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Pharmacokinetics, Efficacy, and Safety of Darunavir/Ritonavir 800/100 mg Once-Daily in Treatment-Naïve and -Experienced Patients

Pharmacokinetics, Efficacy, and Safety of Darunavir/Ritonavir 800/100 mg Once-Daily in... Review Pharmacokinetics, Efficacy, and Safety of Darunavir/Ritonavir 800/100 mg Once-Daily in Treatment-Naïve and -Experienced Patients 1 2 3 Marta Boffito, Diego Miralles, and Andrew Hill 1 2 Chelsea and Westminster Hospital, London, United Kingdom; Tibotec Research and Development, Mechelen, Belgium; Pharmacology Research Laboratories, University of Liverpool, Liverpool, United Kingdom Darunavir is a new protease inhibitor (PI) with in vitro activity against wild-type and PI-resistant HIV; it is used with the pharmacokinetic booster ritonavir. The cur- rently approved dose of darunavir/ritonavir is 600/100 mg twice-daily, licensed for treatment-experienced patients. However, during the clinical development of darunavir, a range of once-daily and twice-daily doses of darunavir/ritonavir were evaluated. The relatively long terminal elimination plasma half-life of darunavir (15 hours) supports once-daily dosing. In treatment-naïve patients, the ARTEMIS trial has shown high rates of HIV RNA suppression for darunavir-ritonavir at the 800/100 mg once-daily dose (84% with HIV RNA <50 copies/mL at Week 48) versus a con- trol arm of lopinavir/ritonavir (78% with HIV RNA <50 copies/mL). In a population pharmacokinetic substudy, darunavir 24-hour minimum plasma concentration lev- els remained above the predefined EC of 55 ng/mL for all 335 patients evaluated in the ARTEMIS trial. Once-daily darunavir/ritonavir has also been evaluated in treatment-experienced patients in the TMC114-C207 proof-of-principle trial and the POWER 1 and 2 trials. For the overall POWER trial population, with significant baseline resistance to PIs, the rates of HIV RNA suppression <50 copies/mL at Week 24 for darunavir/ritonavir 800/100 mg once-daily were lower than for the 600/100 mg twice-daily dosage (31% vs. 47%, respectively). However, for patients with no genotypic darunavir resistance-associated mutations at baseline, rates of HIV RNA suppression were 62% and 67% for the 800/100 mg once-daily and 600/100 mg twice-daily doses. The current evidence from clinical trials of darunavir/ritonavir sup- ports the efficacy of the 800/100 mg once-daily dose for treatment-naïve patients and further evaluation for treatment-experienced patients with no genotypic resis- tance to darunavir. Key words: darunavir, once-daily, pharmacokinetics, ritonavir ver the past 10 years, first-line treatment for proved at the 200 mg twice-daily dose. The main HIV has become increasingly simple to take, advantages of once-daily versus twice-daily PIs Owith reformulations lowering pill counts, are lower pill count, improved convenience (which the coformulation of two or three drugs into single might improve adherence), and halving the daily pills, and the introduction of several drugs with dose of ritonavir needed (normally from 200 mg to once-daily dosing. For first-line treatment of anti - 100 mg), with possible improvements in adverse retroviral naïve patients, the European guidelines recommend a combination of two nucleoside ana- logues (either tenofovir/emtricitabine or abaca- Address for correspondence: Marta Boffito, Chelsea and West - vir/lamivudine, both available as coformulated minster Hospital, 369 Fulham Road, London, SW10 9NH, United Kingdom. Email: marta.boffito@chelwest.nhs.uk once-daily single pill formulations) with a non- nucleoside reverse transcriptase inhibitor (NNRTI) HIV Clin Trials 2008;9(6):418–427 or a boosted protease inhibitor (PI). The NNRTI © 2008 Thomas Land Publishers, Inc. www.thomasland.com efavirenz has shown strong efficacy at the 600 mg once-daily dose, whereas nevirapine is only ap- doi: 10.1310/hct0906-418 418 Pharmacokinetics of o nce -Dy ail Dr V/r • Boffito et al . 419 5 17 events or lipid profiles. First-line use of ritonavir- <50 copies/mL). Therefore, some once-daily PIs boosted PIs involves higher pill counts and more may not provide high enough drug concentrations complex issues with drug-drug interactions com- to overcome partially PI-resistant HIV. Additional pared with NNRTI, but it may lead to a lower risk efficacy data from randomized trials are needed to 6,7 of drug resistance at treatment failure. justify the use of once-daily PIs for treatment-ex- Five ritonavir-boosted PIs have been evaluated perienced patients. at once-daily doses, mainly in treatment-naïve Darunavir is a ritonavir-boosted PI with in vitro patients. Atazanavir/ritonavir 300/100 mg once- activity against both wild-type and PI-resistant daily showed noninferior efficacy compared with HIV isolates. Coadministration with ritonavir twice-daily lopinavir/ritonavir in the CASTLE inhibits clearance of darunavir, increasing the 8 19 trial. Lopinavir/ritonavir 800/200 mg once-daily terminal elimination half-life (t ) to 15 hours, ½term has shown high efficacy in two recent trials of which is relatively long, compared with data from 9,10 20 naïve patients. Darunavir (TMC114) with low- HIV-infected patients for lopinavir (2–6 hours) or dose ritonavir (darunavir/ritonavir) 800/100 mg atazanavir (7–8.5 hours). once-daily showed noninferior efficacy versus During the clinical development of daruna- lopinavir/ritonavir after 48 weeks of treatment in vir, both once-daily and twice-daily dosing were the ARTEMIS trial (TMC114-C211; AntiRetroviral evaluated in a range of naïve and treatment- Therapy with TMC114 Examined In Naïve Sub- experienced patients. The initial European regula- jects). Once-daily doses of ritonavir-boosted sa- tory approval of darunavir was for the 600/100 mg quinavir (1500/100 mg or 2000/100 mg once-daily) twice-daily dose for patients with at least two prior and fosamprenavir (1400/200 mg or 1400/100 mg PIs. However, the 800/100 mg once-daily dose has once-daily) have been evaluated in clinical trials been evaluated in the Phase III ARTEMIS trial of 12–14 19,22 of naïve patients, but these trials were not fully naïve patients, pharmacokinetic studies, and powered randomized comparisons versus recog- three trials in experienced patients: a 14-day proof- nized standard of care control treatments. of-principle trial (TMC114-C207) and the POWER 24,25 The pharmacokinetics of once-daily PIs is gen- 1 and 2 (TMC114-C213 and C202) trials. This erally characterized by high maximum concen- review will describe the evidence supporting the trations (C ) and lower 24-hour concentrations 800/100 mg once-daily dose of darunavir/ritona- max (C or C ), whereas twice-daily use tends vir in naïve patients and review the evidence sup- trough min to lead to more constant plasma PI concentra- porting use of this once-daily dose in patients with tions over the dosing interval. In poorly adherent different levels of prior antiretroviral treatment, patients, who could have suboptimal plasma PI relative to the 600/100 mg twice-daily dose. concentrations after missed doses, a potential dis- advantage of the use of once-daily PIs may be the DOSE-RANGING PHARMACOKINETIC TRIALS emergence of drug resistance. OF DARUNAVIR In several recent trials, once-daily PIs that showed strong efficacy for treatment-naïve In the exploratory dose-ranging pharmacoki- patients