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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Integrase Inhibitors

Dolutegravir

(Last updated: March 5, 2015; last reviewed: March 5, 2015)

Dolutegravir (DTG, Tivicay, GSK1349572)

Dolutegravir (DTG, Tivicay, GSK1349572)

For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations

Tablet: 50 mg
Fixed-Dose Combination Tablet: lamivudine 300 mg + abacavir 600 mg + dolutegravir 50 mg (Triumeq)
Dosing Recommendations

Neonate/Infant Dose:
  • Not approved for use in neonates/infants
Children Aged <12 Years:
  • Not approved for use in children aged <12 years. A clinical trial in treatment-experienced children aged <12 years is under way with an experimental dose of 50 mg in children weighing at least 40 kg.
Children Aged ≥12 Years and Weighing At Least 40 kg (Treatment-Naive or Treatment-Experienced/Integrase Strand Transfer Inhibitor [INSTI]-Naive):
  • 50 mg once daily
  • If co-administered with efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin, dolutegravir should be given twice daily at 50 mg per dose.

Adult Dose

Adult Population Recommended Dose
Treatment-naive or treatment-experienced/INSTI-naive 50 mg once daily
Treatment-naive or treatment-experienced/INSTI-naive when co-administered with the following potent UGT1A/CYP3A inducers: efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin 50 mg twice daily
INSTI-experienced with any INSTI-associated resistance substitutions or clinically suspected INSTI resistancea 50 mg twice daily

a Combinations that do not include metabolic inducers should be considered where possible.

Selected Adverse Events
  • Insomnia
  • Headache
  • Hypersensitivity reactions including rash, constitutional symptoms and organ dysfunction (including liver injury) have been reported rarely.
Special Instructions
  • May be taken without regard to meals
  • Should be taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications
  • Poor virologic response to 50 mg dolutegravir twice daily may occur if INSTI-resistance Q148 substitution is present along with 2 or more additional INSTI-resistance mutations: L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R.
Metabolism
  • UGT1A1 and cytochrome P450 (CYP) 3A substrate
  • Dosing in patients with hepatic impairment: No dose adjustment is necessary in patients with mild or moderate hepatic impairment. Dolutegravir is not recommended in patients with severe hepatic impairment because of lack of data.
  • Dolutegravir decreases tubular secretion of creatinine and slightly increases measured serum creatinine, but does not affect glomerular filtration.
  • Dosing in patients with renal impairment: No dose adjustment is required in INSTI-naive patients with mild, moderate, or severe renal impairment or in INSTI-experienced patients with mild or moderate renal impairment.
  • Use dolutegravir with caution in INSTI-experienced patients with severe renal impairment (creatinine clearance <30 mL/min) because dolutegravir concentrations will be decreased (the cause of this decrease is unknown).

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/)

  • Metabolism: Dolutegravir is a UGT1A1 and CYP 3A substrate and may require dosage adjustments when administered with UGT1A1 or CYP 3A-modulating medications. Because etravirine significantly reduces plasma concentrations of dolutegravir, dolutegravir should not be administered with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir, which counteracts this effect on dolutegravir concentrations. Dolutegravir should not be administered with nevirapine because of insufficient data.
  • Before dolutegravir is administered, a patient’s medication profile should be carefully reviewed for potential drug interactions.
Major Toxicities
  • More common: Insomnia and headache
  • Less common (more severe): Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction.

Resistance
The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (http://www.iasusa.org/sites/default/files/tam/22-3-642.pdf), and the Stanford University HIV Drug Resistance database offers a discussion of integrase strand transfer inhibitor (INSTI) mutations (http://hivdb.stanford.edu/DR/). Poor virologic response to 50 mg dolutegravir twice daily may occur if INSTI-resistance Q148 substitution is present along with two or more additional INSTI-resistance mutations (see table above for list).

Pediatric Use
Approval
Dolutegravir is Food and Drug Administration (FDA)-approved in combination with other antiretroviral drugs for children aged 12 years and older, weighing at least 40 kg, and who are treatment-naive or treatment-experienced and INSTI-naive.

Efficacy and Pharmacokinetics
IMPAACT P1093 is an ongoing open-label trial of HIV-infected children with the plan to enroll down to age 4 weeks. FDA approval of dolutegravir down to age 12 years was based on data from 23 treatment-experienced, INSTI-naive adolescents. Intensive pharmacokinetic (PK) evaluations were performed on the first 10 participants (9 weighing ≥40 kg and receiving 50 mg, 1 weighing 37 kg and receiving 35 mg) and revealed comparable exposures to those seen in adults receiving 50 mg once daily.1 Nine of 10 participants achieved HIV RNA concentration <400 copies/mL at week 4 (optimal background therapy was added 5 to 10 days after dolutegravir was started). An additional 13 participants were then enrolled for evaluation of long-term outcomes. At 24 weeks and 48 weeks, 70% and 61% had achieved HIV RNA concentration <50 copies/mL, respectively.2,3 No safety or tolerability concerns were identified.2 In addition, children aged ≥6 to <12 years are undergoing PK and longer-term follow up in P1093, using investigational tablets of lower strengths (or the 50-mg tablet if they weigh at least 40 kg). To date, data from 11 participants have demonstrated a favorable safety profile, adequate PK, and virologic efficacy through 24 weeks.4 An oral pediatric granule formulation will also be studied.

References

  1. Hazra R, Viani R, Acosta E, et al. Pharmacokinetics, safety and efficacy of dolutegravir (DTG; S/GSK1349572) in HIV-1-positive adolescents: preliminary analysis from IMPAACT P1093. Abstract: TUAB0203. Presented at: XIX International AIDS Conference. 2012. Washington, DC.
  2. Dolutegravir (Tivicay) [Package Insert]. Food and Drug Administration. 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204790lbl.pdf/. Accessed January 8, 2015.
  3. Viani R, Carmelita A, Fenton T, et al. Safety and efficacy of dolutegravir in HIV treatment-experienced adolescents: 48-week results. Presented at: 21st Conference on Retroviruses and Opporunistic Infections. 2014. Boston, MA.
  4. Viani R, Carmelita A, Fenton T, et al. Safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV+ children. Presented at: 21st Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.

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