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Raltegravir PK, safety, efficacy, tolerability, interactions, special populations, phase III, mechanism of action, resistance, food effect- From Merck Briefing Document
 
 
  "For any new antiviral drug, maximum efficacy is expected when the drug is administered with other potent antiretroviral agents to which patient viruses are sensitive. In contrast, administration of a new drug in combination with other drugs to which patient viruses are already resistant increases the chance that resistance will develop to the new drug, resulting in virologic failure."
 
After 16 weeks in phase III in treatment-experienced patients 61.3% had <50 copies/ml compared to 34.6% in placebo arm (see Table 5 below). The viral load reduction was a mean -1.88 log in the raltegravir arm. Mean CD4 increase was 84. Viralogic failure was: non-respomder 2.8% vs 32.9% in placebo arm; 12.3% rebounded in raltegravir arm vs 17.7% in placebo. Discontinuation due to clinical adverse event: 1.5% in raltegravir arm, 2.1% in placebo; due to lab adverse event: 0.2% in raltegravir, 0.0% in placebo. Disct due to other reasons: 1.3% in ralt, 0.4% in placebo. Numbers are similar after 24 weeks.
 
Raltegravir 400 mg b.i.d. in combination with TFV and 3TC does not increase fasting serum cholesterol, LDL- cholesterol, or triglyceride levels based upon post hoc analysis of serum lipids (Table 10). Results for other doses (100, 200, 600 mg, all b.i.d.) were similar. After 24 weeks of taking raltegravir total cholesterol changed by -2.2% (% change in lipids), LDL by 0.4%, triglycerides by 2%, HDL 7.2%; after 48 weeks: total cholesterol by 1.4%, LDL by 4.2%, HDL by 14.3%, triglycerides by 2.7%.. For efavirenz, total cholesterol changed by 13.4%, LDL by 3.1%, HDL 30%, triglycerides by 45.2%.
 

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Malignancy Conclusions
• In the original application, an imbalance in rates of malignancies was noted. The malignancy types and rates in the raltegravir group are those anticipated in a severely immunodeficient HIV/AIDS population and are consistent with reported rates in the literature. A history of malignancy prior to enrollment was common and many of the malignancies in the raltegravir group were likely present at time of study entry or were recurrences of prior diagnosed malignancies.
• Based on an updated analysis of the same study cohorts, the imbalance in rates of malignancies has not been sustained with additional follow-up. This is consistent with the possibility that the original imbalance was a function of small numbers of cases and relatively imprecise estimates of rates.
• While the updated analysis is reassuring, the total amount of safety follow-up is limited and additional data are needed. Further follow-up is proposed in the Risk Management Plan.
 
Lipodystrophy/lipoatrophy
In treatment-experienced patients receiving raltegravir 400 mg b.i.d. or placebo (each with OBT) from Protocol 005 (treatment-experienced) and the Phase III studies, the frequency of treatment emergent lipodystrophy or lipoatrophy reported as adverse experiences was low (<1%) in both treatment groups. Previous history prior to study enrollment was relatively common for lipodystrophy and lipoatrophy, 27.4% and 12.0%, respectively.
 
In Protocol 004 (treatment-naive), body circumference measurements over time were performed. These measurements were found to be similar among treatment groups over 48 weeks. Body circumference measurements in Protocol 005 also showed similar trends in the raltegravir plus OBT groups and the placebo plus OBT groups.
 
In summary, available data do not suggest that raltegravir is associated with lipodystrophy or lipoatrophy.
 
Rash
The proportion of patients with rash (including terms of rash, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, and rash pruritic) was 6.7% (34/507) for the raltegravir group and 3.9% (11/282) for the placebo group. There were no discontinuations due to rash, and no rashes were reported as serious in either treatment group. Several patients reported more than one rash (3 in the raltegravir group and 1 in the placebo group). In the raltegravir group, the intensity of rash was mild-moderate for most patients (33 of 34 or 97.1%) and most patients (25 of 34 or 73.5%) recovered from rash. In the placebo group all rashes were mild to moderate, and most patients (8 of 11 or 72.7%) recovered from rash. It should be noted that the many of the patients in the raltegravir group who had rash (23 of 34 or 67.6%) were taking two or more concomitant medication commonly associated with rash, such as atovaquone, sulfadiazine, sulfamethoxazole + trimethoprim, or OBTs associated with rash such as abacavir, amprenavir, atazanavir, darunavir, efavirenz, fosamprenavir, and tipranavir; in the placebo group 3 of 11 patients (27.3%) used 2 or more of these agents. Interestingly, when comparing the incidence of drug-related rash (and related terms as delineated above) between the raltegravir and placebo arms, the difference in incidence noted above was not seen, with drug related rash being reported in 2.0% (10/507) of the raltegravir arm and 2.5% (7/282) of the placebo arm.
 
