Isentress HD

Isentress HD Mechanism of Action

raltegravir

Manufacturer:

MSD

Distributor:

Zuellig Pharma
Full Prescribing Info
Action
Therapeutic Class: ISENTRESS (raltegravir) is an HIV integrase strand transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1).
Pharmacology: Pharmacodynamics: Mechanism of Action: Raltegravir inhibits the catalytic activity of HIV 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 during the early phase of infection. 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 did not significantly inhibit human phosphoryltransferases including DNA polymerases α, β, and γ.
Clinical Studies: Description of Clinical Studies: Adults: The evidence of durable efficacy of ISENTRESS 400 mg twice daily is based on the analyses of 96-week data from 2 ongoing, randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019), in antiretroviral treatment-experienced HIV-1 infected adult patients, analysis of 240-week data from an ongoing, randomized, double-blind, active-control trial, STARTMRK (P021) evaluating ISENTRESS 400 mg twice daily in treatment-naïve adult patients, and analysis of 96-week data from a randomized, double-blind, active-control trial, ONCEMRK (P292) evaluating ISENTRESS 1200 mg (2 x 600 mg) once daily in treatment-naïve adult patients.
Treatment-Experienced Patients: BENCHMRK 1 and BENCHMRK 2 are Phase III studies to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg b.i.d. in combination with an optimized background therapy (OBT), versus OBT alone, 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 antiretroviral therapies. Randomization was stratified by degree of resistance to PI (1PI vs. >1PI) and the use of enfuvirtide in the OBT. Prior to randomization, OBT was selected by the investigator based on genotypic/phenotypic resistance testing and prior ART history.
Table 1 shows the demographic characteristics between patients in the group receiving ISENTRESS 400 mg b.i.d. and patients in the group receiving placebo. (See Table 1.)

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Table 2 compares the characteristics of optimized background therapy at baseline in the group receiving ISENTRESS 400 mg b.i.d. and patients in the control group. (See Table 2.)

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Week 48 and 96 outcomes for the 699 patients randomized and treated with the recommended dose of ISENTRESS 400 mg b.i.d. or comparator in the pooled BENCHMRK 1 and 2 studies are shown in Table 3. (See Table 3.)

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The percent (95% confidence interval) of patients achieving HIV RNA <50 copies/mL over time is displayed in Figure 1 as Non-Completer = Failure Approach (NC=F). (See Figure 1.)

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Virologic responses at week 96 by baseline genotypic and phenotypic sensitivity score are shown in Table 4. (See Table 4.)

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Switch of Suppressed Patients from Lopinavir (+) Ritonavir to Raltegravir: The SWITCHMRK 1 & 2 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 randomized 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-completer = Failure). In patients who had never experienced virological failure before study entry, similar virologic response rates were seen in the raltegravir and the lopinavir (+) ritonavir groups.
Treatment-Naïve Patients: STARTMRK (Protocol 021; ISENTRESS 400 mg twice daily) STARTMRK is a Phase III study to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg b.i.d. + emtricitabine (+) tenofovir disoproxil fumarate versus efavirenz + emtricitabine (+) tenofovir disoproxil fumarate in treatment-naïve HIV-infected patients with HIV RNA >5000 copies/mL. Randomization was stratified by screening HIV RNA level (≤50,000 copies/mL; and >50,000 copies/mL) and by hepatitis status.
Table 5 shows the demographic characteristics between patients in the group receiving ISENTRESS 400 mg b.i.d and patients in the group receiving efavirenz. (See Table 5.)

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With respect to the primary efficacy endpoint (based on a Non-Completer=Failure approach), the proportion (%) of patients achieving HIV RNA <50 copies/mL at Week 48 was 241/280 (86.1%) in the group receiving ISENTRESS and 230/281 (81.9%) in the group receiving efavirenz. The treatment difference (ISENTRESS-efavirenz) was 4.2% with an associated 95% CI of (-1.9, 10.3) establishing that ISENTRESS is non-inferior to efavirenz (p-value for non-inferiority <0.001). At Week 240, the treatment difference (ISENTRESS-efavirenz) was 9.5% with an associated 95% CI of (1.7, 17.3). Week 48 and 240 outcomes in STARTMRK are shown in Table 6. (See Table 6.)

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Figure 2 presents the proportion of patients with plasma HIV RNA <50 copies/mL over time by treatment group. Patients on ISENTRESS achieved viral suppression (HIV RNA <50 copies/mL) earlier than those receiving EFV. Through 240 weeks of treatment 71% in the group receiving ISENTRESS 400 mg b.i.d. and 61% in the comparator group achieved HIV RNA <50 copies/mL (NC=F approach). (See Figure 2.)

