(Last updated: March 1, 2016; last reviewed: March 1, 2016)
|Raltegravir (RAL, Isentress)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Tablets: 400 mg (film-coated poloxamer tablet)
Chewable Tablets: 100 mg (scored) and 25 mg
Granules for Oral Suspension: Single-use packet of 100 mg
Note: Film-coated tablets, chewable tablets, and oral suspension are not interchangeable.
|Dosing Recommendations||Selected Adverse Events|
Oral Suspension Dosing Tablea
Children Aged ≥4 Weeks and Weighing ≥3 kg to <20 kg:
Note: Maximum dose of oral suspension is 5 mL (100 mg) twice daily.
Children Aged 2 to <12 Years:
Chewable Tablet Dosing Table
Dosinga of Chewable Tablets in Children Aged 2 to <12 Years:
Note: Maximum dose of chewable tablets is 300 mg twice daily.
Adolescent (Aged ≥12 Years) and Adult Dose:
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 AIDS 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/).
Raltegravir is an integrase strand transfer inhibitor indicated in combination with other antiretroviral (ARV) drugs for the treatment of HIV-infection for use in infants and children aged ≥4 weeks and weighing ≥3 kg. Current pediatric FDA approval and dosing recommendations are based upon evaluations in 122 patients aged ≥4 weeks to 18 years enrolled in IMPAACT P1066.1
Efficacy and Pharmacokinetics
Raltegravir pharmacokinetics (PK) exhibit considerable intrasubject and intersubject variability.2,3 Current PK targets are based on results from a clinical trial in adults (QDMRK) in which treatment-naive HIV-infected patients were randomized to receive raltegravir 800 mg once daily versus raltegravir 400 mg twice daily (BID). After 48 weeks of treatment, the percentage of patients achieving HIV RNA viral loads <50 copies/mL was 83% in the once-daily group compared to 89% in the twice-daily group. Patients in the once-daily arm with Ctrough concentrations below 45 nM were at the greatest risk of treatment failure. 2,3 Overall drug exposures were similar in both groups but the association between higher risk of treatment failure and lower Ctrough concentrations suggests that maintaining raltegravir trough plasma concentrations above 45 nM is important for efficacy. 2,3
IMPAACT P1066 was conducted to evaluate the PK, safety, and efficacy of raltegravir in children aged 4 weeks to 18 years. Enrollment by cohort and PK parameters are summarized in Tables A and B.4,5
||Participants Receiving the Final Recommended Dose|
|12 years to <19 years||I||Film-coated tablet||N = 59|
|6 years to <12 years||IIA||Film-coated tablet||N = 4|
|6 years to <12 years||IIB||Chewable tablet||N = 13|
|2 years to <6 years||III||Chewable tablet||N = 20|
|6 months to <2 years||IV||Oral Suspension||N = 14|
|4 weeks to <6 months||V||Oral Suspension||N = 12|
||Intensive PK||Mean Dose mg/kg||GM (CV%)a
|12 years to <19 years||I||Film-coated tablet||N = 11||9.3||15.7 (98)||333 (78)|
|6 years to <12 years||IIA||Film-coated tablet||N = 11||13.5||15.8 (120)||246 (221)|
|6 years to <12 years||IIB||Chewable tablet||N = 10||6.5||22.6 (34)||130 (88)|
|2 years to <6 years||III||Chewable tablet||N = 12||6.2||18.0 (59)||71 (55)|
|6 months to <2 years||IV||Oral Suspension||N = 8||5.9||19.8 (34)||108 (52)|
|4 weeks to <6 months||V||Oral Suspension||N = 11||5.7||22.3 (40)||117 (68)|
|a PK targets for Cohorts I-III: AUC0-12h 14-25 µMxh; C12h nM ≥33 nM|
|b PK targets for Cohorts IV-V: AUC0-12h 14-45 µMxh; C12h nM ≥75 nM|
|Key to Acronyms: GM = geometric mean; PK = pharmacokinetic|
Children Aged 2 to 18 Years
IMPAACT P1066 is a Phase I/II open-label multicenter study to evaluate the PK profile, safety, tolerability, and efficacy of various formulations of raltegravir in antiretroviral treatment (ART)-experienced, HIV-infected children and adolescents aged 2 to 18 years in combination with an optimized background ART regimen.6,7 Subjects received either the 400-mg, film-coated tablet formulation twice daily (patients aged 6–18 years and weighing at least 25 kg) or the chewable tablet formulation at a dose of 6 mg/kg twice daily (aged 2 to <12 years). In IMPAACT P1066, the initial dose-finding stage included intensive PK evaluation in various age cohorts (Cohort I: aged 12 to <19 years; Cohort II: 6 to <12 years, Cohort III: 2 to <6 years). Dose selection was based on achieving target PK parameters similar to those seen in adults: PK targets were geometric mean (GM) area under the curve (AUC0-12h) of 14–25 µMxh and GM 12-hour concentration (C12h) >33 nM. Additional subjects were then enrolled in each age cohort to evaluate long-term efficacy, tolerability, and safety. A total of 126 treatment-experienced subjects were enrolled with 96 receiving the final recommended dose of raltegravir. Only treatment-experienced patients were eligible to enroll and the optimized regimen was determined by the site investigators. Adolescents tended to be more treatment experienced and have more advanced disease than those in the younger cohorts. Ninety-six subjects completed 48 weeks of treatment with 79% achieving HIV RNA <400 copies/mL and 57% achieving HIV RNA <50 copies/mL, with a mean CD4 T lymphocyte (CD4) cell count (percent [%]) increase of 156 cells/µL (4.6%).4,6 Of 36 subjects who experienced virologic failure, development of drug resistance and/or poor adherence were contributing factors. Genotypic resistance data were available for 34 patients with virologic failure and raltegravir-associated mutations were detected in 12/34 of those subjects. The frequency, type, and severity of adverse events (AEs) through week 48 were comparable to those observed in adult studies. AEs were commonly reported but there were few serious AEs considered to be drug-related. Observed AEs considered drug-related included one patient with grade 3 psychomotor hyperactivity, abnormal behavior, and insomnia; and one patient with a grade 2 allergic rash on day 17 and grade 3 ALT and grade 4 AST laboratory elevations after day 122. There were no discontinuations due to AEs and no drug-related deaths.4 Overall, raltegravir administered as a film-coated tablet twice daily in subjects aged 6 to <19 years and chewable tablets at a dose of approximately 6 mg/kg twice daily in subjects aged 2 to <12 years was well tolerated with favorable virologic and immunologic responses.
