Magda Opsomer

Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of darunavir and ritonavir as single agents in healthy volunteers

This study compared the bioavailability of two candidate fixed‐dose combinations (FDCs: G003 and G004) of darunavir/cobicistat 800/150 mg with that of darunavir 800 mg and ritonavir 100 mg coadministered as single agents. Short‐term safety and tolerability of the FDC formulations were also assessed. This open‐label trial included 36 healthy volunteers and assessed steady‐state pharmacokinetics of darunavir over 3 randomized, 10‐day treatment sequences, under fed conditions. Blood samples for determination of plasma concentrations of darunavir and cobicistat or ritonavir were taken over 24 hours on day 10 and analyzed by liquid‐chromatography tandem mass‐spectroscopy. Darunavir AUC24h following administration of the FDCs (G003: 74,780 ng ∙ h/mL and G004: 76,490 ng ∙ h/mL) was comparable to that following darunavir/ritonavir (78,410 ng ∙ h/mL), as was Cmax (6,666 and 6,917 ng/mL versus 6,973 ng/mL, respectively). Modestly lower C0h (1,504 and 1,478 ng/mL versus 2,015 ng/mL) and Cmin (1,167 and 1,224 ng/mL versus 1,540 ng/mL) values were seen with the FDCs. Short‐term tolerability of the FDCs was comparable to that of darunavir/ritonavir when administered as single agents. The most common adverse events reported were headache, gastrointestinal upset, or rash. Cobicistat is an effective pharmacoenhancer of darunavir when administered as an FDC. Short‐term administration of darunavir/ritonavir or darunavir/cobicistat was generally well tolerated.

Efficacy and safety of darunavir/ritonavir at 48 weeks in treatment-naïve, HIV-1-infected adolescents: results from a phase 2 open-label trial (DIONE).

Background: Twice-daily darunavir/ritonavir is indicated in treatment-experienced children (≥3 years). This study assessed once-daily administration in treatment-naïve adolescents. Methods: Phase 2, 48-week, open-label, single-arm study evaluating pharmacokinetics, safety and efficacy of once-daily darunavir/ritonavir 800/100 mg in treatment-naïve, HIV-1–infected adolescents (≥12 to <18 years, ≥40 kg) with zidovudine/lamivudine or abacavir/lamivudine. Results: Twelve patients (67% female; median 14.4 years) were enrolled. After 24 and 48 weeks, respectively, 11 of 12 (92%) and 10 of 12 (83%) patients achieved viral load <50 copies/mL (intent-to-treat time-to-loss of virologic response); all had ≥1 log10 drop in viral load versus baseline. Median CD4+ cell count increased by 175 and 221 cells/mm3 (intent-to-treat-noncompleter = failure) after 24 and 48 weeks, respectively. Eighty-three percent of patients were adherent to darunavir/ritonavir. One patient was never suppressed and 1 patient rebounded. No patients developed darunavir resistance-associated mutations or lost phenotypic susceptibility to any commercially available protease inhibitor or any background nucleoside reverse transcriptase inhibitor. Eleven patients (92%) reported ≥1 adverse event (AE), considered in 2 patients to be at least possibly related to darunavir (gastrointestinal-related events and dizziness). Four patients had ≥1 serious AE. Three patients reported ≥1 grade 3/4 AE; no serious or grade 3/4 AEs were considered darunavir related. No patients discontinued because of AEs. Conclusions: Over 48 weeks, once-daily darunavir/ritonavir 800/100 mg plus NRTIs was effective and well-tolerated for treatment of HIV-1–infected, antiretroviral-naïve adolescents (≥12 to <18 years). These findings support use of once-daily darunavir/ritonavir 800/100 mg in this population.

Etravirine in treatment‐experienced, HIV‐1‐infected children and adolescents: 48‐week safety, efficacy and resistance analysis of the phase II PIANO study

PIANO (Paediatric study of Intelence As an NNRTI Option; TMC125‐C213; NCT00665847) assessed the safety/tolerability, antiviral activity and pharmacokinetics of etravirine plus an optimized background regimen (OBR) in treatment‐experienced, HIV‐1‐infected children (≥ 6 to < 12 years) and adolescents (≥ 12 to < 18 years) over 48 weeks.

Subgroup analysis of virological response rates with once- and twice-daily darunavir/ritonavir in treatment-experienced patients without darunavir resistance-associated mutations in the ODIN trial.

ODIN (once‐daily darunavir in treatment‐experienced patients) was a 48‐week, phase III, randomized, open‐label trial comparing once‐daily (qd) darunavir/ritonavir (DRV/r) 800/100 mg with twice‐daily (bid) DRV/r 600/100 mg, both with an optimized background regimen [OBR; at least two nucleoside reverse transcriptase inhibitors (NRTIs)], in treatment‐experienced, HIV‐1‐infected adults with no DRV resistance‐associated mutations (RAMs) at screening. Week 48 analyses of virological response by subgroups are reported.

Safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients: week 48 results of the ARIEL trial.