Overall, while rash occurred somewhat more frequently in the raltegravir group than in the placebo group, it was generally benign and did not limit study therapy.
 
Immune Reconstitution Syndrome
Immune Reconstitution Syndrome (IRS) has been reported with highly active antiretroviral therapy regimens. There were 3 patients receiving raltegravir for whom IRS was reported as an adverse experience; 2 patients in the raltegravir treatment group in the double-blind cohort, and 1 patient in the OLPVF phase who was originally randomized to placebo. Only the patient in the OLPVF phase had IRS recorded as being drug-related. All 3 cases were considered serious adverse experiences. Study therapy was interrupted for 1 patient in the double-blind phase. Two (2) patients had recovered from the IRS, but the IRS was still listed as ongoing for 1 patient, at the time of the database freeze. The occurrence of IRS in this study population is not unexpected in light of the prompt and potent antiretroviral response observed in the raltegravir treatment group in highly immunodeficient patients.
 
The most frequently reported (incidence ≥2% in one treatment group) overall drug-related clinical adverse experiences of moderate or severe intensity were:
• Diarrhea: in 3.7% (19/507) of patients in the raltegravir group compared to 3.5%
(10/282) of patients in the placebo group.
• Nausea: in 2.2% (11/507) of patients in the raltegravir group compared to 3.2% (9/282) of patients in the placebo group.
• Injection-site reaction related to enfuvirtide use: in 2.4% (12/507) of patients in the raltegravir group compared to 2.8% (8/282) of patients in the placebo group.
• Headache: in 2.2% (11/507) of patients in the raltegravir group compared to 1.4% (4/282) of patients in the placebo group.
 

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Safety Conclusions
1. In treatment-experienced patients failing antiretroviral therapy with triple-class resistant HIV, raltegravir 400 mg b.i.d. administered in combination with Optimized Background Therapy (OBT), as compared to placebo in combination with OBT:
• is generally well tolerated
• does not appear to be associated with lipodystrophy or lipoatrophy
• is generally well tolerated irrespective of gender and race
• is generally well tolerated in patients with active hepatitis B and/or hepatitis C
co-infection.
 
2. In antiretroviral treatment-naive patients, raltegravir when administered with tenofovir and lamivudine, as compared with efavirenz plus tenofovir and lamivudine over 48 weeks of treatment:
• has a generally similar safety profile
• has no adverse effect on fasting lipids.
 
3. In dose-ranging Phase II studies, and in patients using tenofovir and/or atazanavir in OBT, there is no evidence that higher doses or higher exposure due to drug-drug interactions lead to increased drug toxicity.
 
4. In the original application, an imbalance in the rates of malignancies was noted. However, based on an updated analysis of the same study cohorts, the imbalance in the rates of malignancies has not been sustained with further follow-up.
 
5. However, the total amount of safety follow-up is limited, and additional data are needed. Further follow-up is proposed in the Risk Management Plan.
 
Safety Issues Evaluated in Pre-clinical Studies
Extensive pre-clinical studies, conducted to evaluate the non-clinical safety of raltegravir, have demonstrated the antiviral properties of raltegravir and have demonstrated that raltegravir is well tolerated in several animal species. Specific observations of note include:
• Negative genotoxicity studies evaluating mutagenicity and clastogenicity.
• Well tolerated in long-term chronic preclinical animal safety studies at several
exposure multiples over the recommended clinical dose.
• Identification of hepatotoxicity in preclinical studies occurred only after administration of high intravenous doses which produced AUC and Cmax values in animals which were 23-fold and 71-fold, respectively, greater than human AUC and Cmax values at the recommended dose. • In ongoing 105 week animal carcinogenicity studies, squamous cell carcinoma of the nose/nasopharynx was identified in 3 high-dose rats (see Section 4.5.2). These neoplasms are considered to result from local deposition and/or aspiration of drug on the mucosa of the nose/nasopharynx during dosing and are considered an expected consequence of chronic irritation and inflammation. In addition, a single nasal chondrosarcoma was observed in one mid-dose rat and likely resulted also from topic chronic irritation. All other carcinogenicity studies were within historical incidence ranges for spontaneous occurrences. These observations are considered to have little relevance to humans when raltegravir is taken orally as prescribed.
 
