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Table of Contents

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Protease Inhibitors (PIs)

Darunavir

(Last updated:February 12, 2014; last reviewed:February 12, 2014)

Darunavir (DRV, Prezista)
Darunavir (DRV, Prezista)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations
Tablets: 75 mg, 150 mg, 400 mg, 600 mg, 800 mg
Oral suspension: 100 mg/mL
Dosing Recommendations
Note: DRV should not be used without low-dose boosting ritonavir (RTV).

Neonate/Infant Dose:
  • Not approved for use in neonates/infants.
Pediatric Dose
Aged <3 years
  • Do not use DRV in children aged <3 years or weighing ≤10 kg because of concerns related to seizures and death in infant rats due to immaturity of the blood-brain barrier and liver metabolic pathways.
  • The dosing for antiretroviral treatment-naive and treatment-experienced pediatric patients aged ≥3 years (includes patients with or without one or more DRV resistance-associated mutations)
Aged 3 to <18 Years and Weight >10 kg
Weight (kg) Dose
(twice daily with food)
10 to <11 kga DRV 200 mg (2.0 mL) plus RTV 32 mg (0.4 mL)
11 to <12 kga DRV 220 mg (2.2 mL) plus RTV 32 mg (0.4 mLb)
12 to <13 kga DRV 240 mg (2.4 mL) plus RTV 40 mg (0.5 mLb)
13 to <14 kga DRV 260 mg (2.6 mL) plus RTV 40 mg (0.5 mLb)
14 to <15 kg DRV 280 mg (2.8 mL) plus RTV 48 mg (0.6 mLb)
15 to <30 kg DRV 375 mg (combination of tablets or 3.8 mLc) plus RTV 48 mg (0.6 mLb)
30 to <40 kg DRV 450 mg (combination of tablets or 4.6 mLc) plus RTV 100 mg (tablet or 1.25 mLb)
≥40 kg DRV 600 mg (tablet or 6 mL) plus RTV 100 mg (tablet or 1.25 mL) 
a Note that the dose in children weighing 10–15 kg is 20 mg/kg DRV and 3 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 g/mL oral solution.

c The 375 mg and 450- mg DRV doses are rounded for suspension-dose convenience

Adolescent (Aged ≥12 Years)/Adult Dose (Treatment-Naive or Antiretroviral Therapy-Experienced with no DRV Resistance-Associated Mutations)
30 to <40 kg
  • DRV 675 mg (combination of tablets or 6.8 mLa) plus RTV 100 mg (tablet or 1.25 mLb) once daily
≥40 kg:
  • DRV 800 mg (tablet or combination of tablets or 8 mL) plus RTV 100 mg (tablet or 1.25 mLb) once daily
a The 675 mg DRV dose is rounded for convenience. 
b RTV 80 mg/mL oral solution.


Adolescent (Aged ≥18 Years)/Adult Dose (Treatment Experienced with at Least One DRV Resistance-Associated Mutation):
  • DRV 600 mg plus RTV 100 mg, both twice daily with food.
Selected Adverse Events
  • Skin rash, including Stevens-Johnson syndrome and erythema multiforme
  • Hepatotoxicity
  • Diarrhea, nausea
  • Headaches
  • Possible increased bleeding in patients with hemophilia
  • Hyperlipidemia, transaminase elevation, hyperglycemia
  • Fat maldistribution
Special Instructions
  • In patients with one or more DRV-associated mutation(s), DRV should be used only twice daily. DRV resistance-associated mutations are: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V.
  • DRV must be administered with food, which increases area under the curve (AUC) and maximum plasma concentration (Cmax) by 30%. Drug exposure is not significantly altered by the calorie and fat content of the meal.
  • DRV contains a sulfonamide moiety. The potential for cross sensitivity between DRV and other drugs in the sulfonamide class is unknown. Use DRV with caution in patients with known sulfonamide allergy.
  • Pediatric dosing requires co-administration of tablets with different strengths to achieve the recommended doses depending on weight band. Careful instructions to caregivers when recommending a combination of different-strength tablets is very important. Store DRV tablets and oral suspension at room temperature (25ºC or 77ºF). Oral suspension should be stored in the original container and shaken well before dosing.
Metabolism
  • Cytochrome (CYP) P450 3A4 inhibitor and substrate. 
Dosing in Patients with Hepatic Impairment: 
  • DRV is primarily metabolized by the liver. There are no data for dosing adult patients with varying degrees of hepatic impairment; caution should be used when administering DRV to such patients. DRV is not recommended in patients with severe hepatic impairment.
Dosing in Patients with Renal Impairment: 
  • No dose adjustment is required in patients with moderate renal impairment (creatinine clearance [CrCl] 30–60 mL/min). There are no pharmacokinetic data in patients with severe renal impairment or end-stage renal disease.



Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents)

  • Darunavir is primarily metabolized by cytochrome P (CYP) 3A4. Ritonavir inhibits CYP3A4, thereby increasing the plasma concentration of darunavir. Potential exists for multiple drug interactions. Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on the CYP3A clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. 
  • When darunavir plus ritonavir twice daily was used in combination with etravirine in 40 HIV-infected patients aged 11 to 20 years, both darunavir and etravirine exposure were lower than that found in adults.1 When darunavir plus ritonavir twice daily was used in combination with tenofovir in 13 HIV-infected patients aged 13 to 16 years, both tenofovir and darunavir exposures were lower than those found in adults treated with the same combination.2 No dose adjustment is currently recommended for the combination of darunavir/ritonavir with either of these drugs, but caution is advised and therapeutic drug monitoring may be potentially useful. 
  • Before administration, a patient’s medication profile should be carefully reviewed for potential drug interactions.

Major Toxicities

  • More common: Diarrhea, nausea, vomiting, abdominal pain, headache, and fatigue.
  • Less common: Skin rash, including erythema multiforme and Stevens-Johnson syndrome. Fever and elevated hepatic transaminases. Lipid abnormalities.
  • Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing diabetes mellitus, and spontaneous bleeding in hemophiliacs. Hepatic dysfunction, particularly in patients with underlying risk factors (such as hepatitis B or hepatitis C virus coinfection, or those with baseline elevation in transaminases).

Resistance 

The International AIDS Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/resistance_mutations/index.html) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/pages/GRIP/DRV.html).

Pediatric Use

Approval
Darunavir co-administered with ritonavir is approved by the Food and Drug Administration (FDA) as a component of combination antiretroviral therapy in treatment-naive and treatment-experienced children aged 3 years and older. 

Efficacy
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 clinical trial (TMC114-C228) involving 27 children (3 to <6 years of age) from Argentina, Brazil, India, Kenya, and South Africa, 59% of children (out of 27) and 71% (out of 20) had viral load <50 copies/mL at week 24 and at week 48, respectively.3-6

Pharmacokinetics

Pharmacokinetics in Younger Children
Administration of twice-daily ritonavir-boosted darunavir 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 antiretroviral therapy regimen and had fewer than 3 darunavir resistance mutations on genotypic testing.3-5 The darunavir 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.3-5 

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, multi-center study that enrolled 80 treatment-experienced children and adolescents aged 6 to <18 years and weighing ≥20 kg.7 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 area under the curve (AUC)24h 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 123276 ng*h/mL (range 71850–201520) 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 ritonavir-boosted darunavir for treatment-experienced pediatric patients with weight >20 to <40 kg were selected (see Table A).

Table A. Darunavir Pharmacokinetics with Twice-Daily Administration with Ritonavir and Optimized Backbone (Children Aged 3-18 Years and Adults Aged >18 Years).
Population N Dose of DRV/RTV AUC12h (mcg*h/mL)
Mediana
C0h (ng/mL) Mediana
10 to <15 kga 13 20/3 mg/kg  66.0 3,533
10 to <15 kga 4 25/3 mg/kg  116.0 8,522
15 to <20 kga 11 20/3 mg/kg  54.2 3,387
15 to <20 kga 14 25/3 mg/kg 68.6 4,365
Aged 6 to <12 yearsb 24 Weight bandsb 56.4 3,354
Aged 12 to <18 yearsb 50 Weight bandsb 66.4 4,059
Adults aged >18 years, (3 studies)c
285/278/119
600/100 mg 54.7–61.7 3,197–3,539
a FDA pharmacokinetics review 2011 (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 (http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm129567.pdf
c Product label

Dosing

Dosing of Ritonavir with Darunavir
A separate 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).8 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.7,8 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.

Frequency of Administration
In February 2013, FDA approved the use of darunavir once daily 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.6 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 only twice daily in children aged >3 years and <12 years. The Panel recommends that once-daily darunavir with ritonavir be used only in treatment-naive and treatment-experienced adolescents aged ≥12 years and without 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 and inhibitory quotient) evaluation (see Therapeutic Drug Monitoring) and close monitoring of viral load. 

FDA approval was based on the 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).6,9,10 

 

Table B.
FDA-Approved Dosing for Pediatric Patients Aged ≥3 Years and Weight >10 Kg Who Are Antiretroviral Treatment-Naive or Treatment-
Experienced With No DRV Resistance-Associated Mutations
Weight
(kg)
Dose 
(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)
≥40 kg
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 10–15 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 (3.4 mL and 4 mL, respectively) administrations with the included oral dosing syringe, or as one syringe when provided by pharmacy or medical office.

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.6,11 The ritonavir-boosted darunavir 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 ritonavir-boosted darunavir 600 mg/100 mg once daily for children weighing ≥15 kg.6,11 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. 