Background: ARIEL (Darunavir in treatment-experienced pediatric population) was a phase II, open-label study assessing safety and antiviral activity of darunavir/ritonavir twice daily with an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected pediatric patients (3 to <6 years, weighing 10 to <20 kg). Methods: The study consisted of an initial 4-week screening period, 48 weeks of treatment and a 4-week follow-up period. Patients initially received darunavir/ritonavir 20/3 mg/kg twice-daily for 2 weeks. Following review of pharmacokinetic, safety and antiviral data, the doses of darunavir/ritonavir were adjusted to 25/3 mg/kg twice-daily for patients <15 kg, and 375/50 mg twice-daily for patients 15 to <20 kg. Results: Of the 34 patients screened, 21 were treated (median treatment duration 48.6 weeks). Darunavir plus an OBR was well tolerated over 48 weeks, with no new safety concerns, and a comparable safety profile to that seen in older children and adults. All treatment-emergent lipid-related and glucose-related laboratory abnormalities were grade 1 or 2. At week 48, 17 of 21 patients (81.0%) had a confirmed virologic response (intent-to-treat, time-to-loss of virologic response). Improvements in height and weight were seen during the study. Conclusions: No new safety concerns were observed over a 48 week period. These results led to lowering the age to 3 years at which darunavir/ritonavir is indicated for use in treatment-experienced pediatric patients. This study also established doses of darunavir to use in treatment-experienced, HIV-1-infected patients aged 3 to <6 years. A high virologic response was observed with this dose. No development of resistance was observed in patients who experienced virologic failure.

Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected treatment-nave adults

COBI, a PK enhancer with no ARV activity is a more selective cytochrome P450 (CYP)3A inhibitor than ritonavir (RTV), does not induce CYP isozymes, and thus has less potential for drug‐drug interactions. COBI boosts DRV PK as effectively as RTV in healthy volunteers.

Darunavir/cobicistat once daily for the treatment of HIV

A current focus in HIV management is improving adherence by minimizing pill burden with convenient formulations, including fixed-dose combinations (FDCs). Darunavir, a HIV protease inhibitor, co-administered with low-dose ritonavir (800/100 mg once daily), is recommended in guidelines in combination with other antiretrovirals for HIV patients with no darunavir resistance-associated mutations. Cobicistat is an alternative agent to ritonavir for boosting plasma drug levels of darunavir among other antiretrovirals. Cobicistat is a more specific cytochrome P450 3A inhibitor than ritonavir without enzyme-inducing properties. This review describes the differing effects of cobicistat and ritonavir on metabolic enzymes, which explains their differing drug–drug interactions, and summarizes some of the studied drug–drug interactions for cobicistat. It also outlines the clinical development and data for a once-daily darunavir/cobicistat FDC. This FDC thus allows for a once-daily treatment regimen (including background antiretrovirals) with reduced pill burden.

Model‐Based Once‐Daily Darunavir/Ritonavir Dosing Recommendations in Pediatric HIV‐1‐Infected Patients Aged ≥3 to <12 Years

An existing population pharmacokinetic model of darunavir in adults was updated using pediatric data from two studies evaluating weight‐based, once‐daily dosing of darunavir/ritonavir (ARIEL, NCT00919854 and DIONE, NCT00915655). The model was then used to provide once‐daily dosing recommendations for darunavir/ritonavir in pediatric patients aged ≥3 to <12 years. The final model comprised two compartments with first‐order absorption and apparent clearance dependent on the concentration of α1‐acid glycoprotein. The recommended darunavir/ritonavir once‐daily dosing regimens in children aged ≥3 to <12 years are: 35/7 mg/kg from 10 to <15 kg, 600/100 mg from 15 to <30 kg, 675/100 mg from 30 to <40 kg, and 800/100 mg for ≥40 kg. These doses should result in exposures similar to the adult exposure after treatment with darunavir/ritonavir 800/100 mg once daily, while minimizing pill burden and allowing a switch from suspension to tablet(s) as early as possible.

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships of Etravirine in HIV‐1‐Infected, Treatment‐Experienced Children and Adolescents in PIANO

PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment‐experienced, HIV‐1‐infected patients (≥6 to <18 years) received etravirine 5.2 mg/kg twice daily (maximum 200 mg twice daily) plus background antiretrovirals. A population pharmacokinetic model was developed, and etravirine C0h and AUC0‐12h were estimated. Relationships among intrinsic/extrinsic factors and etravirine pharmacokinetics and pharmacokinetics with pharmacodynamics were assessed. The best model describing etravirine pharmacokinetics consisted of a single compartment with sequential zero‐ and first‐order absorption following a lag time. Interindividual variability terms were included on clearance (CL/F) and the first‐order input rate constant (KA). The final model estimates (coefficient of variation, %) for CL/F and KA were 46.3 (11) L/h and 1.07 (34) h−1, respectively. Overall, median (range) estimated etravirine C0h and AUC0‐12h were 287 (2‐2276) ng/mL and 4560 (62‐28,865) ng · h/mL, respectively. Exposure was slightly lower in adolescents vs children. Sex and adherence did not affect etravirine pharmacokinetics. Factors significantly affecting etravirine exposure were body weight (higher with lower weight), race (lower in Asians than in white or black patients), and the use of certain HIV protease inhibitors. Virologic response (<50 copies/mL at week 48) was lower in the lowest etravirine AUC0‐12h quartile vs the upper 3 quartiles (41% vs 67% to 76%). Rash occurred more frequently in the highest quartile than in the lower 3 quartiles (52% versus 8% to 20%). Etravirine 5.2 mg/kg twice daily in treatment‐experienced, HIV‐1‐infected children and adolescents provides comparable exposure to that in adults receiving etravirine 200 mg twice daily and is the recommended dose for children and adolescents.

Week 48 results of a Phase IV trial of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected treatment-experienced adults.

In DUET, etravirine (ETR) 200 mg bid had durable efficacy and a favourable safety profile versus placebo, both arms with an optimised background regimen (BR) including darunavir/ritonavir (DRV/r). TMC125IFD3002 (VIOLIN; NCT01422330) investigated ETR plus ARVs other than DRV/r.