Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Protease Inhibitors (PIs)

Darunavir

Drug Interactions

Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Darunavir (DRV) is primarily metabolized by cytochrome P450 (CYP) 3A4. Both ritonavir (RTV) and cobicistat (COBI) are inhibitors of CYP3A4, thereby increasing the plasma concentration of DRV. Coadministration of DRV plus RTV (DRV/r) or DRV plus COBI (DRV/c) with drugs that are highly dependent on CYP3A clearance creates potential for multiple drug–drug interactions and may be associated with suboptimal efficacy or serious and/or life-threatening events.
• Coadministration of several drugs, including other protease inhibitors and rifampin, is contraindicated with DRV/r and DRV/c. A study involving adults with HIV suggested that etravirine (ETR) may reduce serum DRV concentrations by induction of CYP3A5, which is more commonly expressed in individuals of African descent.¹ Before administering DRV with a pharmacokinetic (PK) enhancer (boosting agent), a patient’s medication profile should be carefully reviewed for potential drug interactions.
• When twice-daily DRV/r was used in combination with tenofovir disoproxil fumarate (TDF) in 13 patients with HIV aged 13 to 16 years, both TDF and DRV exposures were lower than those found in adults treated with the same combination.² No dose adjustment is recommended when using DRV/r with TDF, but caution is advised and therapeutic drug monitoring (TDM) may be useful.³ Data from the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) protocol P1058A indicate that coadministering once-daily DRV/r with once-daily or twice-daily ETR in children, adolescents, and young adults aged 9 years to <24 years did not have a significant effect on DRV plasma concentrations.⁴ When DRV/r was coadministered with ETR twice daily in pediatric patients, target concentrations for both DRV and ETR were achieved.⁵ DRV PKs were not affected when DRV was coadministered with rilpivirine (RPV) in a study of adolescents and young adults.⁶ DRV/r coadministration increased RPV exposure twofold to threefold; close monitoring for RPV-related adverse events is advisable.

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 levels of hepatic transaminases; lipid abnormalities; and crystalluria.
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting 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.

Resistance

The International Antiviral Society–USA maintains a list of updated HIV drug resistance mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use

Approval

DRV/r is approved by the U.S. Food and Drug Administration (FDA) as a component of antiretroviral (ARV) therapy in treatment-naive and treatment-experienced children aged ≥3 years. Because RTV oral solution is no longer commercially available, use of  DRV/r is limited to children weighing ≥20 kg who can use the RTV 100 mg powder packet or 100 mg tablet.

DRV is approved by the FDA to be administered with COBI (Tybost) boosting in pediatric patients weighing ≥40 kg. The fixed-dose combinations (FDCs) DRV/c (Prezcobix) and Symtuza (DRV/c/emtricitabine/tenofovir alafenamide) are also approved by the FDA for use in pediatric patients weighing ≥40 kg.

Efficacy in Clinical Trials

In an international, multisite clinical trial (TMC114-TiDP29-C228) that enrolled treatment-experienced children aged 3 years to <6 years, 17 (81%) of 21 children who received DRV/r twice daily had viral loads <50 copies/mL at Week 48.^7-9

A randomized, open-label, multicenter pediatric trial⁹ that evaluated twice-daily DRV/r among 80 treatment-experienced children aged 6 years to <18 years reported that 66% of patients had plasma HIV RNA <400 copies/mL and 51% had HIV RNA <50 copies/mL at Week 24.

Once-daily DRV/r has been investigated in a small study involving 12 treatment-experienced children aged 6 to 12 years who had maintained HIV viral loads <50 copies/mL for at least 6 months.¹⁰ All but one child continued to have undetectable viral loads during a median of 11.6 months of follow-up (range 0.5–14.2 months). The remaining child had detectable viral load measurements between 20 copies/mL and 200 copies/mL on three occasions during a 3-month period before, again, becoming undetectable without a change in regimen.

In one study, 12 participants aged 12 to 17 years received DRV/r once daily.¹¹ After 48 weeks, all but one participant had viral loads <50 copies/mL.

Pharmacokinetics and Dosing

Pharmacokinetics in Children Aged 3 Years to <6 Years

Twenty-one children aged 3 years to <6 years and weighing 10 kg to <20 kg received twice-daily DRV/r oral suspension. These children had experienced virologic failure on their previous ARV regimens and had fewer than three DRV resistance mutations, confirmed by genotypic testing.^7,8,12 The DRV area under the curve (AUC_0–12h), measured as a percent of the adult AUC value,^7,8,12 was 128% overall: 140% in children weighing 10 kg to <15 kg and 122% in children weighing 15 kg to <20 kg.