have underperformed in treatment- netic trial, darunavir was administered first to experienced patients. In the CONTEXT trial of healthy volunteers as unboosted monotherapy triple-class–experienced patients, the 1400/200 mg and then with ritonavir at dosages of 200/100 mg once-daily dosage of fosamprenavir/ritonavir was once daily, 400/100 mg once daily, 300/100 mg significantly less efficacious than the control arm twice daily, 600/200 mg once daily, and 1200/200 16 19 of lopinavir/ritonavir 400/100 mg twice-daily, mg once daily. Darunavir was rapidly absorbed, with rates of HIV RNA suppression at Week 48 of with a time to C within 3 hours for unboosted max 37% versus 50% in the two arms, respectively. In and boosted dosages. The main effect of ritonavir the BMS-045 trial, HIV RNA suppression rates at was on the clearance of darunavir, with the half-life Week 48 for the atazanavir/ritonavir 300/100 mg increased to 15 hours (Figure 1). In this trial, there once-daily arm were lower for those with three was no additional boosting effect of ritonavir at 200 or more PI mutations at baseline (30% HIV RNA mg, relative to 100 mg. <50 copies/mL at Week 48) compared to those Several doses of darunavir/ritonavir were then with two or fewer PI mutations (51% HIV RNA reevaluated in the TMC114-C137 trial. The study 420 hiV c linical t rials • 9/6 • n oV -Dec 2008 a 10000 400 mg twice daily 800 mg twice daily 800 mg thrice daily 1200 mg thrice daily 0 4 8 12 16 20 24 Time (hours) 200/100 mg once daily 400/100 mg once daily 300/100 mg twice daily 600/200 mg once daily 1200/200 mg once daily 0 4 8 12 16 20 24 Time (hours) Figure 1. Plasma darunavir concentration–time profiles for doses of darunavir without (a) and with (b) ritonavir. Darunavir (ng/mL) Darunavir (ng/mL) Pharmacokinetics of o nce -Dy ail Dr V/r • Boffito et al . 421 population consisted of five panels, each compris - the trial allowed an evaluation of the time taken ing eight healthy volunteers. During five parallel for darunavir concentrations to fall below the pre- sessions, the volunteers were treated from Day specified threshold of 55 ng/mL. Results for the 1 to 7 with the following darunavir/ritonavir 800/100 mg once-daily arm are shown in Figure 2. doses: 400/100 mg once daily, 800/100 mg once Each line represents the plasma concentration-time daily, 1200/100 mg once daily, 400/100 mg twice profile for an individual participant in the trial. daily, and 800/100 mg twice daily. Administra- The darunavir concentrations remained above the tion of ritonavir continued until Day 11 of each 55 ng/mL threshold for 48 hours in all patients. session, and the pharmacokinetics of darunavir A limitation of this analysis is that the ritonavir after stopping the drug were also assessed. The dosing was continued during this phase. These area under the plasma concentration-time curve additional ritonavir doses may have inhibited the from time of administration to 24 hours after dos- clearance of darunavir. ing (AUC ) and C of darunavir seemed to in- 24h min crease dose-proportionally for the once-daily dose Darunavir/Ritonavir Once-Daily in Antiretroviral- regimens, and C seemed to increase less than max Naïve Patients dose-proportionally between the three once-daily doses. A dose-proportional increase in pre-dose In the ARTEMIS trial, 689 treatment-naïve pa- plasma concentration (C ) and C and a less than tients were randomized to tenofovir/emtricitabine 0h min dose-proportional increase in C and AUC was plus either darunavir/ritonavir 800/100 mg once max 12h observed between the twice-daily dose regimens daily or to the control arm lopinavir/ritonavir. of darunavir/ritonavir. On Day 7, the average The randomization was stratified for screening concentrations of darunavir after 800/100 mg once HIV RNA, < versus ≥100,000 copies/mL, and CD4 daily and 400/100 mg twice daily were compara- count. Summary results are shown in Table 2. After ble, suggesting that the daily exposure to daruna- 48 weeks, the percentage of patients with HIV RNA vir after a total daily dose of 800 mg is independent <50 copies/mL in the intent-to-treat (ITT) analysis of the dosing frequency of darunavir/ritonavir for was 84% in the darunavir/ritonavir arm and 78% the doses studied. The mean t of darunavir in the lopinavir/ritonavir arm, which proved ½term ranged from 10.9 to 17.2 hours. Summary phar- noninferiority of darunavir/ritonavir versus lopi- macokinetic results are shown in Table 1 for Day 7 navir/ritonavir (Table 2). Testing for superiority evaluation of the five dose groups. was prespecified in the statistical analysis plan. After the 7 days of combined dosing with da- There was an efficacy advantage of the darunavir/ runavir and ritonavir, the darunavir dosing was ritonavir arm relative to the lopinavir/ritonavir stopped and samples were collected for the next 4 arm of 5.6% (95% confidence intervals [CIs] –0.1% days, with ritonavir given each day. This phase of to +11.3%), which was at borderline statistical Table 1. Pharmacokinetic (PK) parameters of darunavir from TMC114-C137 dose-ranging trial (mean ± standard deviation at Day 7 of the trial) Darunavir/ Darunavir/ Darunavir/ Darunavir/ Darunavir/ Dose group ritonavir ritonavir ritonavir ritonavir ritonavir PK parameter 400/100 mg 800/100 mg 1200/100 mg 400/100 mg 800/100 mg daily once-daily once-daily once-daily twice-daily twice-daily n 8 7 7 8 8 C (ng/mL) 637 ± 458 1067 ± 361 1548 ± 388 1848 ± 528 2893 ± 1965 min C (ng/mL) 3760 ± 937 5259 ± 1576 7320 ± 659 3913 ± 873 5736 ± 1879 max AUC (ng h/mL) — — — 33,511 ± 9540 48,423 ± 22,605 12h AUC (ng h/mL) 38,636 ± 14843 61,106 ± 22,455 89,298 ± 11,897 — — 24h t (hours) 10.9 ± 1.96 14.4 ± 5.17 15.0 ± 6.91 16.6 ± 4.25 17.2 ± 11.4 ½term 422 hiV c linical t rials • 9/6 • n oV -Dec 2008 0 20 40 60 80 100 120 140 Time (hours) Figure 2. Plasma concentration-time profiles of darunavir/r 800/100 mg once-daily in TMC114-C137 trial. significance ( p = .062). The darunavir/ritonavir increases in lipids. The percentage of patients with once-daily arm was superior to lopinavir/rito- treatment-related grade 2–4 diarrhea was 7% for navir for the stratum of patients with baseline darunavir/ritonavir and 14% for lopinavir/ritona- HIV RNA levels ≥100,000 copies/mL, where the vir (p < .05). In addition, the percentage of patients response was 79% for darunavir/ritonavir versus with grade 2–4 elevations in total cholesterol and 67% for lopinavir/ritonavir (p < .05). In terms of triglycerides was lower in the darunavir/ritonavir safety, the main difference between the arms was arm (13% and 3%) than in the lopinavir/ritonavir the occurrence of gastrointestinal side effects and arm (23% and 11%). Table 2. Summary HIV RNA <50 copies/mL at Week 48 in the ARTEMIS trial (naïve patients) for 800/100 mg once-daily and lopinavir/ritonavir 400/100 mg twice-daily doses Darunavir/ritonavir Lopinavir/ritonavir Trial 800/100 mg once-daily 400/100 mg twice-daily n 343 346 Baseline HIV RNA (median) 70,800 62,100 Baseline CD4 cell count (median) 228 218 HIV RNA <50 copies/mL, ITT 84% 78% HIV RNA <50 copies/mL 79% 67% baseline RNA ≥100,000 copies/mL HIV RNA <50 copies/mL 86% 85% baseline RNA <100,000 copies/mL Darunavir (ng/mL) Pharmacokinetics of o nce -Dy ail Dr V/r • Boffito et al . 