Discussion of other Potential Safety Concerns
Summary of Aminotransferase (ALT/AST) Elevations

As discussed above, in the treatment-experienced raltegravir 400 mg b.i.d. cohort, laboratory adverse experiences of increased serum ALT and increased serum AST were reported in 4.5% (23/507) and 4.3% (22/507) of patients, respectively, in the raltegravir group compared with 2.1% (6/282) and 2.5% (7/282) of patients, respectively, in the placebo group. In this cohort, overall drug-related laboratory adverse experiences of increased ALT and increased AST were reported in 3.2% (16/507) and 2.6% (13/507), respectively, of patients in the raltegravir group compared with 0.7% (2/282) and 1.1% (3/282), respectively, of patients in the placebo group. In terms of the predefined limits of change for the treatment-experienced raltegravir 400 mg b.i.d. cohort, serum ALT and AST increases were generally similar in the raltegravir group compared with the placebo group (Appendix 22).
 
Of note, the percentages of patients experiencing AST and/or ALT elevations were low in this treatment experienced population on combination therapy. In addition, these AST and/or ALT elevations generally did not limit study therapy in either the raltegravir group or the placebo group. Furthermore, the aminotransferase elevations were usually transient, resolved with or without interruption of therapy, and did not recur when therapy was re-introduced.
 
Patients with Hepatitis B and/or C Virus Co-infection
Overall, raltegravir was generally well tolerated in patients with hepatitis B and/or C coinfection.
 
In general, patients with hepatitis B and/or C virus co-infection had similar clinical and laboratory adverse experience profiles in both treatment groups as the complement population (patients without hepatitis B and/or C), including for rates of overall adverse experiences, drug-related adverse experiences, and serious adverse experiences. Discontinuations due to adverse experiences were infrequent in all groups. Specifically, hepatobiliary disorders such as hepatitis and jaundice were seen with low and similar frequencies in the 2 populations and in both treatment groups. Additionally, the remainder of the clinical adverse experience profile was similar in the 2 populations and for both treatment groups.
 
Laboratory adverse experiences were also generally similar in both populations and in the 2 treatment groups. Specifically, adverse experiences of increased ALT and AST were marginally higher in both treatment groups for patients with hepatitis B and/or C virus co-infection compared with the hepatitis uninfected (complement) groups but similar in both treatment groups: in patients with hepatitis B and/or C co-infection, adverse experiences of increased ALT and AST were 5.1% and 7.7%, respectively, for the raltegravir group and 5.1% and 5.1%, respectively, for the placebo group.
 
With respect to predefined limits of change for ALT and AST, there appeared to be somewhat higher rates of Grade 1 or higher elevations for the population with hepatitis B and/or C virus coinfection, as compared to the complement group, but the raltegravir and placebo treatment groups were again comparable. Grades 3 and 4 abnormalities were uncommon in both populations and similar in both treatment groups.
 
Summary of Elevations in Creatine Phosphokinase (CPK)
In the treatment-experienced raltegravir 400 mg b.i.d. cohort, laboratory adverse experiences of increased CPK were reported in 3.2% (16/507) of patients in the raltegravir group compared with 0.7% (2/282) of patients in the placebo group. In this cohort, overall drug-related laboratory adverse experiences of increased CPK were reported in 0.8% (4/507) of patients in the raltegravir group compared with 0.7% (2/282) of patients in the placebo group. There were no serious adverse experiences of increased CPK and no patients discontinued therapy due to increased CPK. Many of these elevations were isolated increases that returned to normal with time and elevations for several patients were noted by the investigators to be related to physical exercise.
 
For the Phase III studies, CPK increases were also evaluated for associated clinical adverse experiences. In Protocol 018, no patients with laboratory adverse experiences of increased CPK had associated clinical adverse experiences (e.g., myopathy or rhabdomyolysis). In Protocol 019, one patient in the raltegravir group (AN 15079) had elevated CPK reported as a laboratory adverse experience temporally associated with a clinical adverse experience of myositis, which was considered by the investigator to be due to ritonavir in OBT. The ritonavir dosage was reduced while raltegravir was continued, and the next CPK result (performed 13 days later) had returned to baseline. Another Protocol 019 patient, AN 16272 in the raltegravir group, had elevated (Grade 3) CPK results temporally associated with a clinical adverse experience myalgia. The myalgia was not considered by the investigator to be drug-related and the patients continued on study therapy.
 