Pharmacokinetics in Children Aged ≥6 Years

Initial pediatric PK evaluation of DRV tablets and RTV oral solution or tablets was based on a Phase 2 randomized, open-label, multicenter study that enrolled 80 treatment-experienced children and adolescents aged 6 years to <18 years and weighing ≥20 kg.¹⁴ Part 1 of the trial used a weight-adjusted dose of DRV (9 mg/kg to 15 mg/kg) and RTV (1.5 mg/kg to 2.5 mg/kg) twice daily, approximating the standard adult dose of DRV/r 600 mg/100 mg twice daily on a per-weight basis. This dose resulted in inadequate drug exposure in the pediatric population studied, with a 24-hour AUC (AUC_24h) that was 81% of the AUC_24h observed in adults and a pre-dose concentration (C_0h) that was 91% of the C_0h observed in adults. A pediatric dose that was 20% to 33% higher than the directly scaled adult dose was needed to achieve a drug exposure that was similar to that found in adults, and this was the dose selected for Part 2 of the study. The higher dose used for the safety and efficacy evaluation was DRV 11 mg/kg to 19 mg/kg and RTV 1.5 mg/kg to 2.5 mg/kg twice daily. This dose resulted in a DRV AUC_24h of 123.3 mcg·h/mL (range 71.9–201.5 mcg·h/mL) and a C_0h of 3,693 ng/mL (range 1,842‍–‍7,191 ng/mL), representing 102% and 114% of the respective values in adults. Doses were given twice daily and were stratified into body-weight bands of 20 kg to <30 kg and 30 kg to <40 kg. The current weight-band doses of twice-daily DRV/r for treatment-experienced pediatric patients weighing >20 kg to <40 kg were selected using the findings from the safety and efficacy portion of this study (see Table A below).

A small study that involved 12 treatment-experienced children aged 6 to 12 years examined the PKs and efficacy of DRV/r once daily administered in combination with abacavir and lamivudine.¹⁰ All participants had maintained HIV plasma viral loads <50 copies/mL for at least 6 months prior to beginning this regimen. The weight-based doses used for once-daily DRV/r were based on a prior modeling study:¹⁵ 600 mg/100 mg for patients weighing 15 kg to 30 kg, 675 mg/100 mg for patients weighing 30 kg to 40 kg, and 800 mg/100 mg for patients weighing >40 kg. The geometric mean AUC_0–24h was below the study target of 80% of the value seen in adults (63.1 mg·h/L vs. 71.8 mg·h/L), but the trough values that were observed at 23.1 hours to 25.1 hours after the previous dose exceeded the trough plasma concentration recommended for treatment-experienced adults (0.55 mg/L).¹⁶ One child developed neuropsychiatric symptoms (anxiety and hallucinations) and was removed from study. This child did not have an excessive exposure to DRV; the AUC_0–24 was 47.8 mg·h/L.

Dosing

Pharmacokinetic Enhancers

DRV should not be used without a PK enhancer (boosting agent). RTV may be used as a boosting agent in children and adults. COBI may be used as a boosting agent in children weighing ≥40 kg and adults.

A study that enrolled 19 Thai children used the RTV 100-mg capsule twice daily as the boosting dose for twice-daily DRV 375 mg (in children weighing 20 kg to <30 kg), 450 mg (in children weighing 30‍ kg to 40 kg), and 600 mg (in children weighing ≥40 kg).¹⁷ The DRV exposures with RTV 100 mg twice daily were similar to those obtained in the studies with lower (<100 mg) doses of liquid RTV.^14,17 The tolerability and PK data from this small study support the use of RTV 100 mg for boosting using either the powder or tablet formulation in children weighing ≥20 kg, particularly in instances where the lower-dose formulations are unavailable or a child does not tolerate the liquid RTV formulation. No data are available on the safety and tolerability of using the RTV 100-mg tablet or powder formulation in children weighing <20 kg.

Data on the dosing of DRV/c are available primarily for adult patients.¹⁸ Data on once-daily use of the FDC tablet DRV/c 800 mg/150 mg (Prezcobix) showed bioavailability that was comparable to the bioavailability observed with the use of DRV/r 800 mg/100 mg once daily.¹⁶

In an open-label switch study, eight adolescent patients with a median age of 14 years (range 12‍–‍17 years) who received DRV/c had DRV exposures (AUC_tau) that were similar to those observed in adults, except for a lower trough concentration at the end of the dosing interval (C_tau). The median DRV C_tau (494 ng/mL) was above the protein binding-adjusted half-maximal inhibitory concentration for wild-type virus (55 ng/mL). Adolescent patients in this study received the adult dose of COBI 150 mg daily. DRV dosing was based on weight, with patients who weighed ≥40 kg receiving DRV 800 mg once daily and patients who weighed 30 kg to <40 kg receiving DRV 675 mg once daily. In this small sample, 95.5% of patients had HIV RNA <50 copies/mL at Week 12. COBI appeared to be well tolerated with no discontinuations due to adverse events.¹⁹

