400 mg film-coated tablet: 400 mg BID with or without food.

600 mg HD film-coated tablet: 1200 mg (2 x 600 mg HD tablets) once daily with or without food.

• Raltegravir film-coated tablets must be swallowed whole.
• The 600 mg HD tablet is not interchangeable with the 400 mg film-coated tablet. 

Raltegravir chewable tablets may be chewed or swallowed whole. Because the formulations are not bioequivalent, do not substitute chewable tablets for the 400 mg film-coated tablet.

Dutrebis® (lamivudine 150 mg/raltegravir 300 mg tablet):  1 tablet twice daily with or without food.

Neonate:Term infants > 37 weeks and birth weight at least 2 kg (DHHS Pediatric Guidelines)

In Canada, not approved for children less than 2 years of age.

Limited dosing information available for pre-term or low birth-weight infants. Case report using raltegravir granules for suspension (SAP in Canada) in a pre-term low-birth weight infant with dosing guided by TDM has been published.³²²⁷

• Oral suspension dosing table
  

• If mother has taken raltegravir 2-24 hours prior to delivery, the neonate's first dose should be delayed until 24-48 hours after birth; additional ARV drugs should be started as soon as possible

Infant/Pediatric: at least 4 weeks of age and > 3 kg and < 20 kg (DHHS Pediatric Guidelines)

• Oral suspension dosing table (approximately 6 mg/kg/dose po BID)

• maximum dose of oral suspension is 10 mL (100 mg) PO BID
• For children weighing 11 to 20 kg, either oral suspension or chewable tablets can be used
  

Children and adolescent dose:

• Weight based dosing for chewable tablets (approximately 6 mg/kg/dose po BID)

• Maximum dose of chewable tablets is 300 mg po BID
• The 100 mg chewable tablets may be divided into equal halves

Children/adolescents weighing at least 25 kg and adults

• 400 mg film coated tablet po BID

Adolescents weighing at least 40 kg and adults

• 2 x 600 mg film coated tablet po OD

Pharmacokinetics of HIV/TB Cotreated infants and young children P1011 reported results from dose finding study in HIV/TB co-infected children (receiving rifampin) ages 4 weeks to 2 years using RAL chew tablets as a dispersable tablet. N=13 children started RAL 12mg/kg/dose BID (twice approved pediatric dose) and 2 NNRTIs. RAL PK sampling done 5-8 days after ARV start and a fourth ARV was added. RAL was discontinued at end of TB treatment with follow up for 3 months. Week 8 data available for 12/13 children. 10/12 (83%) had HIV VL<40 copies/ml. RAL discontinued in 6/13; 1 each for grade 4 neutropenia (attributed to TB medication), use of disallowed medication, AUC12h exceeding allowed AUC12h (asymptomatic); 3 stopped for virologic failure (1 at wk 8 very ill; 1 at wk 12 non-adherence; 1 at wk 12 unexplained. Authors concluded 12mg/kg dose BID of RAL chew tabs safely achieved PK targets in HIV/TB co-infected children 4 weeks to < 2 years receiving rifampin with high rates of viral suppression by week 8.³³²²

Raltegravir film-coated tablets must be swallowed whole.

Raltegravir chewable tablets may be chewed, crushed or swallowed whole. The 100 mg chewable tablet can be divided into equal halves. The maximum dose of chewable tablets is 300 mg twice daily.

Raltegravir chewable tablets contain phenylalanine, a component of aspartame.

• each 25 mg chewable tablet contains approximately 0.05 mg phenylalanine.
• each 100 mg chewable tablet contains approximately 0.10 mg phenylalanine.
• Phenylalanine can be harmful to patients with phenylketonuria.
  

Each single-use packet for oral suspension contains 100 mg of raltegravir which is to be suspended in 10 mL of water giving a final concentration of 10 mg/mL. Pour packet contents into 10 mL of water and mix. Once mixed, measure the recommended volume (dose) of suspension with a syringe and administer the dose orally. The oral suspension should be administered orally within 30 minutes of mixing. The maximum dose of oral suspension is 100 mg twice daily.