423 significant correlations between darunavir phar - C (ng/mL) 0h macokinetics. and the incidence of either virologic failure or adverse events. Darunavir/Ritonavir Once-Daily in Antiretroviral- Experienced Patients TMC114-C207: Proof-of-principle trial The first 14-day pilot study with boosted da - runavir (C207) was conducted in 50 PI pretreated patients with HIV RNA >2000 copies/mL at 2000 2041.2 screening. At entry, PIs in nonsuppressive regi- EC for wild-type mens were replaced with darunavir/ritonavir virus = 55 ng/mL at one of three doses (300/100 mg twice daily, 600/100 mg twice daily, 900/100 mg once daily) or left unchanged in the control group. Each treat- Figure 3. C darunavir levels in the ARTEMIS trial (n = min ment arm contained 12–13 patients, which limited 335, sparse sampling) versus protein-binding adjusted the power to reliably compare the three doses of EC for wild-type HIV (55 ng/mL). darunavir/ritonavir. The patients had a median of three primary PI mutations at baseline, with me- A pharmacokinetic substudy was conducted in dian HIV RNA levels ranging from 4.16 to 4.36 log ARTEMIS, looking at the 24-hour pharmacokinetic copies/mL in the four treatment groups. Summary profile of plasma darunavir concentration in a efficacy results at Day 14 are shown in Table 3. subset of nine patients. The 24-hour concentrations Owing to the small sample sizes in each group, it were consistently well above the protein-adjusted was difficult to compare efficacy by darunavir/ IC for darunavir (55 ng/mL). In addition, there ritonavir dosage, but there was clear evidence for a was sparse sampling of 335 patients in the daruna- virologic benefit for the combined darunavir/rito - vir/ritonavir arm used to estimate darunavir phar- navir groups versus the control PI group. In this macokinetic parameters. The median C for the PI-experienced population, the twice-daily dose 0h 800/100 mg once-daily dose was 37-fold above the groups tended to show slightly higher rates of HIV protein-binding corrected EC for darunavir (55 RNA suppression than the 900/100 mg once-daily ng/mL). All 335 patients showed a C above the dose group, but these differences were not statisti- 0h 22 27 55 ng/mL target level (Figure 3). There were no cally significant. The sample sizes were too small Table 3. Summary efficacy at Day 14 in TMC114-C207 trial (PI-experienced patients) for 900/100 mg once-daily, 300/100 mg twice-daily, and 600/100 mg twice-daily doses of darunavir/ritonavir Darunavir/ritonavir Darunavir/ritonavir Darunavir/ritonavir Treatment arm 900/100 mg once-daily 300/100 mg twice-daily 600/100 mg twice-daily Control group n 13 13 12 12 Median HIV RNA –1.13 –1.24 –1.50 –0.03 reduction Percent with 0.5 log 92% 100% 100% 25% reduction in HIV RNA Percent with HIV 31% 46% 42% 8% RNA <400 copies/ mL C (ng/mL) 0h 424 hiV c linical t rials • 9/6 • n oV -Dec 2008 in this pilot study to make reliable statistical com- once-daily arm showed the strongest efficacy (75%) parisons of the dose groups. and the 600/100 mg twice-daily arm the weakest efficacy (59%). In both trials, there was no evidence for dose-related rises in adverse events or labora- POWER 1 and 2 trials (TMC114-C213 and C202) tory abnormalities. Given the results from the TMC114-C207 trial, The combined POWER 1 and 2 trials were then two Phase IIb randomized trials were initiated fol- analyzed in more detail to investigate whether lowing a similar design. The POWER 1 trial was there was a threshold level of baseline PI resistance conducted mainly with European and Brazilian that would discriminate the doses more clearly. sites, while the POWER 2 trial recruited mainly Summary results are shown in Table 4. The da- in the United States and Argentina. In both tri- runavir resistance algorithm was used to predict als, patients with HIV RNA >1000 copies/mL at HIV RNA suppression rates. This is the total num- screening and at least one major IAS-USA PI mu- ber of mutations from the following list: V11I, V32I, tation were randomized to one of four doses of L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and darunavir/ritonavir (400/100 mg and 800/100 mg L89V. The 800/100 mg once-daily and 600/100 once daily, and 400/100 mg and 600/100 mg twice mg twice-daily arms from the combined POWER 1 daily) or investigator-selected control PIs. Patients and 2 trials were compared, based on the number also received an optimized background regimen of baseline darunavir mutations. Summary results of nucleoside analogues with optional enfuvirtide. are shown in Table 4. The trials were continued for 24 weeks of random- For the overall POWER 1 and 2 trial populations, ized treatment, after which there were protocol there was an efficacy advantage for the 600/100 mg amendments to transfer all patients to the 600/100 twice-daily dose relative to the 800/100 mg once- mg twice-daily dose. daily dose, with 47% of patients on the twice-daily The patients receiving darunavir/ritonavir in dose having HIV RNA levels <50 copies/mL at the POWER 1 trial tended to be less treatment- Week 24 versus 31% on the once-daily dose. For the experienced than those in POWER 2, as measured subset of patients with either none or one daruna- by baseline CD4 cell counts (median 176 vs. 99 vir mutation at screening, the responses were com- cells/µL), HIV RNA levels (4.5 vs. 4.7 log copies/ parable (53% vs. 49%), but advantages in efficacy mL), or the percent with at least three primary IAS- were also apparent for the endpoints of mean rise USA PI mutations at baseline (58% vs. 66%). in CD4 cell count and log reduction in HIV RNA. In the POWER 1 trial, all four doses of daruna- The subset of patients with no darunavir mutations vir/ritonavir showed significant efficacy benefits at baseline in the POWER 1 and 2 trials was rela- over the control PI arm, but the efficacy of the tively small, with 23–29 patients per treatment arm. four darunavir/ritonavir doses was similar. The However, in this subset the rates of full virologic percentage of patients with HIV RNA levels <50 suppression were very similar for the 600/100 mg copies/mL at Week 24 was 43%, 48%, 49%, and twice-daily and 800/100 mg once-daily treatment 53% for the 400/100 mg once-daily, 800/100 mg arms. In all the above analyses, the two darunavir/ once-daily, 400/100 mg twice-daily, and 600/100 ritonavir dose groups performed better than the mg twice-daily doses, respectively. Similar results control PI arm in terms of HIV RNA reductions and were seen with the endpoint of at least one log re- increases in CD4 cell counts at Week 24. Stratifying duction in HIV RNA. this analysis by the number of darunavir mutations By contrast in the POWER 2 trial, there was could make interpretation of the efficacy between stronger evidence for dose-related rises in efficacy. the darunavir and control PI arms difficult. How - The percentage of patients with HIV RNA levels ever, the PI mutations associated with resistance to <50 copes/mL at Week 24 was 18%, 20%, 36%, and darunavir also confer high-level resistance to most 39% for the 400/100 mg once-daily, 800/100 mg other PIs. For example in the TITAN trial, which once-daily, 400/100 mg twice-daily, and 600/100 recruited treatment-experienced patients, presence mg twice-daily doses, respectively. Even so, this of at least one darunavir mutation led to a larger result was not seen for the endpoint of at least one fall in efficacy for the lopinavir/ritonavir arm than log reduction in HIV RNA, where the 800/100 mg the darunavir/ritonavir arm. Pharmacokinetics of o nce -Dy ail Dr V/r • Boffito et al . 