Safety and Efficacy of Darunavir/Ritonavir in Treatment-experienced Pediatric Patients

Violari, Avy; Bologna, Rosa; Kumarasamy, Nagalingeswaran; Pilotto, José Henrique; Hendrickx, Annemie; Kakuda, Thomas N.; Lathouwers, Erkki; Opsomer, Magda; Casteele, Tom Van de; Tomaka, Frank

doi:10.1097/inf.0000000000000644

Cited by 17 publications

(21 citation statements)

References 21 publications

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“…Steady‐state darunavir concentrations with the suspension were comparable with previous data with tablets . These results, together with those from pediatric clinical trials, confirm the suitability of this suspension for pediatric use.…”

Section: Discussionsupporting

confidence: 83%

“…The safety profile was as expected from previous short‐term studies with twice‐daily darunavir/ritonavir (600/100 mg) as tablets . The long‐term safety of darunavir/ritonavir has been confirmed in treatment‐naïve and ‐experienced adults, and in children …”

Section: Discussionsupporting

confidence: 78%

“…Drug pharmacokinetics can vary between children and adults due to physiological differences. 22 However, darunavir pharmacokinetics (tablets or suspension as appropriate) were investigated in the pediatric phase 2 clinical trials, DELPHI (NCT00355524), 23 ARIEL (NCT00919854), 24 and DIONE (NCT00915655), 25 confirming that target adult darunavir exposures were achieved across the age and weight categories using weight-based dosing. For example, in ARIEL, twice-daily darunavir (as a suspension) with ritonavir (20/3 mg/kg) administered to children (3 to <6 years, 10 to <20 kg) resulted in darunavir AUC 0-12h equivalent to 102% of the AUC 12h in adults.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of darunavir after administration of an oral suspension with low‐dose ritonavir and with or without food

Kakuda

Sekar

Lavreys

et al. 2014

Clinical Pharm in Drug Dev

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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 × 300-mg tablets (fed, reference), or 6 mL 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 Cmax 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.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of darunavir after administration of an oral suspension with low‐dose ritonavir and with or without food

Kakuda

Sekar

Lavreys

et al. 2014

Clinical Pharm in Drug Dev

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“…[6][7][8][9][10][11][12][13][14] In addition, DRV/r is not recommended in children <3 years of age owing to toxicity concerns in animal studies, and ETR, a second-generation NNRTI, is not recommended in children <6 years of age owing to lack of safety and efficacy data. Until very recently, DTG was only recommended by the US Food and Drug Administration (FDA) for adolescents >12 years of age and >40 kg body weight.…”

Section: Researchmentioning

confidence: 99%

“…[6] Other than phase 2 trials under controlled conditions, two other retrospective studies involving treatment-experienced adolescents in Spain receiving RALor ETR-based regimens in combination with other ARVs have found comparable safety and efficacy outcomes. [7,8,[10][11][12] Although GRT is a prerequisite for accessing these medications in the SA public sector, specific indications for resistance testing are not included in the 2014 national guidelines, and access to GRT has not been uniform in the SA public sector. Before 2015, GRT was generally only available to patients with private medical insurance or through research studies or donor-funded access programmes in the public sector.…”

Section: Researchmentioning

confidence: 99%

Characteristics and early outcomes of children and adolescents treated with darunavir/ritonavir-, raltegravir- or etravirine-containing antiretroviral therapy in the Western Cape Province of South Africa

Nuttall

Pillay

2018

S Afr Med J

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RESEARCHBy 2012, the estimated number of children (0 -14 years of age) receiving antiretroviral therapy (ART) in South Africa (SA) was 140 541, representing an estimated 63% of those requiring treatment. [1,2] As increasing numbers of children are started on first-and second-line ART, the demand for third-line regimens in children and adolescents with treatment failure is likely to increase. It is estimated that currently <1% of people on ART globally are receiving third-line regimens, and it is unknown what proportion of these are children. [3] An unpublished systematic review presented in 2015 assessing second-and third-line ART options for children and adolescents concluded that there is insufficient evidence to directly evaluate alternative second-and third-line ART options for children, and that current recommendations are still based on inference from adult trials.[4] The World Health Organization (WHO) recommends that national programmes should develop policies for third-line ART that should incorporate integrase strand transfer inhibitors (INSTIs), second-generation protease inhibitors (PIs) and secondgeneration non-nucleoside reverse transcriptase inhibitors (NNRTIs) with minimal risk of cross-resistance to previously used regimens. Recommended third-line ART regimens in the WHO 2016 guidelines [5] are: (i) darunavir/ritonavir (DRV/r) plus dolutegravir (DTG) (or raltegravir (RAL)) with or without one to two nucleoside reverse transcriptase inhibitors (NRTIs); (ii) DRV/r plus two NRTIs with or without one NNRTI; or (iii) RAL (or DTG) plus two NRTIs, depending on the preceding first-and second-line ART regimens.Although safety and efficacy of DRV/r, etravirine (ETR) and RAL have been reported in specific age groups of ART-naive and ARTexperienced children and adolescents, there is a paucity of data on treatment-experienced children from resource-constrained settings receiving these drugs as part of routine care. [6][7][8][9][10][11][12][13][14] In addition, DRV/r is not recommended in children <3 years of age owing to toxicity concerns in animal studies, and ETR, a second-generation NNRTI, is not recommended in children <6 years of age owing to lack of safety and efficacy data. Until very recently, DTG was only recommended by the US Food and Drug Administration (FDA) for adolescents >12 years of age and >40 kg body weight.[15] The FDA has recently approved DTG from 6 to <12 years and ≥30 kg in a dose of 35 mg once daily, but suitable formulations that allow for administration of this dose are not yet registered in SA.[16] In SA, DTG has only been approved from 18 years of age. ObjectiveTo describe the characteristics and early outcomes of treatmentexperienced children and adolescents (<20 years of age) in the Western Cape Province of SA who initiated an ART regimen that included one or more of DRV/r, RAL and ETR. Background. There is an increasing need for third-line treatment regimens in HIV-infected children with antiretroviral treatment (ART) failure. Data are limited on darunavir/ritonavir (DRV/r)-, r...

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

Brochot

Kakuda

Casteele

et al. 2015

CPT Pharmacometrics Syst. Pharmacol.

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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.

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Safety and Efficacy of Darunavir/Ritonavir in Treatment-experienced Pediatric Patients

Cited by 17 publications

References 21 publications

Pharmacokinetics of darunavir after administration of an oral suspension with low‐dose ritonavir and with or without food

Pharmacokinetics of darunavir after administration of an oral suspension with low‐dose ritonavir and with or without food

Characteristics and early outcomes of children and adolescents treated with darunavir/ritonavir-, raltegravir- or etravirine-containing antiretroviral therapy in the Western Cape Province of South Africa

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

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