Because the formulations are not bioequivalent, do not substitute chewable tablets or oral suspension for the 400 mg film-coated tablet.

Severe renal insufficiency (ClcrNo dosage adjustment is necessary in patients with renal insufficiency.

Antiretroviral pharmacokinetics were studied in a 49-year old HIV-positive man virologically suppressed on darunavir/ritonavir 600/100 mg twice daily, etravirine 200 mg twice daily and raltegravir 400 mg twice daily while undergoing hemodialysis three times weekly. The morning dose of the antiretrovirals was taken after completion of the 4-hour morning hemodialysis session. After dialysis, darunavir, etravirine, raltegravir and ritonavir concentrations were decreased by 57%, 29%, 82% and 60%, respectively compared to predialysis levels. A supplemental dose of 600 mg darunavir administered prior to the hemodialysis session was successful in restoring darunavir concentrations approximately equal to expected levels, while administration of a supplemental dose of raltegravir 400 mg was not, likely due to wide intra- and inter-patient variability. Dose supplementation of etravirine was not deemed necessary given the relatively low amount removed during hemodialysis. After 1 year of therapy, the patient maintained viral suppression.[Giguere et al. 2009]

Pre- and post-dialysis raltegravir concentrations were measured in 2 ESRD HIV-infected patients. The hemodialysis extraction ratio and raltegravir hemodialysis clearance were 5.5% and 9.1 ml/min in patient 1, and 9.5% and 19.1 ml/min in patient 2. These results suggest minimal raltegravir removal by hemodialysis with no specific raltegravir dosage adjustments required.[Molto et al. 2010]

An HIV-positive patient on continuous venovenous hemodiafiltration (CVVHDF) received raltegravir 400 mg BID, darunavir 600/100 mg BID, zidovudine 300 mg BID and 3TC 50 mg q24h in suspension via gastric port and simultaneous enteral feeding via the duodenal port of a double-lumen nasogastroduodenal tube. Pharmacokinetic sampling and analysis indicated that darunavir and raltegravir were removed by CVVHDF with approximately the same clearance as provided by a normally functioning kidney. Absorption of both drugs after suspension and application via the gastric port with continued administration of feed via the duodenal port of the double-lumen tube was good. As such, dose adjustments are not required for patients receiving darunavir and/or raltegravir while undergoing CVVHDF and that absorption of darunavir and raltegravir is not significantly affected by postpyloric enteral feeding.[ Taegtmeyer et al. 2011]

In a case series, 2 patients on Raltegravir, etravirine and abacavir had intensive PK analysis performed. In one patient,  sampling was perfomred during morning and evening doses on hemodialysis, and during non hemodialysis days. For the second patient, sampling was done during  and after hemodialysis sessions. In all cases, hemodialysis did not seem to affect serum concentrations of raltegravir. Raltegravir Ctrough (239, 197 ng/mL) were well above the reference IC95 (14 ng/mL).  Both patients maintained virological suppression. (Yanagisawa et al. AIDS 2016)

http://nephron.com/cgi-bin/CGSI.cgi

Moderate hepatic insufficiency (Child Pugh score 7 to 9) has no clinically meaningful effect on raltegravir pharmacokinetics (14% ↓ AUC, 37% ↓ Cmax and 26% ↑ C12 vs. healthy matched control subjects).(Iwamoto et al. 2009)

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment.