Table C.
Pharmacokinetics of Once-Daily Darunavir in Children Aged 3–6 Years After 2 Weeks of Therapy with Ritonavir and Optimized Backbone.11
Pharmacokinetic Parameter
Once-Daily Darunavir Sub-Study (n=10)
3-6 years
Adult Study (n=335)
DRV AUC24h geometric mean, ng*h/mL (SD*)
115 (40.6)
89.7 (27.0)
DRV C0h geometric mean, ng/mL (SD*)
3029 (1715)
2027 (1168)
*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).9 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.9,10 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 darunavir 800 mg with ritonavir 100 mg tablets was administered to 24 subjects with median age 19.5 years (14–23 years).12 However, darunavir exposures were slightly below the lower target concentrations in adolescent patients age 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 therapeutic drug monitoring in a highly treatment-experienced adolescent patient.13 

Table D.
Darunavir Pharmacokinetics with Once-Daily Administration (Adolescents Aged ≥12 Years and Adults Aged >18 Years)
Population N  Dose of DRV/RTV
AUC24ha (mcg*h/mL)
median
C0h (ng/mL) median
Aged 12–17 years (mean 14.6)9
12 800/100 mg 86.7 2,141
Aged 14–23 years (mean 19.5)12
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 Product label
       

The efficacy of once-daily darunavir has been established only within a small cohort of adolescent patients with 48 weeks data on virologic and immunologic outcomes.9,10 

Formulations:

Palatability 
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.7 Switching to the higher dose of ritonavir for the palatability of the boosting drug can be considered if the liquid formulation represents a barrier. 

References 

  1. King JR, Yogev R, et al. Low darunavir (DRV) and Etravirine (ETR) exposure when used in combination in HIV-infected chidren and adolescents. Abstract #986. Paper Presented at: 19th Conference on Retroviruses and Opportunistic Infections (CROI); 2012; Seattle, WA.
  2. King JR, Yogev R, Jean-Philippe P, et al. Steady-state pharmacokinetics of tenofovir-based regimens in HIV-infected pediatric patients. Antimicrob Agents Chemother. Sep 2011;55(9):4290-4294. Available at http://www.ncbi.nlm.nih.gov/pubmed/21670182.
  3. FDA. Clinical Review of Darunavir. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM287673.pdf)%20and%20an%20FDA%20Clinical%20Pharmacology%20review. 2011. Available at 
  4. Violari A, Bologna R, et al. ARIEL: 24-Week Safety and Efficacy of DRV/r in Treatment-experienced 3- to <6-Year-old Patients Abstract #713. Paper Presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI). Boston. 2011. 
  5. FDA. Clinical Review of Darunavir. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM287674.pdf. 2011. 
  6. FDA. PREZISTA Drug Label. Clinical Review of Darunavir. 2012. Available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM346671.pdf.
  7. Blanche S, Bologna R, Cahn P, et al. Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents. AIDS. Sep 24 2009;23(15):2005-2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/19724191.
  8. Chokephaibulkit K, Prasitsuebsai W, Wittawatmongkol O, et al. Pharmacokinetics of darunavir/ritonavir in Asian HIV-1-infected children aged >/=7 years. Antivir Ther. 2012;17(7):1263-1269. Available at http://www.ncbi.nlm.nih.gov/pubmed/22954687.
  9. Flynn P, Blanche S, Giaquinto C, et al. 24-week efficacy, safety, tolerability and pharmacokinetics of darunavir/ritonavir once daily in treatment-naïve adolescents aged 12 to < 18 years in DIONE. Abstract # PP_2. Paper presented at: 3rd International Workshop on HIV Pediatrics, July 15–16, 2011. 
  10. Giaquinto C, Flynn P, et al Darunavir/r once daily in treatment-naive adolescents: 48 week results of the DIONE study. Paper presented at: XIX International AIDS Conference; 2012; Washington, DC.
  11. Kakuda TN, Brochot A, van de Casteele T, Opsomer M, Tomaka F. Establishing darunavir dosing recommendations in treatment-naive and treatment-experienced pediatric patients. Paper presented at: 14th Clinical Pharmacology Workshop on HIV; April 22–24 2013; Amsterdam.
  12. King J, Hazra R, et al. Pharmacokinetics of darunavir 800 mg with ritonavir 100mg once daily in HIV+ adolescents and young adults. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 2013; Atlanta, GA.
  13. Rakhmanina NY, Neely MN, Capparelli EV. High dose of darunavir in treatment-experienced HIV-infected adolescent results in virologic suppression and improved CD4 cell count. Ther Drug Monit. Jun 2012;34(3):237-241. Available at http://www.ncbi.nlm.nih.gov/pubmed/22549499.

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