In 19 HIV-infected children and adolescents with multidrug-resistant virus in the HIV Spanish Pediatric Cohort (CoRISe), good virologic response and improved CD4 counts were observed when raltegravir was included in an optimized regimen.8 Additional experience from the French expanded access program in treatment-experienced adolescents support the good virologic and immunologic results observed in IMPAACT P1066.9,10
Infants/Toddlers Aged at Least 4 Weeks to <2 Years
IMPAACT P1066 studied 26 infants and toddlers aged 4 weeks to <2 years who were administered the granules for oral suspension in combination with an optimized background regimen. All subjects had received prior ARV drugs as part of prevention of perinatal transmission and/or treatment of HIV infection, and 69% had baseline plasma HIV-1 RNA exceeding 100,000 copies/mL. PK targets for cohorts IV and V were modified to geometric mean (GM) AUC0-12h of 14 to 45 µMxh and GM 12-hour concentration (C12h) ≥75 nM (33.3 ng/mL). These targets were modified so that greater than 90% of patients would be predicted to have C12h above the 45 nM threshold. By week 48, 2 subjects experienced AEs thought to be related to study drug: 1 patient with a serious erythematous rash that resulted in permanent discontinuation of raltegravir, and 1 patient with immune reconstitution inflammatory syndrome. Virologic success defined as ≥1 log10 decline in HIV RNA or <400 copies/mL at 48 weeks was achieved in more than 87% of subjects. At 48 weeks of follow-up, 45.5% of subjects had HIV RNA <50 copies/mL and mean CD4 cell count (percent [%]) increase of 527.6 cells/mm3 (7.3%) There were 4 subjects in Cohort IV with virologic failure by week 48 and 1 subject with a raltegravir-associated resistance mutation on genotype. Overall, the granules for oral suspension, at a dose of approximately 6 mg/kg twice daily was well tolerated with good efficacy.5
Neonates Aged <4 Weeks
There are no data on the safety and dosing of raltegravir in neonates aged <4 weeks. Raltegravir is metabolized by UGT1A1, the same enzyme responsible for the elimination of bilirubin. UGT enzyme activity is low at birth, and it is likely that raltegravir elimination is prolonged in neonates. In addition, bilirubin and raltegravir may compete for UGT and albumin binding sites.11
Washout PK of raltegravir in neonates born to HIV-infected pregnant women was studied in P1097.12 The neonatal plasma half-life was highly variable, ranging from 9.3 to 184 hours, suggesting potential roles for developmental aspects of neonatal UGT1A1 enzyme activity, redistribution, and/or enterohepatic recirculation of raltegravir.
IMPAACT P1110 is a Phase I trial to evaluate the safety and PK of raltegravir in HIV-1 exposed neonates at high risk of acquiring HIV-1 infection (ClinicalTrials.gov identifier: NCT01780831). Enrollment is ongoing and preliminary safety and PK results for the initial cohort have been presented. After combining RAL concentration data from this small group of neonates receiving only two raltegravir doses with that from older infants and children receiving daily dosing, a population PK model and simulations were used to facilitate the development of a daily-dosing neonatal raltegravir regimen for evaluation in a second cohort of neonates.12,13
The PK of raltegravir was compared in HIV-infected adult patients receiving intact, whole 400-mg tablets and patients who chewed the 400-mg film-coated tablets because of swallowing difficulties. Drug absorption was significantly higher in the group who chewed the tablets, although palatability was rated as poor.14 In adult volunteers, the PK of raltegravir 800 mg taken once daily by chewing was compared to two doses of 400 mg every 12 hours by swallowing. Subjects taking raltegravir by chewing had significantly higher drug exposure and reduced PK variability than swallowing whole tablets as currently recommended.15 According to the manufacturer the film-coated tablets must be swallowed whole.
The raltegravir chewable tablet and oral suspension have higher oral bioavailability than the film-coated tablet based on a comparative study in healthy adult volunteers.16 Inter-patient and intrapatient variability for PK parameters of raltegravir are considerable, especially with the film-coated tablets.1,17 Because of the differences in the bioavailability of the chewable tablets, film-coated tablets, and oral suspension, the dosing recommendations are different and these products are not interchangeable.
Palatability was evaluated as part of P1066. Both chewable tablets and oral granules for suspension were thought to have acceptable palatability. Seventy-three percent of those surveyed reported no problems with chewable tablets; 82.6% reported no problems with administering the oral granules.4,5