The kinetics of raltegravir and darunavir were studied in five HIV- HCV co-infected patients with moderate to severe hepatic impairment (2 with chronic active hepatitis, 3 with cirrhosis). Plasma Ctrough samples were collected at days 14 and 30 after this new regimen was initiated; 24 matched HIV-1 patients with normal liver function treated with raltegravir and darunavir were used as a control group. Mean raltegravir Ctrough was 637 vs. 221 ng/mL in controls. Patients with cirrhosis had higher mean raltegravir Ctrough than patients with active non-cirrhotic hepatitis (665 vs. 581 ng/mL). No differences in viral/immunologic outcome or safety parameters were found between cirrhotic and non-cirrhotic patients. Use raltegravir with caution in patients with moderate to severe liver impairment because of the risk of additive toxicity.(Tommasi et al. 2010)

The kinetics of multi-dose raltegravir 400 mg BID were studied in HIV/HCV coinfected patients with Child-Pugh grade C hepatic cirrhosis on stable cART (lopinavir/r, fosamprenavir/r or darunavir/r) with controlled viremia (<50 copies/ml) for at least 6 months.  Compared to patients with no histologic liver damage, patients with advanced cirrhosis (Child-Pugh C) showed higher RAL exposure, with mean 72% ­ AUC and 6.5-fold ­ C12. No safety issues were identified and RAL was well tolerated by all patients.(Hernandez-Novoa et al. 2014).

The kinetics of raltegravir 400 mg BID plus either abacavir/3TC or tenofovir/FTC were studied in 10 HIV+ patients (80% HCV) with end-stage liver disease: median age 50 (39-63) yrs, 58 (48- 81) kg, CD4 258 (57-604) cells/mm3, MELD and CP scores at screening were 12 [5; 26] and 10 [6; 14], respectively. Median MELD at M1 was 11 [7; 33]. Albumin concentration at M1 was 27 [24; 36] g/L. Raltegravir was well tolerated in all subjects. Raltegravir pharmacokinetics exhibited wide variability, but were within the range historically reported in patients or volunteers with normal liver function.(Barau et al. 2014)

Raltegravir displays dose proportional pharmacokinetics over the clinically relevant dose range (100 to 800 mg).

Adults:
In a single dose pharmacokinetic study in healthy subjects (n = 20), AUC 0-∞ & Cmax of raltegravir were dose proportional for the dose range 100-1600 mg. Raltegravir C12h increased proportionally from 100-800 mg, and slightly less than proportionally from 100-1600mg [Wenning et al. ICAAC 2007]. Considerable intersubject and intrasubject variability was observed in the kinetics.

Subjects who received 400mg BID: AUC 14.3 uM•hr, C12hr 142 nM. Gender, age, body mass index, race, and HIV status had no clinically meaningful effect on raltegravir pharmacokinetics. Similarly, in a study of 44 treatment-naïve African-American patients administered RAL 400 mg BID plus tenofovir/FTC, mean raltegravir AUC 5159 ng.hr/mL (CV 78%), Cmax 1315 ng/mL (CV 109%), C12h after 2^nd dose was 166 ng/mL (CV 94%); these results were comparable to historical controls, suggesting no influence of race on raltegravir pharmacokinetics.[Wohl et al. 2013]

Pediatrics:
Preliminary dose finding study suggest HIV infected adolescents (≥ 12 and < 19 yrs) receiving RAL 8mg/kg BID achieve systemic exposure similar to adults receiving 400mg BID. RAL well tolerated in this preliminary study.(Acosta et al. 2008)

Raltegravir Steady State Pharmacokinetic Parameters in Pediatric Patients Following Administration of Recommended Doses:

 *Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose.
†Geometric coefficient of variation.

The pharmacokinetics of raltegravir in infants under 4 weeks of age has not been established.

Chewing vs. swallowing tablets
The pharmacokinetics of raltegravir were compared in 67 patients who swallowed the intact tablet with 13 HIV-infected patients who chewed the raltegravir tablet due to swallowing difficulties. HIV-infected patients receiving raltegravir by chewing the tablet showed higher drug absorption and reduced pharmacokinetic variability compared with patients swallowing the intact tablet.[Cattaneo et al. 2012]