In summary, the occurrence of CPK elevations, while slightly more common in the raltegravir group than in the placebo group, were generally transient, were not associated with clinically significant adverse experiences, and did not limit therapy. In at least some cases, the CPK elevations observed appeared to be due to increased physical exercise.
 
Summary of Safety Issues Evaluated in Clinical Studies
In considering the safety profile of raltegravir, it is important to consider the study population and the duration of exposure to raltegravir during the clinical development program. There were a total of 8754 persons exposed to raltegravir in Phase II and III studies (representing 536.6 person-years of exposure-See Section 6.2.3 for comparison of exposure versus duration of follow-up/time at risk). Raltegravir has been studied indifferent demographic groups and populations including in patients with hepatitis B virus and/or C virus co-infection; there is very limited data in the pediatric population (adolescents age 16 and older were eligible for Phase II studies) and elderly patients (above 65 years of age). There is no experience with raltegravir in pregnant or lactating females, patients with extreme hepatic dysfunction (AST, ALT, and/or alkaline phosphatase ≥5 times the upper limit of normal), and patients with severe renal insufficiency (serum creatinine ≥ 2 times the upper limit of normal) or urinary obstructive disease. While extensive efforts were made to enroll higher percentages of patients of different races and genders, there was a predominance of whites (62%) and males (86%) exposed to raltegravir in clinical trials. Nevertheless, the safety profile of raltegravir was consistent among these different demographic groups and populations studied. Raltegravir was generally well tolerated. Upon detailed review of the clinical safety database and taking into account adverse event profiles seen in heavily treatment experienced HIV-infected patients, several issues of interest were identified:
 
• Immune reconstitution inflammatory syndrome (IRS): IRS has been described in patients initiating ART, generally within the first 2 to 3 months of therapy, and is an expected consequence of effective antiretroviral therapy. As one would anticipate given the demonstrated potency of raltegravir-based regimens, events of IRS were reported in patients receiving raltegravir.
 
• Viral resistance: Development of resistance by HIV during treatment has been described with all antiretroviral agents, particularly with monotherapy, either as a single agent or in the setting of functional monotherapy in an inadequate combination regimen. HIV from patients failing raltegravir-based regimens demonstrated mutations in the integrase gene. It is of particular importance to note, however, that the best response rates with raltegravir-based therapies occurred when raltegravir was combined with at least one other potent active agent.
 
• Malignancies: Patients with AIDS are at high risk of developing malignancies, including AIDS-defining and non-AIDS-defining malignancies. In the Phase II and Phase III studies, a numerically higher number of malignancies were noted in patients receiving raltegravir in comparison to those receiving control study medications. The malignancies reported were consistent with the types anticipated in this highly immunodeficient population. For malignancies for which published rates in the HIV population are available, the observed rates of individual malignancies among raltegravir groups are similar to previously published rates. Furthermore, the overall rate of malignancies did not increase with increased duration of treatment. Several of the malignancies represented recurrences of previously diagnosed cases. Many of the malignancies were identified within 3 months after study entry, suggesting the cancers were preexisting conditions. More importantly, based on an updated analysis of the same study cohorts, the imbalance in the rates of malignancies has not been sustained with additional follow-up. Overall, based on a complete review of the data, there is no evidence of a direct drug relationship for these events.
 
• Drug-Drug interactions: HIV-infected patients are treated with a multitude of medications. In preclinical and clinical investigation, the major pathway of metabolism of raltegravir involves glucuronidation, primarily by UGT1A1. Based on in vitro and in vivo data, raltegravir has very low potential to produce clinically significant changes in levels of other drugs. Drugs that are potent inducers and inhibitors of UGT1A1 were assessed in a number of drug interaction studies with raltegravir and demonstrated that, in general, effects were slight to modest in degree and not considered to be clinically meaningful. Rifampin, a potent inducer of drug metabolizing enzymes, resulted in a modest decrease in raltegravir levels; however, based on the extent of the effect, it is recommended as a conservative measure to consider a dose increase of raltegravir to 800 mg twice daily when co administered with rifampin and the similarly potent broad inducers phenytoin and phenobarbital. Clinical trial data demonstrated that raltegravir has broad therapeutic efficacy with potent efficacy across all doses studied including in the presence of inducers and inhibitors of UGT1A1. Similarly, no dose limiting toxicities were identified including in the presence of inhibitors of UGT1A1. With the exception of rifampin, phenytoin, and phenobarbital, no dose adjustment of raltegravir is required in combination with other drugs.
 