Frequency of Administration

In February 2013, the FDA approved the use of once-daily DRV for treatment-naive children and for treatment-experienced children without DRV resistance-associated mutations (see Table B below). Population PK modeling and simulation were used to develop recommendations for once-daily dosing in younger pediatric subjects aged 3 years to <12 years and weighing 10 kg to <40 kg.^8,20 Currently, limited data exist on the efficacy of once-daily DRV/r dosing in treatment-naive or treatment-experienced children aged <6 years. Therefore, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) generally recommends dosing DRV/r twice daily in children aged ≥3 years to <12 years (see Once-Daily Administration in Children Aged <12 Years and Weighing <40 kg below). The Panel recommends that once-daily DRV/r be used only in treatment-naive and treatment-experienced adolescents weighing ≥40 kg who do not have mutations that are associated with DRV resistance. If DRV and RTV are used once daily in children aged <12 years, the Panel recommends conducting a PK evaluation of plasma concentrations of DRV and closely monitoring viral load.

Table B. U.S. Food and Drug Administration–Approved Once-Daily Dosing for Pediatric Patients Aged ≥3 Years and Weighing >10 kg Who Are Treatment Naive or Treatment Experienced with No Darunavir Resistance-Associated Mutations

Note: The Panel generally recommends dosing DRV plus RTV twice daily in children aged ≥3 years to <12 years.

Once-Daily Administration in Children Aged <12 Years and Weighing <40 kg

During the TMC114-C228 trial, the researchers investigated once-daily dosing of DRV for 2 weeks; DRV PKs were evaluated in treatment-experienced children aged 3 years to <12 years as part of a substudy. After the conclusion of the substudy, the participants switched back to a twice-daily regimen.^16,20 The DRV/r dose for once-daily use, which was based on PK simulation and which did not include a relative bioavailability factor, was DRV 40 mg/kg coadministered with approximately 7 mg/kg of RTV for children weighing <15 kg and DRV/r 600 mg/100 mg once daily for children weighing ≥15 kg.^20,21 The PK data obtained from 10 children aged 3 to 6 years in this substudy (see Table C below) were included as part of the population PK modeling and simulation that was used to determine the FDA-approved dose for once-daily DRV/r in children aged 3 years to <12 years.

In a small study in which DRV/r was administered once daily to 12 treatment-experienced children aged 6 to 12 years,¹⁰ the geometric mean AUC_0–24h achieved was below the study target of 80% of the value seen in adults (63.1 mg·h/L vs. 71.8 mg·h/L). Trough values exceeded the plasma concentration that is recommended for treatment-experienced patients (0.55 mg/L). Despite the FDA dosing guidelines, the Panel generally recommends dosing DRV/r twice daily in children aged ≥3 years to <12 years. The Panel makes this recommendation because of the small data set used for once-daily DRV/r PK modeling and the limited amount of data on the use of once-daily DRV/r in children aged <12 years.

Once-Daily Administration in Adolescents Aged ≥12 Years and Weighing ≥40 kg

A substudy of once-daily dosing of DRV/r 800 mg/100 mg demonstrated that DRV exposures in 12 treatment-naive adolescents (aged 12–17 years and weighing ≥40 kg) were similar to those seen in adults treated with once-daily DRV (see Table D below).¹¹ After 48 weeks, 83.3% of patients had viral loads <50 copies/mL and 91.7% had viral loads <400 copies/mL.¹¹ Interestingly, no relationship was observed between DRV AUC_0-24h and C_0h and virologic outcome (HIV RNA <50 copies/mL) in this study. DRV exposures were found to be similar to those observed in adults with once-daily dosing in another study in which a single dose of DRV 800 mg with RTV 100 mg was administered to 24 subjects with a median age of 19.5 years (range 14–23 years).²² However, DRV exposures were slightly below the lower target concentrations in adolescent patients aged 14 to 17 years (n = 7) within the cohort, suggesting that higher doses may be needed in younger adolescents. A single case report involving a highly treatment-experienced adolescent patient suggests that using an increased DRV dose with standard RTV boosting and employing TDM can lead to virologic suppression.