425 Table 4. Summary HIV RNA <50 copies/mL at Week 24 in POWER trials (triple-class–experienced patients) for darunavir/ritonavir 800/100 mg once-daily, 600/100 mg twice-daily doses, and control PI arm Darunavir/ritonavir Darunavir/ritonavir Trial 600/100 mg twice-daily 800/100 mg once-daily Control PI POWER 1 and 2 subgroup Total population n 99 100 100 HIV RNA <50 copies/mL 47% 31% 10% Log reduction in HIV RNA –1.85 –1.43 –0.27 Change in CD4 cell count +75 +55 +15 <2 darunavir mutations n 62 59 56 HIV RNA <50 copies/mL 53% 49% 18% Log reduction in HIV RNA –2.29 –2.00 –0.71 Change in CD4 cell count +118 +90 +25 0 darunavir mutations n 29 23 29 HIV RNA <50 copies/mL 62% 67% 11% Log reduction in HIV RNA –2.35 –2.39 –0.68 Change in CD4 cell count +111 +88 +33 SUMMARY navir/ritonavir in the POWER trials. For highly treatment-experienced patients, other novel drugs There is evidence from clinical pharmacology are typically used twice-daily, such as the integrase trials and Phase II and III efficacy trials to support inhibitor raltegravir, the CCR5 antagonist maravi- use of the 800/100 mg once-daily dose of darunavir roc, the NNRTI etravirine, or the fusion inhibitor 30,31 in naïve patients plus those with no evidence for enfuvirtide. resistance to darunavir, as defined by the daruna - For patients with a lesser degree of treatment ex- vir resistance algorithm. This guideline may be perience, the DRV/r 800/100 mg once-daily dose useful in deciding which dose of darunavir/rito- of darunavir/ritonavir appears to show strong navir to choose for patients with little treatment efficacy. Nevertheless, the data so far available on experience. the effectiveness of this dose in moderately expe- For treatment-naïve patients, the ARTEMIS trial rienced patients have been obtained from limited has established the efficacy of the 800/100 mg numbers of patients. These data, however, will be once-daily dose, with results showing noninferior confirmed soon by a currently recruiting study. The efficacy versus lopinavir/ritonavir after 48 weeks ODIN study (TMC114-C229) is aimed at evaluating of treatment, and superior efficacy for patients with the efficacy of darunavir/ritonavir 800/100 mg baseline HIV RNA levels ≥100,000 copies/mL. once daily in treatment-experienced patients. The For patients with extensive treatment experience ODIN trial is a randomized comparison of the two and baseline resistance to PIs, the POWER 1 and doses of darunavir/ritonavir: 600/100 mg twice 2 trials have clearly identified the darunavir/rito - daily versus 800/100 mg once daily. This trial is navir 600/100 mg twice-daily dose as optimal, currently recruiting 600 antiretroviral-experienced confirming the need of higher plasma concentra - patients with HIV RNA levels >1000 copies/mL at tions over the dosing interval in the presence of screening but no darunavir mutations. remarkable drug resistance. It is important to note, If darunavir/ritonavir is effective at the 800/100 however, the darunavir/ritonavir 600/100 mg mg once-daily dose in naïve patients, similar ef- twice-daily dose has shown efficacy advantages ficacy might be observed for patients who have over investigator-selected control PIs such as lopi- never previously received PIs. It would seem 426 hiV c linical t rials • 9/6 • n oV -Dec 2008 and abstracts of the 15th Conference on Retroviruses and reasonable to use the once-daily dose of daruna- Opportunistic Infections; February 3–6, 2008; Boston, MA. vir/ritonavir for patients switching off a first-line Abstract 37. antiretroviral regimen because of adverse events 9. Smith K, Fine D, Patel P, et al. Efficacy and safety of aba - while fully virologically suppressed. In the ongo- cavir/lamivudine compared to tenofovir/emtricitabine in ing 48-week MONET trial, a total of 256 patients combination with once-daily lopinavir-ritonavir through 48 weeks in the HEAT study. In: Program and abstracts of the with full virologic suppression on prior first-line 15th Conference on Retroviruses and Opportunistic Infec- antiretroviral therapy have been randomized to re- tions; February 3–6, 2008; Boston, MA. Abstract 774. ceive darunavir/ritonavir 800/100 mg once-daily, 10. Gathe J, daSilva B, Loufty M, et al. Study M05-730 primary either with or without two nucleoside analogues. efficacy results at week 48: Phase 3, randomized, open- In summary, the current evidence from clinical label study of lopinavir-ritonavir (LPV/r) tablets once-daily (OD) versus twice-daily (BID), co-administered with tenofo- trials of darunavir/ritonavir supports the efficacy vir (TDF) + emtricitabine (FTC) in antiretroviral naïve (ARV) of the 800/100 mg once-daily dose for treatment- HIV-1 infected subjects. In: Program and abstracts of the naïve patients and the further evaluation of this 15th Conference on Retroviruses and Opportunistic Infec- once-daily dose for treatment-experienced patients tions; February 3–6, 2008; Boston, MA. Abstract 775. with no genotypic resistance to darunavir. 11. DeJesus E, Ortiz R, Khanlou H, et al. Efficacy and safety of darunavir/ritonavir versus lopinavir/ritonavir in ARV treatment-naive HIV-1-infected patients at Week 48: AR- TEMIS (TMC114-C211). 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In: Program and abstracts of the failure of first-line HAART in resource rich and poor set - 10th Conference on Retroviruses and Opportunistic Infec- tings—a meta-analysis. In: Program and abstracts of the tions; February 10–14, 2003; Boston, MA. Abstract 178. 15th Conference on Retroviruses and Opportunistic Infec- 17. Naeger LK, Struble KA. Effect of baseline protease genotype tions; February 3–6, 2008; Boston, MA. Abstract 891. and phenotype on HIV response to atazanavir/ritonavir in 8. Molina J, Andrade-Villanueva J, Echevarria J, et al. Efficacy treatment-experienced patients. AIDS. 2006;20:847–853. and safety of once-daily atazanavir-ritonavir compared to 18. De Meyer S, Azijn H, Surleraux D, et al. TMC114, a novel twice-daily lopinavir-ritonavir, each in combination with human immunodeficiency virus type 1 protease inhibitor tenofovir and emtricitabine in ARV-naïve HIV-1 infected active against protease inhibitor-resistant viruses, includ- subjects: The CASTLE study, 48 week results. In: Program Pharmacokinetics of o nce -Dy ail Dr V/r • Boffito et al . 427 ing a broad range of clinical isolates. Antimicrob Agents file of darunavir with low-dose ritonavir (DRV/r) in various Chemother. 2005;49:2314–2321. multiple-dose regimens over 120 hours. 9th International 19. Hoetelmans R, Van der Sandt I, De Pauw M, et al. TMC114, Workshop on Clinical Pharmacology of HIV Therapy; April a next generation HIV protease inhibitor: Pharmacokinetics 7–9, 2008; New Orleans, USA. Abstract P31. and safety following oral administration of multiple doses 27. Arasteh K, Clumeck N, Pozniak A, et al. First clinical results with and without low doses of ritonavir in healthy volun- on antiretroviral activity, pharmacokinetics, and safety of teers. In: Program and abstracts of the 10th Conference TMC114, an HIV-1 protease inhibitor, in multiple PI expe- on Retroviruses and Opportunistic Infections; February rienced patients. In: Program and abstracts of the 10th 10–14, 2003; Boston, MA. Abstract and poster 549. Conference on Retroviruses and Opportunistic Infections; 20. Cvetkovic RS, Goa KL. Lopinavir/ritonavir: A review of its February 10–14, 2003; Boston, MA. Abstract 8. use in the management of HIV infection. Drugs. 