In 12 healthy volunteers, the pharmacokinetics of raltegravir 400 mg BID by swallowing was compared to raltegravir 800 mg QD where the tablets were chewed. While large inter-patient variability was observed with the BID dosing, variability was reduced by 20-1500% when raltegravir tablets were chewed. Chewing raltegravir also led to significantly higher raltegravir AUC (40722 ± 14843 vs. 21753 ± 12229 ng*h/mL, p<0.0001) and no difference in Cmin (36 ± 23 vs. 43 ± 23 ng/mL, p=0.298). compared to swallowing the tablets.[Cattaneo et al. 2013][Rizk et al. 2014]

Reformulated 600 mg tablet
In healthy volunteers, the effect of food on single dose pharmacokinetics of raltegravir 1200 mg, administered as either 3 x 400 mg marketed tablet or 2 x 600 mg reformulated tablet. For the reformulated tablet, administration with a low fat meal resulted in 40% ↓ AUC, 52% ↓ Cmax and 16% ↓ C24h, while administration with a high fat meal resulted in 3% ↑ AUC, 28% ↓ Cmax and 12% ↓ C24h.[Krishna et al. 2013]

Dutrebis fixed dose combination tablet:

One tablet was shown to provide comparable lamivudine and raltegravir exposures to one Epivir 150 mg tablet plus one Isentress 400 mg tablet. Due to the higher bioavailability of raltegravir contained in Dutrebis, the exposures provided by the 300 mg dose of raltegravir are comparable to 400 mg of ralegravir given as the raltegravir poloxamer formulation (Isentress), which accounts for the difference in raltegravir dose.

Concentrations in UGT1A1*28/*28 genotype
The pharmacokinetics of single dose raltegravir was studied in subjects with generally low UGT1A1 activity (UGT1A1*28/*28 genotype) compared to subjects with normal activity (UGT1A1*1/*1 gentoype). Raltegravir AUC ↑ 41%, Cmax ↑ 40% and Cmin ↑ 91% in individuals with the UGT1A1*28/*28 genotype relative to the UGT1A1*1/*1 genotype. However, these differences are not considered to be clinically important, and the Tmax and t1⁄2 values were similar for both genotypes. No dose adjustment of raltegravir is required for individuals with the UGT1A1*28/*28 genotype.[Petry A et al. ICAAC 2008]

Cervicovaginal fluid concentrations
Simultaneous plasma and cervicovaginal fluid (CVF) samples were obtained in 7 HIV-negative women taking raltegravir for 7 days. Raltegravir was detectable in CVF 6 hours post-dose, Tmax 12h, CVF t1⁄2 17 hours (vs. plasma t1⁄2 7 hours), with CVF:plasma AUC ratio of 64% on day 1 and 93% on day 7. Raltegravir CVF concentrations were C12h 607 ng/mL, AUC 1677 ng.hr/mL.[Jones A et al. 10th IWCPHT 2009, #O_06]. In 6 HIV-positive women taking raltegravir 400 mg BID for at least 4 weeks, similar raltegravir CVF concentrations were observed.[Patterson et al. IAC 2010]

Semen concentrations
A total of 96 blood and 96 semen samples were collected within 1 hour of each other in 16 HIV-infected men virally suppressed on raltegravir-based therapy for a median of 21 months. The median seminal plasma to blood plasma ratios and AUC0-12h seminal plasma to blood plasma ratios of raltegravir were 3.25 (interquartile range 1.46 to 5.37) and 2.26 (interquartile range 1.05 to 4.45), respectively. Concentrations of raltegravir in seminal plasma are several fold-higher than those attained in blood plasma and those required to inhibit viral replication in this compartment.[Antoniou et al. 2014]

Raltegravir concentrations and HIV-1 RNA levels were measured in simultaneous semen and plasma samples from 10 treatment-experienced patients on 24 weeks of raltegravir-based therapy. In all samples, semen RNA was 

Intracellular concentrations
Paired plasma and intracellular samples were obtained from 12 HIV-infected adults taking raltegravir BID and after switching to once daily. With BID dosing, no plasma trough concentrations were below the IC95, in contrast to 33% for once daily dosing. Fifty percent of the once daily group had intracellular trough concentrations below the inhibitory concentration 95 (IC95), 25% in the b.i.d. group. Lower plasma and intracellular concentrations may contribute to inferior virologic suppression rates observed with once daily raltegravir dosing.[Sandkovsky et al. AIDS 2012].

