ritonavir-boosted darunavir vs. ritonavir- boosted atazanavir on lipid and glucose parameters in HIV-negative, healthy volunteers

Darunavir (TMC114) is a new HIV protease inhibitor (PI).

Pharmacokinetic Interaction between Darunavir Boosted with Ritonavir and Omeprazole or Ranitidine in Human Immunodeficiency Virus-Negative Healthy Volunteers

ABSTRACT Darunavir (DRV; TMC114; Prezista) is a human immunodeficiency virus (HIV) protease inhibitor used in combination with low-dose ritonavir (RTV) (DRV/r) as a pharmacokinetic enhancer. Protease inhibitor absorption may be decreased during coadministration of drugs that limit stomach acid secretion and increase gastric pH. This study was conducted to investigate the effect of ranitidine and omeprazole on the plasma pharmacokinetics of DRV and RTV in HIV-negative healthy volunteers. Sixteen volunteers completed the study and received DRV/r, DRV/r plus ranitidine, and DRV/r plus omeprazole, in three separate sessions. Treatment was given for 4 days with an additional morning dose on day 5, and regimens were separated by a washout period of 7 days. Samples were taken over a 12-h period on day 5 for the assessment of DRV and RTV plasma concentrations. Pharmacokinetic parameters assessed included DRV area under the curve, maximum plasma concentration, and trough plasma concentration. The least-squares mean ratios and 90% confidence intervals are reported with treatment of DRV/r alone as a reference. Compared with DRV/r alone, no significant changes in DRV pharmacokinetic parameters were observed during coadministration of DRV/r and either ranitidine or omeprazole. Treatment regimens were generally well tolerated, and no serious adverse events were reported. In conclusion, coadministration of DRV/r and ranitidine or omeprazole was well tolerated by the volunteers. Ranitidine and omeprazole did not have a significant influence on DRV pharmacokinetics. No dose adjustments are required when DRV/r is coadministered with omeprazole or ranitidine.

Suboptimal adherence to darunavir/ritonavir has minimal effect on efficacy compared with lopinavir/ritonavir in treatment-naive, HIV-infected patients: 96 week ARTEMIS data

OBJECTIVES To examine how treatment adherence differences in ARTEMIS (96 week analysis) affected clinical outcome, and to assess factors impacting adherence. PATIENTS AND METHODS ARTEMIS is a Phase III trial, in HIV-1-infected treatment-naive patients, comparing efficacy and safety of once-daily darunavir/ritonavir (800/100 mg) versus lopinavir/ritonavir (800/200 mg total daily dose), each with a fixed-dose background tenofovir and emtricitabine regimen. Self-reported treatment adherence was assessed using the Modified Medication Adherence Self-Report Inventory (M-MASRI). In post-hoc analyses, mean adherence from weeks 4-96 was used to assess overall adherence for each patient, and transformed into a binary variable (>95% , adherent; < or = 95% , suboptimally adherent). RESULTS Overall adherence was high: 83% of darunavir/ritonavir-treated patients and 78% of lopinavir/ritonavir-treated patients were >95% adherent. The difference in virological response rate for adherent versus suboptimally adherent patients was smaller for darunavir/ritonavir (6% difference: 82% versus 76%, P = 0.3312) than for lopinavir/ritonavir (25% difference: 78% versus 53%, P < 0.0001). In suboptimally adherent patients, a higher virological response rate was seen with darunavir/ritonavir (76%) versus lopinavir/ritonavir (53%) (P < 0.01). Suboptimally adherent patients (both treatment groups) reported more adverse events (AEs), including gastrointestinal AEs, than adherent patients. Darunavir/ritonavir had a lower rate of AEs, including gastrointestinal AEs, than lopinavir/ritonavir, in adherent and suboptimally adherent patients. CONCLUSIONS Suboptimal adherence had no significant effect on the virological response rate with once-daily darunavir/ritonavir treatment. In contrast, the lopinavir/ritonavir response rate was significantly reduced in suboptimally adherent patients compared with adherent patients. Once-daily darunavir/ritonavir resulted in a higher virological response rate in suboptimally adherent patients compared with lopinavir/ritonavir.

Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in HIV-negative healthy volunteers.

ABSTRACT The drug-drug interaction between rifabutin (RFB) and darunavir/ritonavir (DRV/r) was examined in a randomized, three-way crossover study of HIV-negative healthy volunteers who received DRV/r 600/100 mg twice a day (BID) (treatment A), RFB 300 mg once a day (QD) (treatment B), and DRV/r 600/100 mg BID plus RFB 150 mg every other day (QOD) (treatment C). The sequence of treatments was randomized, and each treatment period lasted 12 days. Full pharmacokinetic profiles were determined for DRV, ritonavir, and RFB and its active metabolite, 25-O-desacetylrifabutin (desRFB), on day 13. The DRV and ritonavir areas under the plasma concentration-time curve from zero to 12 h (AUC12h) increased by 57% and 66%, respectively, in the presence of RFB. The RFB exposure was comparable between treatment with RFB QD alone (treatment B) and treatment with DRV/r plus RFB QOD (treatment C); however, based on least-square means ratios, the minimum plasma concentration (Cmin) increased by 64% and the maximum plasma concentration (Cmax) decreased by 28%, respectively. The exposure (AUC within the dosage interval and at steady state [AUCτ]) to desRFB was considerably increased (by 881%) following treatment with DRV/r/RFB. The exposure to the parent drug plus the metabolite increased 1.6-fold in the presence of DRV/r. Adverse events (AEs) were more commonly reported during combined treatment (83% versus 44% for RFB and 28% for DRV/r); similarly, grade 3-4 AEs occurred in 17% versus 11% and 0%, respectively, of volunteers. Eighteen of 27 volunteers (66.7%) prematurely discontinued the trial; all volunteers discontinuing for safety reasons (n = 9) did so during RFB treatment phases. These results suggest that DRV/r may be coadministered with RFB with a dose adjustment of RFB to 150 mg QOD and increased monitoring for RFB-related AEs. Based on the overall safety profile of DRV/r, no dose adjustment of DRV/r is considered to be warranted. Given the safety profile seen with the combination of RFB with a boosted protease inhibitor in this and other studies, it is not recommended to conduct further studies with this combination in healthy volunteers.

Pharmacokinetic Interactions of Maraviroc with Darunavir-Ritonavir, Etravirine, and Etravirine-Darunavir-Ritonavir in Healthy Volunteers: Results of Two Drug Interaction Trials

ABSTRACT 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.