2003;63: 28. De Meyer S, Spinoza-Guzman S, Vangenuegden T, de Bet- 769–802. hune M, Miralles D. Efficacy of darunavir (DRV)/r 800/100 21. Bristol-Myers Squibb. Atazanavir (atazanavir capsules) US mg qd in patients with low DRV resistance. In: Program and prescribing information. Available at http://packageinserts. abstracts of the 5th European HIV Drug Resistance Work- bms.com/pi/pi_reyataz.pdf. Accessed February 2008. shop; March 28–30, 2007; Cascais, Portugal. Abstract 48. 22. Sekar V, Vanden Abeele C, Van Baelen B, Vis P, Lavreys L, 29. Madruga J, Berger D, McMurchie M, et al. Efficacy De Pauw M. Pharmacokinetic-pharmacodynamic analyses and safety of darunavir-ritonavir compared with that of of once-daily darunavir-ritonavir in the ARTEMIS study. In: lopinavir-ritonavir at 48 weeks in treatment-experienced, Program and abstracts of the 15th Conference on Retro- HIV-infected patients in TITAN: A randomized, controlled viruses and Opportunistic Infections; February 3–6, 2008; Phase III trial. Lancet. 2007; 370:49–58. Boston, MA. Abstract 769. 30. C o o p e r D , G a t e l l J , R o c k s t ro h J , e t a l . R e s u l t s o f 23. Arastéh K, Clumeck N, Pozniak A, et al. TMC114/ritonavir BENCHMRK-1, a Phase III study evaluating the efficacy substitution for protease inhibitor(s) in a non-suppressive and safety of MK-0518, a novel HIV-1 integrase inhibitor, antiretroviral regimen: A 14-day proof-of-principle trial. in patients with triple-class resistant virus. In: Program and AIDS. 2005;19:943–947. abstracts of the 14th Conference on Retroviruses and Op- 24. Katlama C, Esposito R, Gatell JM, et al. Efficacy and safety portunistic Infections; February 25–28, 2007; Los Angeles, of TMC114/ritonavir in treatment-experienced HIV patients: CA. Abstract 105aLB. 24-week results of POWER 1. AIDS. 2007;21:395–402. 31. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety 25. Haubrich R, Berger D, Chiliade P, et al. Week 24 efficacy of TMC125 (etravirine) in treatment-experienced HIV-1- and safety of TMC114/ritonavir in treatment-experienced infected patients in DUET-1: 24-week results from a ran- HIV patients. AIDS. 2007;21:F11–F18. domised, double-blind, placebo-controlled trial. Lancet. 26. Boffito M, Moyle G, Hill A, et al. The pharmacokinetic pro - 2007;370:29–38. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png HIV Clinical Trials Taylor & Francis

Pharmacokinetics, Efficacy, and Safety of Darunavir/Ritonavir 800/100 mg Once-Daily in Treatment-Naïve and -Experienced Patients

HIV Clinical Trials , Volume 9 (6): 10 – Dec 1, 2008

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References (34)

Publisher
Taylor & Francis
Copyright
©2008 Thomas Land Publishers, Inc.
ISSN
1528-4336
eISSN
1945-5771
DOI
10.1310/hct0906-418
pmid
19203907
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Abstract

Review Pharmacokinetics, Efficacy, and Safety of Darunavir/Ritonavir 800/100 mg Once-Daily in Treatment-Naïve and -Experienced Patients 1 2 3 Marta Boffito, Diego Miralles, and Andrew Hill 1 2 Chelsea and Westminster Hospital, London, United Kingdom; Tibotec Research and Development, Mechelen, Belgium; Pharmacology Research Laboratories, University of Liverpool, Liverpool, United Kingdom Darunavir is a new protease inhibitor (PI) with in vitro activity against wild-type and PI-resistant HIV; it is used with the pharmacokinetic booster ritonavir. The cur- rently approved dose of darunavir/ritonavir is 600/100 mg twice-daily, licensed for treatment-experienced patients. However, during the clinical development of darunavir, a range of once-daily and twice-daily doses of darunavir/ritonavir were evaluated. The relatively long terminal elimination plasma half-life of darunavir (15 hours) supports once-daily dosing. In treatment-naïve patients, the ARTEMIS trial has shown high rates of HIV RNA suppression for darunavir-ritonavir at the 800/100 mg once-daily dose (84% with HIV RNA <50 copies/mL at Week 48) versus a con- trol arm of lopinavir/ritonavir (78% with HIV RNA <50 copies/mL). In a population pharmacokinetic substudy, darunavir 24-hour minimum plasma concentration lev- els remained above the predefined EC of 55 ng/mL for all 335 patients evaluated in the ARTEMIS trial. Once-daily darunavir/ritonavir has also been evaluated in treatment-experienced patients in the TMC114-C207 proof-of-principle trial and the POWER 1 and 2 trials. For the overall POWER trial population, with significant baseline resistance to PIs, the rates of HIV RNA suppression <50 copies/mL at Week 24 for darunavir/ritonavir 800/100 mg once-daily were lower than for the 600/100 mg twice-daily dosage (31% vs. 47%, respectively). However, for patients with no genotypic darunavir resistance-associated mutations at baseline, rates of HIV RNA suppression were 62% and 67% for the 800/100 mg once-daily and 600/100 mg twice-daily doses. The current evidence from clinical trials of darunavir/ritonavir sup- ports the efficacy of the 800/100 mg once-daily dose for treatment-naïve patients and further evaluation for treatment-experienced patients with no genotypic resis- tance to darunavir. Key words: darunavir, once-daily, pharmacokinetics, ritonavir ver the past 10 years, first-line treatment for proved at the 200 mg twice-daily dose. The main HIV has become increasingly simple to take, advantages of once-daily versus twice-daily PIs Owith reformulations lowering pill counts, are lower pill count, improved convenience (which the coformulation of two or three drugs into single might improve adherence), and halving the daily pills, and the introduction of several drugs with dose of ritonavir needed (normally from 200 mg to once-daily dosing. For first-line treatment of anti - 100 mg), with possible improvements in adverse retroviral naïve patients, the European guidelines recommend a combination of two nucleoside ana- logues (either tenofovir/emtricitabine or abaca- Address for correspondence: Marta Boffito, Chelsea and West - vir/lamivudine, both available as coformulated minster Hospital, 369 Fulham Road, London, SW10 9NH, United Kingdom. Email: marta.boffito@chelwest.nhs.uk once-daily single pill formulations) with a non- nucleoside reverse transcriptase inhibitor (NNRTI) HIV Clin Trials 2008;9(6):418–427 or a boosted protease inhibitor (PI). The NNRTI © 2008 Thomas Land Publishers, Inc. www.thomasland.com efavirenz has shown strong efficacy at the 600 mg once-daily dose, whereas nevirapine is only ap- doi: 10.1310/hct0906-418 418 Pharmacokinetics of o nce -Dy ail Dr V/r • Boffito et al . 