Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Pharmacotherapeutic group: antivirals for systemic use, other antivirals
ATC code: J05AX08
Raltegravir is an integrase strand transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1). Raltegravir inhibits the catalytic activity of integrase, an HIV-encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of the HIV genome into the host cell genome. HIV genomes that fail to integrate cannot direct the production of new infectious viral particles, so inhibiting integration prevents propagation of the viral infection.
Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (IC95) of HIV-1 replication (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir inhibited viral replication in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates from 5 non-B subtypes, and isolates resistant to reverse transcriptase inhibitors and protease inhibitors. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV isolates representing 5 non-B subtypes and 5 circulating recombinant forms with IC50 values ranging from 5 to 12 nM.
Most viruses isolated from patients failing raltegravir had high-level raltegravir resistance resulting from the appearance of two or more mutations in integrase. Most had a signature mutation at amino acid 155 (N155 changed to H), amino acid 148 (Q148 changed to H, K, or R), or amino acid 143 (Y143 changed to H, C, or R), along with one or more additional integrase mutations (e.g., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, S230R). The signature mutations decrease viral susceptibility to raltegravir and addition of other mutations results in a further decrease in raltegravir susceptibility. Factors that reduced the likelihood of developing resistance included lower baseline viral load and use of other active anti-retroviral agents. Mutations conferring resistance to raltegravir generally also confer resistance to the integrase strand transfer inhibitor elvitegravir. Mutations at amino acid 143 confer greater resistance to raltegravir than to elvitegravir, and the E92Q mutation confers greater resistance to elvitegravir than to raltegravir. Viruses harbouring a mutation at amino acid 148, along with one or more other raltegravir resistance mutations, may also have clinically significant resistance to dolutegravir.
The evidence of efficacy of raltegravir was based on the analyses of 96-week data from two randomised, double-blind, placebo-controlled trials (BENCHMRK 1 and BENCHMRK 2, Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult patients, the analysis of 240-week data from randomised, double-blind, active-control trial (STARTMRK, Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult patients and the analysis of 96-week data from randomised, double-blind, active-control trial (ONCEMRK, Protocol 292) in antiretroviral treatment-naïve HIV-1 infected adult patients.
BENCHMRK 1 and BENCHMRK 2 (multi-centre, randomised, double-blind, placebo-controlled trials) evaluated the safety and anti-retroviral activity of raltegravir 400 mg twice daily vs. placebo in a combination with optimised background therapy (OBT), in HIV-infected patients, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NRTIs, NNRTIs, PIs) of anti-retroviral therapies. Prior to randomisation, OBT were selected by the investigator based on the patient’s prior treatment history, as well as baseline genotypic and phenotypic viral resistance testing.
Patient demographics (gender, age and race) and baseline characteristics were comparable between the groups receiving raltegravir 400 mg twice daily and placebo. Patients had prior exposure to a median of 12 anti-retrovirals for a median of 10 years. A median of 4 ARTs was used in OBT.
Durable outcomes (Week 48 and Week 96) for patients on the recommended dose raltegravir 400 mg twice daily from the pooled studies BENCHMRK 1 and BENCHMRK 2 are shown in Table 2.
Table 2. Efficacy Outcome at Weeks 48 and 96:
Raltegravir achieved virologic responses (using Not Completer=Failure approach) of HIV RNA <50 copies/mL in 61.7% of patients at Week 16, in 62.1% at Week 48 and in 57.0% at Week 96. Some patients experienced viral rebound between Week 16 and Week 96. Factors associated with failure include high baseline viral load and OBT that did not include at least one potent active agent.
The SWITCHMRK 1 & 2 (Protocols 032 & 033) studies evaluated HIV-infected patients receiving suppressive (screening HIV RNA <50 copies/mL; stable regimen >3 months) therapy with lopinavir 200 mg ( + ) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors and randomised them 1:1 to continue lopinavir ( + ) ritonavir 2 tablets twice daily (n=174 and n=178, respectively) or replace lopinavir ( + ) ritonavir with raltegravir 400 mg twice daily (n=174 and n=176, respectively). Patients with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited.