EFFICACY
 
Efficacy by Darunavir, Enfuvirtide, and Darunavir Plus Enfuvirtide

Additional analyses to evaluate the effect of more recently available ART used in OBT were performed. The efficacy analysis by darunavir, enfuvirtide, and darunavir plus enfuvirtide use in OBT demonstrated that raltegravir had potent efficacy as compared to placebo across all subgroups (see Table 6 and Figure 14). In fact, when patients in the raltegravir group had first use of both darunavir and enfuvirtide, 98% achieved HIV RNA <400 copies/mL at Week 16 (vs 87% in placebo). These data suggest that while raltegravir demonstrates potent efficacy in patients with few or no fully active agents for use in OBT, best overall treatment responses may be seen when raltegravir is used in combination with 1 or 2 newer active antiretrovirals such as enfuvirtide and/or darunavir. 90% of Fuzeon-naive patients using Fuzeon but not darunavir achieved <400 c/ml. 90% of patients Darunavir-naive and not using Fuzeon achieved <400 c/ml.
 

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Efficacy by Tipranavir Use
In light of the potential inductive effect of tipranavir on the pharmacokinetics of raltegravir, analysis of tipranavir use in the Phase III studies was undertaken (See Table 7 and Figure 15). Raltegravir demonstrated potent efficacy as compared to placebo regardless of whether or not tipranavir was used as part of OBT. In patients with genotypically tipranavir sensitive HIV, 86% of patients receiving raltegravir achieved HIV RNA<400 copies/mL as compared to 48% of patients receiving placebo. The evaluation of raltegravir in patients utilizing tipranavir in the setting of tipranavir-resistant HIV represents a strict test of the impact of the pharmacokinetic interaction between tipranavir and raltegravir because in these patients tipranavir would not be predicted to be adding substantive antiretroviral efficacy into the regimen and would modestly reduce raltegravir levels; 56% of genotypically tipranavir resistant patients on raltegravir versus 26% on placebo achieved HIV RNA <400 copies/mL. The response rates were lower in both groups as one would anticipate because tipranavir was not active in the regimen and no other protease inhibitor would likely be used in a tipranavir containing OBT. Despite this, the magnitude of the treatment effect versus placebo was preserved in the raltegravir group. Overall, these data support that the impact of tipranavir on raltegravir PK is unlikely to be clinically significant in the setting of combination therapy.
 
Efficacy in Special Populations
Efficacy analyses by gender, race, viral subtype (B versus non-B clade), and geographic region demonstrated potent efficacy of raltegravir as compared to placebo and this efficacy did not appear different in any of the subgroups analyzed (Figure 16). Given the limited number of patients 65 years or older studied (N=9), assessment of efficacy of raltegravir in this patient population could not be made. There were no data in the pediatric patient population (age <16) and no data in pregnant HIV-infected women. Appendix 13, Appendix 14, and Appendix 15 contain the supporting data.
 
Efficacy in Phase III (Protocol 018 and Protocol 019)
The individual Phase III studies, Protocols 018 and 019 (treatment-experienced), each confirmed the superiority of raltegravir 400 mg b.i.d. in combination with OBT as compared to placebo, through at least Week 16 (100% of patients enrolled), with confirmatory data available for the ∼60% of patients who had reached Week 24 as of 13-Dec-06, the cut-off used for the original application. After the original application, Week 24 data for all patients was available, and was supplied to the FDA. With the agreement with the FDA, Week 24 data for all patients are also provided in this document, though these data were not reviewed by the FDA as part of the original application.
 
Figure 9 displays the percent of patients achieving HIV RNA <400 copies/mL, HIV RNA <50 copies/mL and the change from baseline CD4 cell count for Protocol 018 and for Protocol 019 individually. Approximately 75% of patients in both studies achieved HIV RNA <400 copies/mL and approximately 60% of patients in both studies achieved HIV RNA<50 copies/mL by Week 16 and this was maintained through Week 24, in the NC=F analyses. At Week 16, which is the primary time point for efficacy analysis, raltegravir was found to be superior to placebo (p<0.001) in both studies.
 