The efficacy of once-daily DRV has been established within a limited number of studies in small cohorts of adolescents that reported long-term data on virologic and immunologic outcomes.^11,23

References

1. Belkhir L, Elens L, Zech F, et al. Interaction between darunavir and etravirine is partly mediated by CYP3A5 polymorphism. PLoS One. 2016;11(10):e0165631. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27788239.
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. 2011;55(9):4290-4294. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21670182.
3. Mujuru A, Strehalu R, Rakhmanina N, et al. Six-month outcome of F/TAF Cobicistat-boosted Darunavir in children 14 to <25kg. Presented at: Conference on Retroviruses and Opportunistic Infections; 2023. Seattle, Washington. Available at: https://www.croiconference.org/abstract/six-month-outcome-of-f-taf-cobicistat-boosted-darunavir-in-children-14-to-25kg.
4. Larson KB, Cressey TR, Yogev R, et al. Pharmacokinetics of once-daily darunavir/ritonavir with and without etravirine in human immunodeficiency virus-infected children, adolescents, and young adults. J Pediatric Infect Dis Soc. 2016;5(2):131-137. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27199469.
5. Cressey TR, Yogev R, Wiznia A, et al. Pharmacokinetics of darunavir/ritonavir with etravirine both twice daily in human immunodeficiency virus-infected adolescents and young adults. J Pediatric Infect Dis Soc. 2017;6(3):294-296. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27103489.
6. Foca M, Yogev R, Wiznia A, et al. Rilpivirine pharmacokinetics without and with darunavir/ritonavir once daily in adolescents and young adults. Pediatr Infect Dis J. 2016;35(9):e271-274. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27187753.
7. Violari A, Bologna R, Kumarasamy N, et al. Safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients: week 48 results of the ARIEL trial. Pediatr Infect Dis J. 2015;34(5):e132-137. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25719453.
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10. Bastiaans DET, Geelen SPM, Visser EG, et al. Pharmacokinetics, short-term safety and efficacy of the approved once-daily darunavir/ritonavir dosing regimen in HIV-infected children. Pediatr Infect Dis J. 2018;37(10):1008-1010. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29474261.
11. Flynn P, Komar S, Blanche S, et al. Efficacy and safety of darunavir/ritonavir at 48 weeks in treatment-naive, HIV-1-infected adolescents: results from a phase 2 open-label trial (DIONE). Pediatr Infect Dis J. 2014;33(9):940-945. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25361024.
12. Food and Drug Administration. Clinical pharmacology review of darunavir. 2011. Available at: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM287674.pdf.
13. Blanche S, Bologna R, Cahn P, et al. Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents. AIDS. 2009;23(15):2005-2013. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19724191.
14. Brochot A, Kakuda TN, Van De Casteele T, et al. Model-based once-daily darunavir/ritonavir dosing recommendations in pediatric HIV-1-infected patients aged ≥3 to <12 years. CPT Pharmacometrics Syst Pharmacol. 2015;4(7):406-414. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26312164.
15. Kakuda TN, Brochot A, Tomaka FL, Vangeneugden T, Van De Casteele T, Hoetelmans RM. Pharmacokinetics and pharmacodynamics of boosted once-daily darunavir. J Antimicrob Chemother. 2014;69(10):2591-2605. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24951533.
16. 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: https://www.ncbi.nlm.nih.gov/pubmed/22954687.
17. Cobicistat (Tybost) [package insert]. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203094s016lbl.pdf.
18. McFarland E, Heresi G, Batra J, et al. Pharmacokinetics, safety, and efficacy of atv or drv with cobi in adolescents. Abstract 425. Presented at: Conference on Retroviruses and Opportunistic Infections; 2017. Seattle, Washington. Available at: https://www.croiconference.org/sessions/pharmacokinetics-safety-and-efficacy-atv-or-drv-cobi-adolescents.
19. Prezista drug label. Clinical review of darunavir [package insert]. Food and Drug Administration. 2012. Available at: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM346671.pdf.
20. Kakuda TN, Brochot A, van de Casteele T, Opsomer M, Tomaka F. Establishing darunavir dosing recommendations in treatment-naive and treatment-experienced pediatric patients. Presented at: 14th Clinical Pharmacology Workshop on HIV; 2013. Amsterdam, Netherlands. Available at: https://www.natap.org/2013/Pharm/Pharm_19.htm.
21. 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. Presented at: 3rd International Workshop on HIV Pediatrics; 2011. Rome, Italy. Available at: https://www.natap.org/2011/IAS/IAS_40.htm.
22. King J, Hazra R, et al. Pharmacokinetics of darunavir 800 mg with ritonavir 100mg once daily in HIV+ adolescents and young adults. Presented at: Conference on Retroviruses and Opportunistic Infections 2013. Atlanta, GA.
23. Chokephaibulkit K, Rungmaitree S, Phongsamart W, et al. Pharmacokinetics and efficacy of darunavir/ritonavir once daily in virologically suppressed, treatment-experienced HIV-infected children. HIV Med. 2014;15(8):511-512. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25138061.