These studies were terminated after the primary efficacy analysis at Week 24 because they failed to demonstrate non-inferiority of raltegravir versus lopinavir ( + ) ritonavir. In both studies at Week 24, suppression of HIV RNA to less than 50 copies/mL was maintained in 84.4% of the raltegravir group versus 90.6% of the lopinavir ( + ) ritonavir group, (Non-completers = Failure). See section 4.4 regarding the need to administer raltegravir with two other active agents.
STARTMRK (multi-centre, randomised, double-blind, active-control trial) evaluated the safety and anti-retroviral activity of raltegravir 400 mg twice daily vs. efavirenz 600 mg at bedtime, in a combination with emtricitabine ( + ) tenofovir disoproxil fumarate, in treatment-naïve HIV-infected patients with HIV RNA >5,000 copies/mL. Randomisation was stratified by screening HIV RNA level (≤ 50,000 copies/mL; and >50,000 copies/mL) and by hepatitis B or C status (positive or negative).
Patient demographics (gender, age and race) and baseline characteristics were comparable between the group receiving raltegravir 400 mg twice daily and the group receiving efavirenz 600 mg at bedtime.
With respect to the primary efficacy endpoint, the proportion of patients achieving HIV RNA <50 copies/mL at Week 48 was 241/280 (86.1%) in the group receiving raltegravir and 230/281 (81.9%) in the group receiving efavirenz. The treatment difference (raltegravir-efavirenz) was 4.2% with an associated 95% CI of (-1.9, 10.3) establishing that raltegravir is non-inferior to efavirenz (pvalue for non-inferiority <0.001). At Week 240, the treatment difference (raltegravir – efavirenz) was 9.5% with an associated 95% CI of (1.7, 17.3). Week 48 and Week 240 outcomes for patients on the recommended dose of raltegravir 400 mg twice daily from STARTMRK are shown in Table 3.
Table 3. Efficacy Outcome at Weeks 48 and 240:
ONCEMRK (multi-centre, randomised, double-blind, active-control trial; Protocol 292) evaluated the safety and anti-retroviral activity of raltegravir 1,200 mg once daily + emtricitabine ( + ) tenofovir disoproxil fumarate vs. raltegravir 400 mg twice daily, in combination with emtricitabine ( + ) tenofovir disoproxil fumarate, in treatment-naïve HIV-infected patients with HIV RNA >1,000 copies/mL. Randomisation was stratified by screening HIV RNA level (≤100,000 copies/mL; and >100,000 copies/mL) and by hepatitis B or C status (positive or negative).
Patient demographics (gender, age and race) and baseline characteristics were comparable between the group receiving raltegravir 1,200 mg once daily and the group receiving raltegravir 400 mg twice daily.
With respect to the primary efficacy endpoint, the proportion of patients achieving HIV RNA <40 copies/mL at Week 48 was 472/531(88.9%) in the group receiving raltegravir 1,200 mg once daily and 235/266 (88.3%) in the group receiving raltegravir 400 mg twice daily. The treatment difference (raltegravir 1,200 mg once daily-raltegravir 400 mg twice daily) was 0.5% with an associated 95% CI of (-4.2, 5.2) establishing that raltegravir 1,200 mg once daily is non-inferior to raltegravir 400 mg twice daily.
At Week 96, the proportion of patients achieving HIV RNA <40 copies/mL was 433/531(81.5%) in the group receiving raltegravir 1,200 mg once daily and 213/266 (80.1%) in the group receiving raltegravir 400 mg twice daily. The treatment difference (raltegravir 1,200 mg once daily-raltegravir 400 mg twice daily) was 1.5% with an associated 95% CI of (-4.4, 7.3). Week 48 and Week 96 outcomes from ONCEMRK are shown in Table 4.