Patient Demographics: Overview and Relevance of the Patient Population
Figure 10 displays the accounting of all screened patients in Protocols 018 and 019 combined. Of the 1012 patients screened 309 did not meet one or more entry criteria. Most of the screening failures were due either to an HIV RNA level below the study cutoff of 1000 copies/mL, or to a lack of documented resistance to at least 1 agent in each of the 3 classes NRTI, NNRTI, and PI. Of the 703 patients randomized, 699 received at least one dose of study medication. A high proportion of patients randomized to the raltegravir arm (413/462; 89%) remained in the double blind phase through the frozen file. A substantially lower proportion of patients randomized to the placebo arm (145/237; 61%) remained in the double blind portion of the study as 85 patients entered the OLPVF in order to receive raltegravir and 7 discontinued the study. Appendix 2 and Appendix 3 provide the patient accounting for Protocol 018 and Protocol 019 individually.
 
Table 3 and Table 4 present important characteristics of the treatment experienced populations in Protocols 018 and 019 combined. All patients had advanced HIV disease and extensive prior ART experience. The median baseline CD4 cell counts for the raltegravir group and placebo group were 119 cells/mm3 and 123 cells/mm3, respectively, with approximately 32% of patients in both groups having CD4 cell counts of ≦50 cells/mm3 at baseline. Tables presenting this data for Protocols 018 and 019 individually can be found in Appendix 4, Appendix 5, Appendix 6, and Appendix 7. Overall, the baseline data were homogenous for the two studies, and thus combinable.
 
In order for the results of the Phase III studies to be most informative for the likely patient population in clinical practice, the studies allowed: the inclusion of patients regardless of CD4 cell counts; patients with hepatitis B and/or C virus co-infection; and patients with abnormal baseline laboratory values (e.g., ALT/AST up to 5 times the upper limit of normal). Overall, there was a broad representation of gender, race, international geographic region, and viral subtype. Furthermore, the studies allowed patients in the Phase III studies to utilize certain investigational agents, darunavir and tipranavir, in the OBT subject to local regulatory agencies' approval, in order to maximize the chance that the patient would receive an effective regimen.
 
As a consequence, patients in the Phase III studies generally had a greater number of active agents in OBTs than those in the Phase II treatment experienced study. In Protocol 005, 71% (32/45) of patients receiving raltegravir 400 mg b.i.d. and 51% (23/45) receiving placebo had GSS of 0. In contrast, in Protocols 018 and 019 combined, 25% (115/462) of patients receiving raltegravir 400 mg b.i.d. and 27% (65/237) of patients receiving placebo had a GSS of 0.
 

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Calculating GSS and PSS
The contribution of the OBT to therapy was assessed by the genotypic sensitivity score (GSS) and the phenotypic sensitivity score (PSS). These scores were generated using the results from the genotypic and phenotypic resistance assay of the patients' HIV at screening; the Phenosense GT assay (Monogram Biosciences) was utilized for Phase II and Phase III studies. The baseline GSS and PSS were defined as the total ARTs in the OBT to which the patient's viral isolate showed genotypic and phenotypic sensitivity, respectively. Because there is no widely agreed upon clinical cutoff, enfuvirtide use in enfuvirtide-naive patients was counted as an active drug and added (+1) to the GSS and PSS. Because the resistance testing for darunavir was not available at the time of Phase III initiation, darunavir use in darunavir-naive patients was counted as an active drug and added (+1) to the GSS and PSS. This convention may not provide a perfect estimate of the contribution of darunavir to the OBT. For instance, in darunavir-naive patients receiving darunavir, the antiviral activity of darunavir may be less than its activity in a protease inhibitor naive patient, as darunavir displays cross resistance with other protease inhibitors.

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Efficacy in Protocols 018 and 019 Combined
Protocols 018 and 019 combined, demonstrated the consistently superior efficacy of raltegravir 400 mg b.i.d. plus OBT over placebo plus OBT at Week 16 (Table 5). Data from the 62% of patients who had reached Week 24 were consistent with the Week 16 data (Table 5). In Protocols 018 and 019 combined, the primary efficacy endpoint (percent of patients achieving HIV RNA <400 copies/mL) and all secondary endpoints demonstrated superiority of raltegravir 400 mg b.i.d. over placebo (p<0.001 by logistic regression model). Data for the individual studies can be found in Appendix 8, Appendix 9, Appendix 10, and Appendix 11 and show similar results.
 