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In the STARTMRK trial of combination antiretroviral therapy in treatment-naive patients, ISENTRESS with emtricitabine (+) tenofovir disoproxil fumarate demonstrated consistent virologic and immunologic efficacy relative to efavirenz with emtricitabine (+) tenofovir disoproxil fumarate across demographic and baseline prognostic factors, including: baseline plasma HIV RNA level >100,000 copies/mL, baseline CD4 cells ≤50 cells/mm3, demographic groups (including age, gender, region, and race), viral hepatitis co-infection status (hepatitis B and/or C) and viral subtypes (comparing non-clade B as a group to clade B).
Consistent efficacy of ISENTRESS was observed in all HIV subtypes with 89.6% (155/173) and 87.0% (40/46) of patients with B and non-B subtypes respectively, achieving HIV RNA <50copies/mL at week 240 (OF approach).
ONCEMRK (Protocol 292; ISENTRESS 1200 mg [2 x 600 mg] once daily): ONCEMRK is a Phase III study to evaluate the safety and antiretroviral activity of ISENTRESS 1200 mg (2 x 600 mg) once daily versus ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naïve HIV-infected patients with HIV RNA ≥ 1000 copies/mL. Randomization was stratified by screening HIV RNA level (≤100,000 copies/mL; and >100,000 copies/mL) and by hepatitis status.
Table 7 shows the demographic characteristics for both treatment groups. (See Table 7.)

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The ISENTRESS 1200 mg (2 x 600 mg) once daily regimen was non-inferior to the ISENTRESS 400 mg twice daily regimen at both Weeks 48 and 96. At Week 48, 88.9% versus 88.3% of once-daily and twice-daily patients, respectively had HIV RNA <40 copies/mL. At Week 96, 81.5% versus 80.1% of once-daily and twice-daily patients, respectively had HIV RNA <40 copies/mL. A summary of antiretroviral response and immunologic effect at Week 48 and Week 96 is shown in Table 8. (See Table 8.)

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Virologic outcomes by the Snapshot Approach at Week 48 and Week 96 are shown in Table 9. (See Table 9.)

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Figure 3 presents the proportion of patients with HIV RNA <40 copies/mL over time by treatment group. Through 96 weeks of treatment 81.5% in the group receiving ISENTRESS 1200 mg (2 x 600 mg) once daily and 80.1% in the group receiving ISENTRESS 400 mg twice daily achieved HIV RNA <40 copies/mL (NC=F approach). (See Figure 3.)