Table 4. Efficacy Outcome at Weeks 48 and 96:
As demonstrated in healthy volunteers administered single oral doses of raltegravir in the fasted state, raltegravir is rapidly absorbed with a Tmax of approximately 3 hours postdose. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1,600 mg. Raltegravir C12hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1,600 mg.
With twice-daily dosing, pharmacokinetic steady state is achieved rapidly, within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax and evidence of slight accumulation in C12hr. The absolute bioavailability of raltegravir has not been established.
Raltegravir 1,200 mg once daily is also rapidly absorbed with median Tmax ~1.5 to 2 hours in the fasted state and generates a sharper absorption peak with a tendency to higher Cmax in comparison to raltegravir twice daily (1 × 400 mg tablet twice daily). In addition, relative to the raltegravir 400 mg formulation the raltegravir 600 mg formulation used in the 1,200 mg (2 × 600 mg) once daily dosing regimen has higher relative bioavailability (by 21 to 66%). Once absorbed, both formulations of raltegravir exhibit similar systemic pharmacokinetics. In patients, after 1,200 mg once daily raltegravir dosing, steady state AUC0-24 was 53.7 h·μM, C24 was 75.6 nM, and median Tmax was 1.50 h.
Raltegravir 400 mg twice daily may be administered with or without food. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-infected patients. Administration of multiple doses of raltegravir following a moderate-fat meal did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13% relative to fasting. Raltegravir C12hr was 66% higher and Cmax was 5% higher following a moderate-fat meal compared to fasting. Administration of raltegravir following a high-fat meal increased AUC and Cmax by approximately 2-fold and increased C12hr by 4.1-fold. Administration of raltegravir following a low-fat meal decreased AUC and Cmax by 46% and 52%, respectively; C12hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.
Raltegravir 600 mg tablets (2 × 600 mg once daily) may be administered with or without food. A single dose food effect study demonstrated that the 1,200 mg once daily had similar or smaller food effects when studied under high-fat and low-fat meal conditions when compared to the 400 mg twice daily. Administration of a low fat meal with raltegravir 1,200 mg once daily resulted in a 42% decrease in AUC0-last, 52% decrease in Cmax, and 16% decrease in C24hr. Administration of a high fat meal resulted in a 1.9% increase in AUC0-last, 28% decrease in Cmax, and 12% decrease in C24hr.
Overall, considerable variability was observed in the pharmacokinetics of raltegravir. For observed C12hr in BENCHMRK 1 and 2 the coefficient of variation (CV) for inter-subject variability = 212% and the CV for intra-subject variability = 122%. Sources of variability may include differences in co-administration with food and concomitant medicines.
Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 µM.
Raltegravir readily crossed the placenta in rats, but did not penetrate the brain to any appreciable extent.
In two studies of HIV-1 infected patients who received raltegravir 400 mg twice daily, raltegravir was readily detected in the cerebrospinal fluid. In the first study (n=18), the median cerebrospinal fluid concentration was 5.8% (range 1 to 53.5%) of the corresponding plasma concentration. In the second study (n=16), the median cerebrospinal fluid concentration was 3% (range 1 to 61%) of the corresponding plasma concentration. These median proportions are approximately 3- to 6-fold lower than the free fraction of raltegravir in plasma.
The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in faeces and urine, respectively. In faeces, only raltegravir was present, most of which is likely to be derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.
In a comparison of 30 subjects with *28/*28 genotype to 27 subjects with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09) and the geometric mean ratio of C12hr was 1.91 (1.43, 2.55). Dose adjustment is not considered necessary in subjects with reduced UGT1A1 activity due to genetic polymorphism.
Based on a formulation comparison study in healthy adult volunteers, the chewable tablet and granules for oral suspension have higher oral bioavailability compared to the 400 mg tablet. In this study, administration of the chewable tablet with a high fat meal led to an average 6% decrease in AUC, 62% decrease in Cmax, and 188% increase in C12hr compared to administration in the fasted state. Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food. The effect of food on the granules for oral suspension formulation was not studied.