The percentages of patients achieving HIV RNA <400 copies/mL, <50 copies/mL, and the change from baseline in CD4 cell count over time are displayed graphically in Figure 11. It is of note that in Protocols 018 and 019, the percentages of patients receiving placebo who had a virologic response was higher than that observed in Protocol 005 (Figure 7). This is most likely related to the permitted use of investigational ARTs in OBT in the Phase III studies, but not in Protocol 005.
 
TLOVR analysis from Protocols 018 and 019 combined, demonstrate that failures beyond Week 16 were uncommon based on available data up to Week 32 (Figure 12).
 

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Introduction
Integrase is 1 of 3 HIV-1 enzymes required for viral replication. Integrase catalyzes the stepwise process that results in the integration of the HIV-1 deoxyribonucleic acid (DNA) into the genome of the host cell (Figure 1). Integration is required for stable maintenance of the viral genome as well as efficient viral gene expression.
 
To date, there are no approved drugs targeting the HIV integrase enzyme. A compound targeting HIV integrase would complement currently licensed HIV-1 antiretroviral agents as it would likely show no cross-resistance to agents from other mechanistic classes. Raltegravir, an HIV integrase inhibitor, was discovered by Merck & Co., Inc. Raltegravir blocks the strand transfer step of integration, thus blocking viral replication. Preclinical data suggested that raltegravir had the promise to be a clinically effective HIV integrase inhibitor with broad activity against circulating variants of HIV-1, including variants with resistance to currently licensed compounds. Laboratory studies demonstrated that HIV-1 viral mutants resistant to raltegravir retained susceptibility to currently licensed agents including efavirenz (EFV), tenofovir (TFV), emtricitabine (FTC), and zidovudine (AZT).
 
In this briefing document, data are presented that support the proposed indication for the use of raltegravir, 400 mg b.i.d., in treatment experienced HIV-1 infected patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

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Mechanism of Action
Integrase is the only HIV-1 protein known to be required to catalyze each of the specific steps required for integration of the viral DNA into the host cell genome [119; 118], namely assembly with and processing of the HIV-1 DNA followed by strand transfer or joining of the viral and cellular DNAs. Raltegravir inhibits the latter, integrase strand transfer reaction. It has a novel mechanism of action compared with all currently approved antiretroviral agents.
 
Biochemical studies have shown that raltegravir is highly selective for HIV integrase and suggest the potential for off-target effects is limited. Raltegravir exhibited >1,000-fold selectively for integrase with respect to human DNA polymerases _, _, and _ and showed no significant findings in a screen of 166 assays for cellular enzymes, transporters, and receptors when tested at concentrations of 10 _M or greater.
 
The mechanism by which raltegravir inhibits HIV-1 replication (see Figure 1) has been studied in cell culture. Normally, after HIV-1 enters a host cell and HIV-1's RNA genome is reverse-transcribed into a linear, double-stranded DNA form, integrase binds to both viral DNA ends and thereby helps to form the "preintegration complex" (PIC). Integrase then cleaves two nucleotides from each 3' DNA end in a step called 3' processing. The PIC migrates into the host cell's nucleus, where integrase binds to the host cell's genomic DNA and then catalyzes the covalent joining, or "strand transfer", of the viral DNA 3' ends to the cell's genomic DNA. The resulting gaps and ragged DNA ends are repaired, probably by host cell enzymes, to yield the fully integrated HIV-1 provirus. Sometimes the HIV-1 DNA fails to become correctly integrated into host cell DNA, and in these cases the HIV-1 DNA is either circularized by host enzymes to form "1-LTR circle" or a "2-LTR circle" or is degraded. In these cases, the viral replication cycle cannot continue because the HIV-1 DNA is shunted into dead-end circular or degraded forms.
 
Studies using quantitative PCR assays to measure early and late HIV-1 reverse transcriptase products and various unintegrated and integrated forms of HIV-1 DNA support the conclusion that raltegravir inhibits integration. Raltegravir had no significant effect on the appearance of late reverse transcription products when measured at either 6 hours or 48 hours after HIV-1 infection, indicating that raltegravir does not inhibit viral entry or reverse transcription. However, raltegravir significantly inhibited integration of HIV-1 DNA as measured 48 hours post-infection using a quantitative "Alu-LTR" PCR assay, which detects HIV-1 proviruses integrated near the abundant human repetitive DNA sequence Alu [117]. Furthermore, raltegravir promoted a significant increase in the abundance of 2-LTR circular forms of the HIV-1 DNA. 2-LTR circles are known to increase in abundance when integration is prevented due to either genetic ablation [124; 120] or pharmacologic inhibition [120] of integrase. An increase in circular DNA abundance is therefore considered a surrogate marker for HIV-1 DNA blocked at the point of integration. Taken together, the results of these studies demonstrate that raltegravir does not inhibit viral entry or reverse transcription and support the view that raltegravir's antiviral activity can be directly attributed to inhibiting HIV-1 integrase and preventing integration. Additional evidence for integrase as the physiologic target of raltegravir is provided in Section 3.3, which shows that mutations in integrase acquired either in vitro or in vivo affect susceptibility to raltegravir.
 