419 5 17 events or lipid profiles. First-line use of ritonavir- <50 copies/mL). Therefore, some once-daily PIs boosted PIs involves higher pill counts and more may not provide high enough drug concentrations complex issues with drug-drug interactions com- to overcome partially PI-resistant HIV. Additional pared with NNRTI, but it may lead to a lower risk efficacy data from randomized trials are needed to 6,7 of drug resistance at treatment failure. justify the use of once-daily PIs for treatment-ex- Five ritonavir-boosted PIs have been evaluated perienced patients. at once-daily doses, mainly in treatment-naïve Darunavir is a ritonavir-boosted PI with in vitro patients. Atazanavir/ritonavir 300/100 mg once- activity against both wild-type and PI-resistant daily showed noninferior efficacy compared with HIV isolates. Coadministration with ritonavir twice-daily lopinavir/ritonavir in the CASTLE inhibits clearance of darunavir, increasing the 8 19 trial. Lopinavir/ritonavir 800/200 mg once-daily terminal elimination half-life (t ) to 15 hours, ½term has shown high efficacy in two recent trials of which is relatively long, compared with data from 9,10 20 naïve patients. Darunavir (TMC114) with low- HIV-infected patients for lopinavir (2–6 hours) or dose ritonavir (darunavir/ritonavir) 800/100 mg atazanavir (7–8.5 hours). once-daily showed noninferior efficacy versus During the clinical development of daruna- lopinavir/ritonavir after 48 weeks of treatment in vir, both once-daily and twice-daily dosing were the ARTEMIS trial (TMC114-C211; AntiRetroviral evaluated in a range of naïve and treatment- Therapy with TMC114 Examined In Naïve Sub- experienced patients. The initial European regula- jects). Once-daily doses of ritonavir-boosted sa- tory approval of darunavir was for the 600/100 mg quinavir (1500/100 mg or 2000/100 mg once-daily) twice-daily dose for patients with at least two prior and fosamprenavir (1400/200 mg or 1400/100 mg PIs. However, the 800/100 mg once-daily dose has once-daily) have been evaluated in clinical trials been evaluated in the Phase III ARTEMIS trial of 12–14 19,22 of naïve patients, but these trials were not fully naïve patients, pharmacokinetic studies, and powered randomized comparisons versus recog- three trials in experienced patients: a 14-day proof- nized standard of care control treatments. of-principle trial (TMC114-C207) and the POWER 24,25 The pharmacokinetics of once-daily PIs is gen- 1 and 2 (TMC114-C213 and C202) trials. This erally characterized by high maximum concen- review will describe the evidence supporting the trations (C ) and lower 24-hour concentrations 800/100 mg once-daily dose of darunavir/ritona- max (C or C ), whereas twice-daily use tends vir in naïve patients and review the evidence sup- trough min to lead to more constant plasma PI concentra- porting use of this once-daily dose in patients with tions over the dosing interval. In poorly adherent different levels of prior antiretroviral treatment, patients, who could have suboptimal plasma PI relative to the 600/100 mg twice-daily dose. concentrations after missed doses, a potential dis- advantage of the use of once-daily PIs may be the DOSE-RANGING PHARMACOKINETIC TRIALS emergence of drug resistance. OF DARUNAVIR In several recent trials, once-daily PIs that showed strong efficacy for treatment-naïve In the exploratory dose-ranging pharmacoki- patients have underperformed in treatment- netic trial, darunavir was administered first to experienced patients. In the CONTEXT trial of healthy volunteers as unboosted monotherapy triple-class–experienced patients, the 1400/200 mg and then with ritonavir at dosages of 200/100 mg once-daily dosage of fosamprenavir/ritonavir was once daily, 400/100 mg once daily, 300/100 mg significantly less efficacious than the control arm twice daily, 600/200 mg once daily, and 1200/200 16 19 of lopinavir/ritonavir 400/100 mg twice-daily, mg once daily. Darunavir was rapidly absorbed, with rates of HIV RNA suppression at Week 48 of with a time to C within 3 hours for unboosted max 37% versus 50% in the two arms, respectively. In and boosted dosages. The main effect of ritonavir the BMS-045 trial, HIV RNA suppression rates at was on the clearance of darunavir, with the half-life Week 48 for the atazanavir/ritonavir 300/100 mg increased to 15 hours (Figure 1). In this trial, there once-daily arm were lower for those with three was no additional boosting effect of ritonavir at 200 or more PI mutations at baseline (30% HIV RNA mg, relative to 100 mg. <50 copies/mL at Week 48) compared to those Several doses of darunavir/ritonavir were then with two or fewer PI mutations (51% HIV RNA reevaluated in the TMC114-C137 trial. The study 420 hiV c linical t rials • 9/6 • n oV -Dec 2008 a 10000 400 mg twice daily 800 mg twice daily 800 mg thrice daily 1200 mg thrice daily 0 4 8 12 16 20 24 Time (hours) 200/100 mg once daily 400/100 mg once daily 300/100 mg twice daily 600/200 mg once daily 1200/200 mg once daily 0 4 8 12 16 20 24 Time (hours) Figure 1. Plasma darunavir concentration–time profiles for doses of darunavir without (a) and with (b) ritonavir. Darunavir (ng/mL) Darunavir (ng/mL) Pharmacokinetics of o nce -Dy ail Dr V/r • Boffito et al . 421 population consisted of five panels, each compris - the trial allowed an evaluation of the time taken ing eight healthy volunteers. During five parallel for darunavir concentrations to fall below the pre- sessions, the volunteers were treated from Day specified threshold of 55 ng/mL. Results for the 1 to 7 with the following darunavir/ritonavir 800/100 mg once-daily arm are shown in Figure 2. doses: 400/100 mg once daily, 800/100 mg once Each line represents the plasma concentration-time daily, 1200/100 mg once daily, 400/100 mg twice profile for an individual participant in the trial. daily, and 800/100 mg twice daily. Administra- The darunavir concentrations remained above the tion of ritonavir continued until Day 11 of each 55 ng/mL threshold for 48 hours in all patients. session, and the pharmacokinetics of darunavir A limitation of this analysis is that the ritonavir after stopping the drug were also assessed. The dosing was continued during this phase. These area under the plasma concentration-time curve additional ritonavir doses may have inhibited the from time of administration to 24 hours after dos- clearance of darunavir. ing (AUC ) and C of darunavir seemed to in- 24h min crease dose-proportionally for the once-daily dose Darunavir/Ritonavir Once-Daily in Antiretroviral- regimens, and C seemed to increase less than max Naïve Patients dose-proportionally between the three once-daily doses. A dose-proportional increase in pre-dose In the ARTEMIS trial, 689 treatment-naïve pa- plasma concentration (C ) and C and a less than tients were randomized to tenofovir/emtricitabine 0h min dose-proportional increase in C and AUC was plus either darunavir/ritonavir 800/100 mg once max 12h observed between the twice-daily dose regimens daily or to the control arm lopinavir/ritonavir. of darunavir/ritonavir. On Day 7, the average The randomization was stratified for screening concentrations of darunavir after 800/100 mg once HIV RNA, < versus ≥100,000 copies/mL, and CD4 daily and 400/100 mg twice daily were compara- count. Summary results are shown in Table 2. After ble, suggesting that the daily exposure to daruna- 48 weeks, the percentage of patients with HIV RNA vir after a total daily dose of 800 mg is independent <50 copies/mL in the intent-to-treat (ITT) analysis of the dosing frequency of darunavir/ritonavir for was 84% in the darunavir/ritonavir arm and 78% the doses studied. The mean t of darunavir in the lopinavir/ritonavir arm, which proved ½term ranged from 10.9 to 17.2 hours. Summary phar- noninferiority of darunavir/ritonavir versus lopi- macokinetic results are shown in Table 1 for Day 7 navir/ritonavir (Table 2). Testing for superiority evaluation of the five dose groups. was prespecified in