Plasma and intracellular raltegravir concentrations after single dose raltegravir 400 mg were measured for 48 hours in healthy subjects. Intracellular raltegravir concentrations were 24% of plasma concentrations, and intracellular:plasma ratios were stable without significant time-related trends suggesting no intracellular accumulation.[Wang et al. ICAAC 2010]

Gut-associated lymphoid tissue concentrations
Concentrations of raltegravir in gut-associated lymphoid tissue (GALT) were compared to blood plasma concentrations in healthy male volunteers who received raltegravir 400 mg BID for 7 days. After multiple doses, raltegravir AUCs in the terminal ileum, splenic flexure and rectal tissue were 84-fold, 679-fold and 239-fold higher than blood concentrations, respectively. The raltegravir accumulation ratio was 0.9 for terminal ileum, 8.4 for splenic flexure and 5.5 for rectal tissue. These data suggest that RAL may also have a role in PEP/PrEP and treatment of primary HIV infection.[Patterson et al. HIV PK 2012, #O_11]

IC95 = 15 ng/mL

In vitro simulations suggest that antiviral effect is consistent with AUC rather than trough [McSharry J et al. 10th IWCPHT 2009, #O_09].

Based on data from two healthy volunteer studies, C2h or AUC_0-3h may be used to reliably predict AUC_0-12h, which may be a better PK parameter for raltegravir TDM.[Burger et al. 2010]

In 18 HIV-positive patients, raltegravir concentrations were measured in matched CSF and plasma samples. Raltegravir was present in all CSF specimens with a median concentration of 13.9 ng/mL (IQR 8.9, 24.6). The median CSF-to-plasma ratio was 7.3% (IQR 2.2%, 17%). CSF concentrations correlated with plasma concentrations (rho = 0.47, p = 0.03) but not with post-dose sampling time. Raltegravir concentrations in CSF exceeded the IC50 of wild-type HIV in all but 1 specimen by a median of 4.1-fold (IQR 2.6, 7.2).[Letendre S et al. ICAAC 2009]

In 3 HIV-positive patients who started a raltegravir-based regimen and underwent lumbar punctures for clinical reasons, raltegravir CSF trough concentrations were above or very close to in-vitro 95% inhibitory concentration (IC95) (14.6 ng/ml).[Calcagno et al. 2010]

In 27 HIV-positive patients on raltegravir who underwent lumbar punctures for clinical reasons, the median raltegravir CSF:plasma ratio was 0.25 (IQR 0.10-0.42). At the end of the dosing interval, patients on boosted PIs had higher CSF trough concentrations compared to those on other ARVs (difference not significant). Patients with altered BBB function had higher CSF:plasma ratios (0.57 vs. 0.18, p=0.01). In 4 patients on rifampin (3 on RAL 800 mg BID), CSF:plasma ratio was 0.31.[Calcagno et al. 2012]

2010 CNS Penetration Effectiveness (CPE) Score: 3 [Letendre S et al. 2010]

Mutations in the integrase gene associated with resistance to raltegravir (IAS-USA Fall 2017 Resistance Mutations):

Resistance is associated with mutations at Q148H/K/R, or N155H, or Y143R/H/C, plus at least 1 additional minor mutation (i.e., L74M, E92Q, T97A, E138A/K, G140A/S, R263K). Both of the integrase variants, Q148K and E138A/G140A/Q148K, engender a substantial loss of susceptibility to raltegravir.

There seems to be cross-resistance between raltegravir and elvitegravir. Viruses with integrase inhibitor resistance mutations remain fully sensitive to the effects of non-nucleoside reverse transcriptase inhibitors as well as nucleosides and protease inhibitors.