(Last updated: March 1, 2016; last reviewed: March 1, 2016)
|Darunavir (DRV, Prezista)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
Oral suspension: 100 mg/mL
Tablets: 75 mg, 150 mg, 400 mg, 600 mg, and 800 mg
Fixed-Dose Combination Tablets:
|Dosing Recommendations||Selected Adverse Events|
Note: Darunavir should not be used without a pharmacokinetic (PK) enhancer (boosting agent): ritonavir (children and adults) or cobicistat (adults only).
Aged <3 Years:
Boosting darunavir with cobicistat is currently not recommended in children aged <18 years; however, the PK, efficacy, and safety of darunavir/cobicistat is currently under investigation in children aged 12 to 18 years.
Adolescent (Aged 12 ≥Years and Weighing ≥30 kg) and Adult Dose (Treatment-Naive or Treatment-Experienced with No Darunavir Resistance-Associated Mutations)
30 to <40 kg:
Adolescent (Aged ≥12 Years and Weighing ≥30 to <40 kg; Treatment-Experienced with at Least One Darunavir Resistance-Associated Mutation):
Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)
The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://iasusa.org/sites/default/files/tam/october_november_2015.pdf#page=10) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/DR/).
Darunavir co-administered with ritonavir is approved by the Food and Drug Administration (FDA) as a component of antiretroviral therapy (ART) in treatment-naive and treatment-experienced children aged 3 years and older.
Data from the randomized, open-label, multicenter pediatric trial, which evaluated darunavir with ritonavir twice daily among 80 treatment-experienced children aged 6 to <18 years, demonstrated that 66% of patients had week 24 plasma HIV RNA <400 copies/mL and 51% had HIV RNA <50 copies/mL.3 In another international, multisite clinical trial (TMC114-TiDP29-C228) involving treatment-experienced children aged 3 to <6 years, 81% of children (out of 21) had viral load <50 copies/mL at week 48.4
Pharmacokinetics in Younger Children
Administration of twice-daily darunavir/ritonavir oral suspension in children aged 3 to <6 years and weighing 10 to <20 kg was conducted in 27 children (see above) who experienced failure of their previous ART regimen and had fewer than three darunavir resistance mutations on genotypic testing.3,4 The darunavir area under the curve [AUC(0–12h)], measured as a percent of the adult AUC value, was 128% overall: 140% in subjects weighing 10 to <15 kg and 122% in subjects weighing 15 to <20 kg.3,4
Pharmacokinetics in Older Children
Using darunavir tablets and ritonavir liquid or tablets, initial pediatric pharmacokinetic (PK) evaluation was based upon a Phase II randomized, open-label, multicenter study that enrolled 80 treatment-experienced children and adolescents aged 6 to <18 years and weighing ≥20 kg.5 In Part I of the trial, a weight-adjusted dose of darunavir 9 to 15 mg/kg and ritonavir 1.5 to 2.5 mg/kg twice daily, equivalent to the standard adult dose of darunavir/ritonavir 600/100 mg twice daily, resulted in inadequate drug exposure in the pediatric population studied with 24-hour AUC (AUC24h) of 81% and pre-dose concentration (C0h) of 91% of the corresponding adult PK parameters. A pediatric dose 20% to 33% higher than the directly scaled adult dose was needed to achieve drug exposure similar to that found in adults and was the dose selected for Part II of the study. The higher dose used for the safety and efficacy evaluation was darunavir 11 to 19 mg/kg and ritonavir 1.5 to 2.5 mg/kg twice daily. This resulted in darunavir AUC24h of 123.276 mcg*h/mL (range 71.850–201.520) and C0h of 3693 ng/mL (range 1842–7191), 102% and 114% of the respective PK values in adults. Doses were given twice daily and were stratified by body weight bands of 20 to <30 kg and 30 to <40 kg. Based on the findings in the safety and efficacy portion of the study, current weight-band doses of twice-daily darunavir/ritonavir for treatment-experienced pediatric patients with weight >20 to <40 kg were selected (see Table A).
|Population||N||Dose of DRV/RTV||AUC12h (mcg*h/mL)
|10 to <15 kga||13
|10 to <15 kga||4
|15 to <20 kga||11||20/3 mg/kg||54.2||3,387|
|15 to <20 kga
|Aged 6 to <12 yearsb
|Aged 12 to <18 yearsb||50
|Adults aged >18 years, (3 studies)c||285/278/119
|a Source: Food and Drug Administration. FDA pharmacokinetics review 2011. Available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM287674.pdf.|
|b Weight band dosing was with darunavir/ritonavir at doses of 375/50 mg twice daily for body weight 20 to <30 kg, 450/60 mg twice daily for 30 to <40 kg, and 600/100 mg twice daily for ≥40 kg. Data from FDA pharmacokinetics review 2008, available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm129567.pdf.|
|c Source: Darunavir [package insert]. Food and Drug Administration.