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In the ONCEMRK trial, ISENTRESS 1200 mg (2 x 600 mg) once daily demonstrated consistent virologic and immunologic efficacy relative to ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, across demographic and baseline prognostic factors, including: baseline HIV RNA levels >100,000 copies/mL and >500,000 copies/mL, baseline CD4 cells ≤50 cells/mm3, demographic groups (including age, gender, race, ethnicity and region), viral hepatitis co-infection status (hepatitis B and/or C), concomitant proton pump inhibitors/H2 blockers use and viral subtypes (comparing non-clade B as a group to clade B).
Consistent efficacy in patients receiving ISENTRESS 1200 mg (2 x 600 mg) once daily was observed across HIV subtypes with 90.0% (270/300) and 89.5% (162/181) of patients with B and non-B subtypes, respectively, achieving HIV RNA <40 copies/mL at week 96 (OF approach).
Pediatric Patients: IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled 126 treatment experienced children and adolescents 2 to 18 years of age. Patients were stratified by age, enrolling adolescents first and then successively younger children. Patients received either the 400 mg tablet formulation (6 to 18 years of age) or the chewable tablet formulation (2 to less than 12 years of age). Raltegravir was administered with an optimized background regimen.
The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based upon achieving similar raltegravir plasma exposure and trough concentration as seen in adults, and acceptable short term safety. After dose selection, additional patients were enrolled for evaluation of long term safety, tolerability and efficacy. Of the 126 patients, 96 received the recommended dose of ISENTRESS (see Dosage & Administration).
These 96 patients had a median age of 13 (range 2 to 18) years, were 51% Female, 34% Caucasian, and 59% Black. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL, median CD4 cell count was 481 cells/mm3 (range: 0 - 2361) and median CD4% was 23.3% (range: 0 - 44). Overall, 8% had baseline plasma HIV-1 RNA >100,000 copies/mL and 59% had a CDC HIV clinical classification of category B or C. Most patients had previously used at least one NNRTI (78%) or one PI (83%).
Ninety-three (97%) patients 2 to 18 years of age completed 24 weeks of treatment (3 discontinued due to non-compliance). At Week 24, 72% achieved ≥1 log10 HIV RNA drop from baseline or <400 copies/mL; 54% achieved HIV RNA <50 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 119 cells/mm3 (3.8%).
Seventy-two (95%) patients 6 to 18 years of age completed 48 weeks of treatment (4 discontinued due to non-compliance). At Week 48, 77% achieved ≥1 log10 HIV RNA drop from baseline or <400 copies/mL; 56% achieved HIV RNA <50 copies/mL. The mean CD4 count (percent) increase from baseline to Week 48 was 155 cells/mm3 (4.7%).
Pharmacokinetics: Absorption - Adults: As demonstrated in healthy volunteers administered single oral doses of raltegravir (400 mg film coated tablet) in the fasted state, raltegravir 400 mg twice daily is rapidly absorbed with a Tmax of approximately 3 hours postdose in the fasted state. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1600 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 1600 mg. In patients on 400 mg twice daily monotherapy, raltegravir drug exposures were characterized by a geometric mean AUC0-12hr of 14.3 μM•hr and C12hr of 142 nM. 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 1200 mg (2 x 600 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 x 400 mg tablet twice daily). In addition, relative to the raltegravir 400 mg formulation the raltegravir 600 mg formulation used in the 1200 mg (2 x 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 1200 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. Steady-state is generally reached in 2 days, with little to no accumulation with multiple dose administration.
Effect of Food on Oral Absorption: ISENTRESS 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.
The effect of consumption of low-, moderate- and high-fat meals on steady-state raltegravir pharmacokinetics was assessed in healthy volunteers. Administration of multiple doses of 400 mg twice daily 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 400 mg twice daily raltegravir following a high-fat meal increased AUC and Cmax by approximately 2-fold and increased C12hr by 4.1-fold. Administration of 400 mg twice daily 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.
A single dose food effect study demonstrated that 1200 mg (2 x 600 mg) once daily had similar or smaller food effects when studied under high-fat and low-fat meal conditions when compared to 400 mg twice daily. Administration of a low fat meal with ISENTRESS 1200 mg (2 x 600 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.
Distribution - Adults: 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.
Metabolism and Excretion - Adults: 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 feces and urine, respectively. In feces, only raltegravir was present, most of which is likely 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.
Characteristics in Patients: Gender: A study of the pharmacokinetics of raltegravir 400 mg twice daily was performed in young adult healthy males and females. Additionally, the effect of gender was evaluated in a composite analysis of pharmacokinetic data from 103 healthy subjects and 28 HIV patients receiving raltegravir monotherapy with fasted administration. The effect of gender was also evaluated in a population pharmacokinetic (PK) analysis of concentration data from 80 healthy subjects and HIV patients receiving raltegravir alone or in combination with other drugs and in fasted and fed conditions. There were no clinically important pharmacokinetic differences due to gender. For raltegravir 1200 mg (2 x 600 mg) once daily, based on population pharmacokinetic analysis, there were no clinically important pharmacokinetic differences due to gender. No dosage adjustment is necessary.
Age: The effect of age (18 years and older) on the pharmacokinetics of raltegravir was evaluated in the composite analysis and the population PK analysis. There was no clinically meaningful effect of age on raltegravir pharmacokinetics. No dosage adjustment is necessary.
Pediatric: Based on a formulation comparison study in healthy adult volunteers, the chewable tablet has 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 doses recommended for HIV-infected children and adolescents 2 to 18 years of age (see Dosage & Administration) resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily. Table 10 displays pharmacokinetic parameters in the 400 mg tablet (6 to 18 years of age) and the chewable tablet (2 to less than 12 years of age), by body weight. (See Table 10.)