the statistical analysis plan. After the 7 days of combined dosing with da- There was an efficacy advantage of the darunavir/ runavir and ritonavir, the darunavir dosing was ritonavir arm relative to the lopinavir/ritonavir stopped and samples were collected for the next 4 arm of 5.6% (95% confidence intervals [CIs] –0.1% days, with ritonavir given each day. This phase of to +11.3%), which was at borderline statistical Table 1. Pharmacokinetic (PK) parameters of darunavir from TMC114-C137 dose-ranging trial (mean ± standard deviation at Day 7 of the trial) Darunavir/ Darunavir/ Darunavir/ Darunavir/ Darunavir/ Dose group ritonavir ritonavir ritonavir ritonavir ritonavir PK parameter 400/100 mg 800/100 mg 1200/100 mg 400/100 mg 800/100 mg daily once-daily once-daily once-daily twice-daily twice-daily n 8 7 7 8 8 C (ng/mL) 637 ± 458 1067 ± 361 1548 ± 388 1848 ± 528 2893 ± 1965 min C (ng/mL) 3760 ± 937 5259 ± 1576 7320 ± 659 3913 ± 873 5736 ± 1879 max AUC (ng h/mL) — — — 33,511 ± 9540 48,423 ± 22,605 12h AUC (ng h/mL) 38,636 ± 14843 61,106 ± 22,455 89,298 ± 11,897 — — 24h t (hours) 10.9 ± 1.96 14.4 ± 5.17 15.0 ± 6.91 16.6 ± 4.25 17.2 ± 11.4 ½term 422 hiV c linical t rials • 9/6 • n oV -Dec 2008 0 20 40 60 80 100 120 140 Time (hours) Figure 2. Plasma concentration-time profiles of darunavir/r 800/100 mg once-daily in TMC114-C137 trial. significance ( p = .062). The darunavir/ritonavir increases in lipids. The percentage of patients with once-daily arm was superior to lopinavir/rito- treatment-related grade 2–4 diarrhea was 7% for navir for the stratum of patients with baseline darunavir/ritonavir and 14% for lopinavir/ritona- HIV RNA levels ≥100,000 copies/mL, where the vir (p < .05). In addition, the percentage of patients response was 79% for darunavir/ritonavir versus with grade 2–4 elevations in total cholesterol and 67% for lopinavir/ritonavir (p < .05). In terms of triglycerides was lower in the darunavir/ritonavir safety, the main difference between the arms was arm (13% and 3%) than in the lopinavir/ritonavir the occurrence of gastrointestinal side effects and arm (23% and 11%). Table 2. Summary HIV RNA <50 copies/mL at Week 48 in the ARTEMIS trial (naïve patients) for 800/100 mg once-daily and lopinavir/ritonavir 400/100 mg twice-daily doses Darunavir/ritonavir Lopinavir/ritonavir Trial 800/100 mg once-daily 400/100 mg twice-daily n 343 346 Baseline HIV RNA (median) 70,800 62,100 Baseline CD4 cell count (median) 228 218 HIV RNA <50 copies/mL, ITT 84% 78% HIV RNA <50 copies/mL 79% 67% baseline RNA ≥100,000 copies/mL HIV RNA <50 copies/mL 86% 85% baseline RNA <100,000 copies/mL Darunavir (ng/mL) Pharmacokinetics of o nce -Dy ail Dr V/r • Boffito et al . 423 significant correlations between darunavir phar - C (ng/mL) 0h macokinetics. and the incidence of either virologic failure or adverse events. Darunavir/Ritonavir Once-Daily in Antiretroviral- Experienced Patients TMC114-C207: Proof-of-principle trial The first 14-day pilot study with boosted da - runavir (C207) was conducted in 50 PI pretreated patients with HIV RNA >2000 copies/mL at 2000 2041.2 screening. At entry, PIs in nonsuppressive regi- EC for wild-type mens were replaced with darunavir/ritonavir virus = 55 ng/mL at one of three doses (300/100 mg twice daily, 600/100 mg twice daily, 900/100 mg once daily) or left unchanged in the control group. Each treat- Figure 3. C darunavir levels in the ARTEMIS trial (n = min ment arm contained 12–13 patients, which limited 335, sparse sampling) versus protein-binding adjusted the power to reliably compare the three doses of EC for wild-type HIV (55 ng/mL). darunavir/ritonavir. The patients had a median of three primary PI mutations at baseline, with me- A pharmacokinetic substudy was conducted in dian HIV RNA levels ranging from 4.16 to 4.36 log ARTEMIS, looking at the 24-hour pharmacokinetic copies/mL in the four treatment groups. Summary profile of plasma darunavir concentration in a efficacy results at Day 14 are shown in Table 3. subset of nine patients. The 24-hour concentrations Owing to the small sample sizes in each group, it were consistently well above the protein-adjusted was difficult to compare efficacy by darunavir/ IC for darunavir (55 ng/mL). In addition, there ritonavir dosage, but there was clear evidence for a was sparse sampling of 335 patients in the daruna- virologic benefit for the combined darunavir/rito - vir/ritonavir arm used to estimate darunavir phar- navir groups versus the control PI group. In this macokinetic parameters. The median C for the PI-experienced population, the twice-daily dose 0h 800/100 mg once-daily dose was 37-fold above the groups tended to show slightly higher rates of HIV protein-binding corrected EC for darunavir (55 RNA suppression than the 900/100 mg once-daily ng/mL). All 335 patients showed a C above the dose group, but these differences were not statisti- 0h 22 27 55 ng/mL target level (Figure 3). There were no cally significant. The sample sizes were too small Table 3. Summary efficacy at Day 14 in TMC114-C207 trial (PI-experienced patients) for 900/100 mg once-daily, 300/100 mg twice-daily, and 600/100 mg twice-daily doses of darunavir/ritonavir Darunavir/ritonavir Darunavir/ritonavir Darunavir/ritonavir Treatment arm 900/100 mg once-daily 300/100 mg twice-daily 600/100 mg twice-daily Control group n 13 13 12 12 Median HIV RNA –1.13 –1.24 –1.50 –0.03 reduction Percent with 0.5 log 92% 100% 100% 25% reduction in HIV RNA Percent with HIV 31% 46% 42% 8% RNA <400 copies/ mL C (ng/mL) 0h 424 hiV c linical t rials • 9/6 • n oV -Dec 2008 in this pilot study to make reliable statistical com- once-daily arm showed the strongest efficacy (75%) parisons of the dose groups. and the 600/100 mg twice-daily arm the weakest efficacy (59%). In both trials, there was no evidence for dose-related rises in adverse events or labora- POWER 1 and 2 trials (TMC114-C213 and C202) tory abnormalities. Given the results from the TMC114-C207 trial, The combined POWER 1 and 2 trials were then two Phase IIb randomized trials were initiated fol- analyzed in more detail to investigate whether lowing a similar design. The POWER 1 trial was there was a threshold level of baseline PI resistance conducted mainly with European and Brazilian that would discriminate the doses more clearly. sites, while the POWER 2 trial recruited mainly Summary results are shown in Table 4. The da- in the United States and Argentina. In both tri- runavir resistance algorithm was used to predict als, patients with HIV RNA >1000 copies/mL at HIV RNA suppression rates. This is the total num- screening and at least one major IAS-USA PI mu- ber of mutations from the following list: V11I, V32I, tation were randomized to one of four doses of L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and darunavir/ritonavir (400/100 mg and 800/100 mg L89V. The 800/100 mg once-daily and 600/100 once daily, and 400/100 mg and 600/100 mg twice mg twice-daily arms from the combined POWER 1 daily) or investigator-selected control PIs. Patients and 2 trials were compared, based on the number also received an optimized background regimen of baseline darunavir mutations. Summary results of nucleoside analogues with optional enfuvirtide. are shown in Table 4. The trials were continued for 24 weeks of random- For the overall POWER 1 and 2 trial populations, ized treatment, after