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 2nd 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:
| Body Weight | Formulation | Dose | N* | Geometric Mean (%CV†) AUC0-12hr (μM●hr) | Geometric Mean (%CV†) C12hr (nM)
|
≥25 kg
| Film-coated tablet
| 400 mg twice daily
| 18 | 14.1 (121%)
| 233 (157%)
|
≥25 kg
| Chewable tablet
| Weight based dosing
| 9 | 22.1 (36%)
| 113 (80%)
|
| 11 to | Chewable tablet
| Weight based dosing
| 13 | 18.6 (68%)
| 82 (123%)
|
| 3 to | Oral tablet
| Weight based dosing
| 19 | 24.5 (43%)
| 113 (69%)
|
*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]