Table 5 displays pharmacokinetic parameters in the 400 mg tablet, the chewable tablet, and the granules for oral suspension, by body weight.
Table 5. Raltegravir Pharmacokinetic Parameters IMPAACT P1066 Following Administration of Doses in Section 4.2 (excluding neonates):
| 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, see dosing tables for the chewable tablet. | 9 | 22.1 (36%) | 113 (80%) |
| 11 to less than 25 kg | Chewable tablet | Weight based dosing, see dosing tables for the chewable tablet | 13 | 18.6 (68%) | 82 (123%) |
| 3 to less than 20 kg | Oral suspension | Weight based dosing, see dosing table for granules for oral suspension. | 19 | 24.5 (43%) | 113 (69%) |
* Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose.
† Geometric coefficient of variation.
There was no clinically meaningful effect of age on raltegravir pharmacokinetics over the age range studied with raltegravir 400 mg twice daily. There was no clinically meaningful effect of age on raltegravir pharmacokinetics over the age range studied in ONCEMRK with raltegravir 1,200 mg (2 × 600 mg) once daily.
There were no clinically important pharmacokinetic differences due to gender, race, ethnicity or body weight in adults for raltegravir 400 mg twice daily, and no clinically meaningful effect on raltegravir pharmacokinetics was concluded. For raltegravir 1,200 mg (2 × 600 mg) once daily, population PK analysis also demonstrated that the impacts of gender, race, ethnicity and body weight are not clinically meaningful.
Renal clearance of unchanged medicinal product is a minor pathway of elimination. In adults, there were no clinically important pharmacokinetic differences between patients with severe renal insufficiency and healthy subjects (see section 4.2 of the 400 mg twice daily SmPC). Because the extent to which raltegravir may be dialysable is unknown, dosing before a dialysis session should be avoided. No renal impairment study was conducted with raltegravir 1,200 mg once daily however, based on results with the 400 mg twice daily tablet, no clinically meaningful effect is anticipated.
Raltegravir is eliminated primarily by glucuronidation in the liver. In adults, there were no clinically important pharmacokinetic differences between patients with moderate hepatic insufficiency and healthy subjects. The effect of severe hepatic insufficiency on the pharmacokinetics of raltegravir has not been studied (see sections 4.2 and 4.4 of the 400 mg twice daily SmPC). No hepatic impairment study has been conducted with raltegravir 1,200 mg once daily, however, based on results with the 400 mg twice daily tablet, no clinically meaningful effect is expected for mild and moderate hepatic impairment.
Non-clinical toxicology studies, including conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, developmental toxicity and juvenile toxicity, have been conducted with raltegravir in mice, rats, dogs and rabbits. Effects at exposure levels sufficiently in excess of clinical exposure levels indicate no special hazard for humans.
No evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage and in vitro and in vivo chromosomal aberration studies.
A carcinogenicity study of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was similar to that at the clinical dose of 1,200 mg once daily. In rats, tumours (squamous cell carcinoma) of the nose/nasopharynx were identified at 300 and 600 mg/kg/day in females and at 300 mg/kg/day in males. This neoplasia could result from local deposition and/or aspiration of drug on the mucosa of the nose/nasopharynx during oral gavage dosing and subsequent chronic irritation and inflammation; it is likely that it is of limited relevance for the intended clinical use. At the NOAEL, systemic exposure was similar to that at the clinical dose of 1,200 mg once daily. Standard genotoxicity studies to evaluate mutagenicity and clastogenicity were negative.
Raltegravir was not teratogenic in developmental toxicity studies in rats and rabbits. A slight increase in incidence of supernumerary ribs, a variant in the normal developmental process, was observed in rat foetuses of dams exposed to raltegravir at approximately 4.4-fold human exposure at the recommended human dose (RHD) based on AUC0-24 hr. No development effects were seen at 3.4-fold human exposure at the RHD. Similar findings were not observed in rabbits.
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