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The pharmacokinetics of raltegravir as 400 mg tablets in children less than 6 years of age has not been established. The pharmacokinetics of raltegravir chewable tablets in children less than 2 years of age has not been established.
ISENTRESS 1200 mg (2 x 600 mg) once daily was not evaluated in a pediatric clinical study, however, population PK modeling and simulation analyses were conducted. Given that all the pediatric simulated exposures are within the adult exposures observed from Phase III ONCEMRK (Protocol 292), and that there are no safety concerns at the same exposure values, a weight cutoff of 40 kg is deemed adequate to achieve a safe administration of ISENTRESS 1200 mg (2 x 600 mg) once daily while maintaining clinical efficacy. These results support the use of ISENTRESS 1200 mg (2 x 600 mg) once daily in pediatric patients weighing at least 40 kg.
Race and Ethnicity: The effect of race on the pharmacokinetics of raltegravir was evaluated in the composite analysis for ISENTRESS 400 mg twice daily, and no clinically meaningful effect of race on raltegravir pharmacokinetics was concluded. For ISENTRESS 1200 mg (2 x 600 mg) once daily, population PK analysis also demonstrated that the impacts of race and ethnicity are not clinically meaningful. No dosage adjustment is necessary.
Body Mass Index (BMI) and Body Weight: The composite analysis assessed the effect of BMI on the pharmacokinetics of raltegravir in adults. There was no clinically meaningful effect of BMI on raltegravir pharmacokinetics. Additionally, no clinically meaningful effect of body weight on raltegravir pharmacokinetics was identified in the population PK analysis for both ISENTRESS 400 mg twice daily and ISENTRESS 1200 mg (2 x 600 mg) once daily. No dosage adjustment is necessary.
Hepatic Insufficiency: Raltegravir is eliminated primarily by glucuronidation in the liver. A study of the pharmacokinetics of raltegravir was performed in adult patients with moderate hepatic insufficiency. Additionally, hepatic insufficiency was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between patients with moderate hepatic insufficiency and healthy subjects. No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency. No hepatic impairment study has been conducted with ISENTRESS 1200 mg (2 x 600 mg) once daily; however, based on results with ISENTRESS 400 mg twice daily tablet, no clinically meaningful effect is expected for mild and moderate hepatic impairment. The effect of severe hepatic insufficiency on the pharmacokinetics of raltegravir has not been studied. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment.
Renal Insufficiency: Renal clearance of unchanged drug is a minor pathway of elimination. A study of the pharmacokinetics of raltegravir was performed in adult patients with severe renal insufficiency. Additionally, renal insufficiency was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between patients with severe renal insufficiency and healthy subjects. No dosage adjustment is necessary. No renal impairment study was conducted with ISENTRESS 1200 mg (2 x 600 mg) once daily; however, based on results with ISENTRESS 400 mg twice daily tablet, no clinically meaningful effect is anticipated. Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided.
UGT1A1 Polymorphism: There is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinically meaningful extent. In a comparison of 30 adult subjects with *28/*28 genotype (associated with reduced activity of UGT1A1) to 27 adult subjects with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09).
Microbiology: Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (IC95) of viral spread (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 at concentrations of 6 to 50 nM resulted in 95% inhibition of viral spread 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. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (IC95 = 6 nM). Additive to synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with nucleoside analog reverse transcriptase inhibitors (zidovudine, zalcitabine, stavudine, abacavir, tenofovir disoproxil fumarate, didanosine, or lamivudine); non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine, or delavirdine); protease inhibitors (indinavir, saquinavir, ritonavir, amprenavir, lopinavir, nelfinavir, or atazanavir); or the entry inhibitor enfuvirtide.
Drug Resistance: The mutations observed in HIV-1 integrase that contributed to raltegravir resistance (evolved either in vitro or in patients treated with raltegravir) generally included a substitution at either Y143 (changed to C, H or R) or Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional mutations (e.g., L74I/M, E92Q, Q95K/R, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230R, and D232N). E92Q and F121C are occasionally seen in the absence of substitutions at Y143, Q148, or N155 in raltegravir-treatment failure subjects.
Recombinant viruses containing a single primary mutation (Q148H, K or R, or N155H) displayed decreased replication capacity and reduced susceptibility to raltegravir in vitro. Secondary mutations further decreased susceptibility to raltegravir and sometimes acted as compensatory mutations for viral replication capacity.
Treatment-Naïve Adult Subjects: By Week 240 in the STARTMRK trial, the primary raltegravir resistance-associated substitutions were observed in 4 (2 with Y143H/R and 2 with Q148H/R) of the 23 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates.
Treatment-Experienced Adult Subjects: By Week 96 in the BENCHMRK trials, at least one of the primary raltegravir resistance-associated substitutions, Y143C/H/R, Q148H/K/R, and N155H, was observed in 76 of the 112 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. The emergence of the primary raltegravir resistance-associated substitutions was observed cumulatively in 70 subjects by Week 48 and 78 subjects by Week 96, 15.2% and 17% of the raltegravir recipients, respectively. Some (n=58) of those HIV-1 isolates harboring one or more of the primary raltegravir resistance-associated substitutions were evaluated for raltegravir susceptibility yielding a median decrease of 26.3-fold (mean 48.9 ± 44.8-fold decrease, ranging from 0.8- to 159-fold) compared to the wild-type reference.
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 harboring a mutation at amino acid 148, along with one or more other raltegravir resistance mutations, may also have clinically significant resistance to dolutegravir.
Cardiac Electrophysiology: In a randomized, placebo-controlled, crossover study, 31 healthy subjects were administered a single oral supratherapeutic dose of raltegravir 1600 mg and placebo. There was no effect on the QTc interval. Peak raltegravir plasma concentrations were approximately 4-fold higher than the peak concentrations following a 400-mg dose.
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