2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021976s030,202895s007lbl.pdf.
Accessed February 3, 2015.
|Key to Acronyms: AUC = area under the curve; C0h = pre-dose concentration; DRV = darunavir; RTV = ritonavir|
Darunavir should not be used without a PK enhancer (boosting agent): ritonavir (children and adults) or cobicistat (adults only).
A study in 19 Thai children used ritonavir 100-mg capsule twice daily as the boosting dose with twice-daily darunavir doses of 375 mg (body weight 20 to <30 kg), 450 mg (body weight 30–40 kg), and 600 mg twice daily (body weight ≥40 kg).6 The darunavir exposures with 100-mg ritonavir twice daily were similar to those obtained in the studies with lower (<100 mg) liquid preparation-based ritonavir doses.5,6 The tolerability and PK data from this small study support the higher doses of ritonavir boosting with 100-mg capsule or tablet in children with body weight ≥20 kg, particularly when lower-dose formulations are unavailable or if a child does not tolerate the liquid ritonavir formulation. Data are not available to evaluate the safety and tolerability of using ritonavir 100-mg tablet/capsule formulations in children who weigh less than 20 kg.
The data on the dosing of cobicistat with darunavir are available in adult patients only.7 Data on a fixed-dose combination of 800/150 mg darunavir/cobicistat once daily showed comparable bioavailability to that obtained with 800/100 mg of darunavir/ritonavir once daily.8
Frequency of Administration
In February 2013, the FDA approved the use of once-daily darunavir for treatment-naive children and for treatment-experienced children without darunavir resistance-associated mutations (see Table B). To derive once-daily pediatric dosing recommendations for younger pediatric subjects aged 3 to <12 years weighing 10 to <40 kg, population PK modeling and simulation was used.9 A dedicated pediatric trial evaluating once-daily darunavir with ritonavir dosing in children aged 6 to <12 years was not conducted. No efficacy data have been obtained regarding use of once-daily darunavir with ritonavir in treatment-naive or treatment-experienced children aged <12 years. Therefore, the Panel recommends dosing darunavir with ritonavir twice daily in children aged >3 years to <12 years (see Once-Daily Dosing section). The Panel recommends that once-daily darunavir with ritonavir be used only in treatment-naive and treatment-experienced adolescents aged ≥12 years who do not have darunavir resistance-associated mutations. If darunavir and ritonavir are used once daily in children aged <12 years, the Panel recommends conducting PK (measurement of plasma concentrations) evaluation (see Therapeutic Drug Monitoring) and close monitoring of viral load.
FDA approval was based on results from two small pediatric trials: TMC114-C230 evaluating once-daily dosing in treatment-naive adolescents aged 12 to 18 years and weighing ≥40 kg (see below) and the TMC114-C228 sub-trial evaluating once-daily dosing in treatment-experienced children aged 3 to <6 years (see below).9-11
(Once daily with food)
|10 to <11 kga||DRV 350 mg (3.6 mLb) plus RTV 64 mg (0.8 mLc)|
|11 to <12 kga||DRV 385 mg (4 mLb) plus RTV 64 mg (0.8 mLc)|
|12 to <13 kga||DRV 420 mg (4.2 mL) plus RTV 80 mg (1 mLc)|
|13 to <14 kga||DRV 455 mg (4.6 mLb) plus RTV 80 mg (1 mLc)|
|14 to <15 kg||DRV 490 mg (5 mLb) plus RTV 80 mg (1 mLc)
|15 to <30 kg||DRV 600 mg (tablet or combination of tablets or 6 mL) plus RTV 100 mg (tablet or 1.25 mLc)|
|30 to <40 kg||DRV 675 mg (combination of tablets or 6.8 mLb,d) plus RTV 100 mg (tablet or 1.25 mLc)|
||DRV 800 mg (tablet or combination of tablets or 8 mLd) plus RTV 100 mg (tablet or 1.25 mLc)|
|a The dose in children weighing 10 to 15 kg is 35 mg/kg DRV and 7 mg/kg RTV per kg body weight per dose, which is higher than the weight-adjusted dose in children with higher weight.|
|b RTV 80 mg/mL oral solution.|
|c The 350-mg, 385-mg, 455-mg, 490-mg, and 675-mg DRV doses are rounded for suspension-dose convenience.|