which there were protocol there was an efficacy advantage for the 600/100 mg amendments to transfer all patients to the 600/100 twice-daily dose relative to the 800/100 mg once- mg twice-daily dose. daily dose, with 47% of patients on the twice-daily The patients receiving darunavir/ritonavir in dose having HIV RNA levels <50 copies/mL at the POWER 1 trial tended to be less treatment- Week 24 versus 31% on the once-daily dose. For the experienced than those in POWER 2, as measured subset of patients with either none or one daruna- by baseline CD4 cell counts (median 176 vs. 99 vir mutation at screening, the responses were com- cells/µL), HIV RNA levels (4.5 vs. 4.7 log copies/ parable (53% vs. 49%), but advantages in efficacy mL), or the percent with at least three primary IAS- were also apparent for the endpoints of mean rise USA PI mutations at baseline (58% vs. 66%). in CD4 cell count and log reduction in HIV RNA. In the POWER 1 trial, all four doses of daruna- The subset of patients with no darunavir mutations vir/ritonavir showed significant efficacy benefits at baseline in the POWER 1 and 2 trials was rela- over the control PI arm, but the efficacy of the tively small, with 23–29 patients per treatment arm. four darunavir/ritonavir doses was similar. The However, in this subset the rates of full virologic percentage of patients with HIV RNA levels <50 suppression were very similar for the 600/100 mg copies/mL at Week 24 was 43%, 48%, 49%, and twice-daily and 800/100 mg once-daily treatment 53% for the 400/100 mg once-daily, 800/100 mg arms. In all the above analyses, the two darunavir/ once-daily, 400/100 mg twice-daily, and 600/100 ritonavir dose groups performed better than the mg twice-daily doses, respectively. Similar results control PI arm in terms of HIV RNA reductions and were seen with the endpoint of at least one log re- increases in CD4 cell counts at Week 24. Stratifying duction in HIV RNA. this analysis by the number of darunavir mutations By contrast in the POWER 2 trial, there was could make interpretation of the efficacy between stronger evidence for dose-related rises in efficacy. the darunavir and control PI arms difficult. How - The percentage of patients with HIV RNA levels ever, the PI mutations associated with resistance to <50 copes/mL at Week 24 was 18%, 20%, 36%, and darunavir also confer high-level resistance to most 39% for the 400/100 mg once-daily, 800/100 mg other PIs. For example in the TITAN trial, which once-daily, 400/100 mg twice-daily, and 600/100 recruited treatment-experienced patients, presence mg twice-daily doses, respectively. Even so, this of at least one darunavir mutation led to a larger result was not seen for the endpoint of at least one fall in efficacy for the lopinavir/ritonavir arm than log reduction in HIV RNA, where the 800/100 mg the darunavir/ritonavir arm. Pharmacokinetics of o nce -Dy ail Dr V/r • Boffito et al . 425 Table 4. Summary HIV RNA <50 copies/mL at Week 24 in POWER trials (triple-class–experienced patients) for darunavir/ritonavir 800/100 mg once-daily, 600/100 mg twice-daily doses, and control PI arm Darunavir/ritonavir Darunavir/ritonavir Trial 600/100 mg twice-daily 800/100 mg once-daily Control PI POWER 1 and 2 subgroup Total population n 99 100 100 HIV RNA <50 copies/mL 47% 31% 10% Log reduction in HIV RNA –1.85 –1.43 –0.27 Change in CD4 cell count +75 +55 +15 <2 darunavir mutations n 62 59 56 HIV RNA <50 copies/mL 53% 49% 18% Log reduction in HIV RNA –2.29 –2.00 –0.71 Change in CD4 cell count +118 +90 +25 0 darunavir mutations n 29 23 29 HIV RNA <50 copies/mL 62% 67% 11% Log reduction in HIV RNA –2.35 –2.39 –0.68 Change in CD4 cell count +111 +88 +33 SUMMARY navir/ritonavir in the POWER trials. For highly treatment-experienced patients, other novel drugs There is evidence from clinical pharmacology are typically used twice-daily, such as the integrase trials and Phase II and III efficacy trials to support inhibitor raltegravir, the CCR5 antagonist maravi- use of the 800/100 mg once-daily dose of darunavir roc, the NNRTI etravirine, or the fusion inhibitor 30,31 in naïve patients plus those with no evidence for enfuvirtide. resistance to darunavir, as defined by the daruna - For patients with a lesser degree of treatment ex- vir resistance algorithm. This guideline may be perience, the DRV/r 800/100 mg once-daily dose useful in deciding which dose of darunavir/rito- of darunavir/ritonavir appears to show strong navir to choose for patients with little treatment efficacy. Nevertheless, the data so far available on experience. the effectiveness of this dose in moderately expe- For treatment-naïve patients, the ARTEMIS trial rienced patients have been obtained from limited has established the efficacy of the 800/100 mg numbers of patients. These data, however, will be once-daily dose, with results showing noninferior confirmed soon by a currently recruiting study. The efficacy versus lopinavir/ritonavir after 48 weeks ODIN study (TMC114-C229) is aimed at evaluating of treatment, and superior efficacy for patients with the efficacy of darunavir/ritonavir 800/100 mg baseline HIV RNA levels ≥100,000 copies/mL. once daily in treatment-experienced patients. The For patients with extensive treatment experience ODIN trial is a randomized comparison of the two and baseline resistance to PIs, the POWER 1 and doses of darunavir/ritonavir: 600/100 mg twice 2 trials have clearly identified the darunavir/rito - daily versus 800/100 mg once daily. This trial is navir 600/100 mg twice-daily dose as optimal, currently recruiting 600 antiretroviral-experienced confirming the need of higher plasma concentra - patients with HIV RNA levels >1000 copies/mL at tions over the dosing interval in the presence of screening but no darunavir mutations. remarkable drug resistance. It is important to note, If darunavir/ritonavir is effective at the 800/100 however, the darunavir/ritonavir 600/100 mg mg once-daily dose in naïve patients, similar ef- twice-daily dose has shown efficacy advantages ficacy might be observed for patients who have over investigator-selected control PIs such as lopi- never previously received PIs. It would seem 426 hiV c linical t rials • 9/6 • n oV -Dec 2008 and abstracts of the 15th Conference on Retroviruses and reasonable to use the once-daily dose of daruna- Opportunistic Infections; February 3–6, 2008; Boston, MA. vir/ritonavir for patients switching off a first-line Abstract 37. antiretroviral regimen because of adverse events 9. Smith K, Fine D, Patel P, et al. Efficacy and safety of aba - while fully virologically suppressed. In the ongo- cavir/lamivudine compared to tenofovir/emtricitabine in ing 48-week MONET trial, a total of 256 patients combination with once-daily lopinavir-ritonavir through 48 weeks in the HEAT study. In: Program and abstracts of the with full virologic suppression on prior first-line 15th Conference on Retroviruses and Opportunistic Infec- antiretroviral therapy have been randomized to re- tions; February 3–6, 2008; Boston, MA. Abstract 774. ceive darunavir/ritonavir 800/100 mg once-daily, 10. Gathe J, daSilva B, Loufty M, et al. 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Journal

HIV Clinical TrialsTaylor & Francis

Published: Dec 1, 2008

Keywords: darunavir; once-daily; pharmacokinetics; ritonavir

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