|d The 6.8-mL and 8-mL DRV doses can be taken as two administrations (3.4 mL and 4 mL, respectively) with the included oral dosing syringe, or as onesyringe when provided by pharmacy or medical office.|
|Key to Acronyms: DRV = darunavir; RTV = ritonavir|
Once-Daily Administration in Children Aged <12 Years
As part of the TMC114-C228 trial that evaluated twice-daily dosing in treatment-experienced children aged 3 to <12 years, once-daily dosing of darunavir for 2 weeks with PK evaluation was conducted as a sub-study, after which the participants switched back to the twice-daily regimen.9,12 The darunavir/ritonavir dosage for once-daily use in the trial, based on PK simulation (which did not include a relative bioavailability factor), was 40 mg/kg of darunavir co-administered with approximately 7 mg/kg of ritonavir once daily for children weighing <15 kg, and darunavir/ritonavir 600 mg/100 mg once daily for children weighing ≥15 kg.9,12 The PK data obtained from 10 children aged 3 to 6 years in this sub-study (Table C) were included as part of the population PK modeling and simulation, which proposed the FDA-approved dose for once-daily darunavir with ritonavir in children aged 3 to <12 years.
||Once-Daily Darunavir Sub-Study (n = 10)
(n = 335)
|DRV AUC24h geometric mean, ng*h/mL (SD)||115 (40.6)||89.7 (27.0)|
|DRV C0h geometric mean, ng/mL (SD)
||3,029 (1,715)||2,027 (1,168)|
|Key to Acronyms: AUC = area under the curve; C0h = pre-dose concentration; DRV = darunavir; SD = standard deviation|
Once-Daily Administration in Adolescents Age ≥12 Years
A sub-study of once-daily dosing of darunavir 800 mg with ritonavir 100 mg in 12 treatment-naive adolescents (aged 12–17 years and ≥40 kg body weight) demonstrated darunavir exposures similar to those seen in adults treated with once-daily darunavir (see Table D).10 In this study, the proportion of patients with viral load <50 copies/mL and <400 copies/mL at 48 weeks was 83.3% and 91.7%, respectively.11 Interestingly, no relationship was observed between darunavir AUC24h and C0h and virologic outcome (HIV RNA <50 copies/mL) in this study. Darunavir exposures were found to be similar to those in adults with once-daily dosing in another study in which a single dose of darunavir 800 mg with ritonavir 100-mg tablets was administered to 24 subjects with median age 19.5 years (14–23 years).13 However, darunavir exposures were slightly below the lower target concentrations in adolescent patients aged 14 to 17 years (n = 7) within the cohort, suggesting the potential need for higher doses in younger adolescents. A single case report suggests the potential therapeutic benefit of virologic suppression using an increased darunavir dose with standard ritonavir booster following TDM in a highly treatment-experienced adolescent patient.14
|Population||N||Dose of DRV/RTV||AUC24ha (mcg*h/mL)
|C0h (ng/mL) median|
|Aged 12–17 years (mean 14.6)10||12||800/100 mg||86.7||2,141|
|Aged 14–23 years (mean 19.5)13||24||800/100 mg||69.5||1,300|
|Adults aged >18 years (2 studies)a||335/280||800/100 mg||87.8–87.9||1,896–2,041|
a Source: Darunavir [package insert]. Food and Drug Administration. 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021976s030,202895s007lbl.pdf. Accessed February 3, 2015.
Key to Acronyms: AUC24h = 24-hour area under the curve; C0h = pre-dose concentration; DRV = darunavir; RTV = ritonavir
The efficacy of once-daily darunavir has been established within a limited number of studies in small cohorts of adolescents that reported long-term data on virologic and immunologic outcomes.11,15
Darunavir oral suspension is better tasting than the ritonavir oral solution needed for PK boosting, which is seen as a greater challenge to palatability. In a Phase II initial approval study, 27 of the 80 participants switched from the ritonavir liquid solution to ritonavir 100-mg capsules, which are much easier to tolerate for children who can swallow pills.5 Switching to the higher dose of ritonavir for the palatability of the boosting drug can be considered if the liquid formulation represents a barrier. No data are available on the use of cobicistat in pediatric patients.