Resistance in vitro
HIV-1 develops resistance to antiretroviral agents through a process of mutation and selection. The potential for HIV-1 to develop resistance to raltegravir was evaluated in cell culture using that laboratory HIV-1 isolate (H9IIIb) in the human T lymphoid H9 cell line. Over the course of several months and increasing concentrations of raltegravir, this selection process produced viral variants that were able to replicate in higher concentrations of raltegravir. Viruses were characterized by amplifying and cloning the integrase gene and determining the nucleotide sequence. These analyses showed that a series of specific amino acid changes occurred over time during culture in increasing raltegravir concentrations. The first change observed was Q148K, which arose during growth in 25 to 50 nM raltegravir and persisted in concentrations up to 500 nM. After passage at 1 _M raltegravir, E138A and G140A were sequentially incorporated and higher concentrations resulted in the acquisition of additional mutations in integrase (e.g., S230R). Thus, the ability of HIV-1 variants to replicate in higher concentrations of raltegravir correlated with the appearance of integrase mutations.
 
To evaluate the affect of these mutations on raltegravir activity, they were introduced into a wild-type HIV-1 IIIb isolate and the mutant viruses evaluated in a single-cycle HIV-1 infectivity assay. The mutations Q148K, E138A/Q148K, and E138A/G140A/Q148K resulted in average fold-shift in raltegravir IC50 of 46-fold, 90-fold, and 508-fold, respectively. These mutations had no effect on sensitivity to reverse transcriptase inhibitors. In addition, all of the mutations resulted in reduced viral replication (infectivity) compared with the wild-type virus. These results demonstrate that integrase mutations which arise during viral growth in the presence of raltegravir confer reduced susceptibility to raltegravir, but these mutations also reduce viral replication. Viruses containing integrase mutations observed in HIV-1-infected subjects failing treatment regimens including raltegravir were also evaluated (see also Section 7.4). The primary mutations N155H, Q148H, and Q148R each conferred a greater than 10-fold increase in the raltegravir IC50, but did not confer resistance to reverse transcriptase inhibitors. Each of the primary mutations reduced viral replication. In contrast, the mutations E92Q and G140S conferred only 2- to 3-fold resistance to raltegravir, but addition of these mutations to primary mutations at positions 155 or 148 resulted in marked increases in the raltegravir fold-change IC50 values. In some cases, the addition of these secondary mutations mitigated the defects in replication observed with primary resistance mutations.
 
In summary, specific mutations in the HIV-1 integrase gene confer resistance to raltegravir. Single primary mutations (Q148H, Q148R, N155H) can confer 13- to 27-fold resistance but generally result in reduced viral replication. The addition of secondary mutations such as E92Q or G140S augment raltegravir resistance. In some cases, these secondary mutations also improved the replication of viruses with primary resistance mutations.
 
In reproductive toxicity studies, raltegravir did not affect fertility in either male or female rats at 600 mg/kg/day. In a toxicokinetic study in pregnant and lactating rats, raltegravir was shown to cross the placental barrier with fetal exposure values up to 1.5- to 2.5-fold greater than in maternal plasma mean drug concentrations and was also concentrated in milk about 3-fold compared to plasma. In developmental toxicity studies in rats, a slight increase in the incidence of supernumerary ribs relative to control was found at the top dose of 600 mg/kg/day. There were no external or visceral abnormalities and no other fetal or postnatal developmental effects at this dose. Based on these results, the safety margin at the no observed effect level for developmental toxicity is approximately 3.4-fold the AUC at the 400 mg b.i.d. clinical dose. In rabbits no developmental toxicity was found at the maximum dose of 1000 mg/kg/day, resulting in a safety margin of about 3.7-fold relative the AUC in patients at the 400 mg b.i.d. clinical dose.
 
Hepatotoxicity
Liver toxicity was not observed in dogs receiving raltegravir orally for 1 year at exposures up to 9-fold above the exposure of the 400 mg b.i.d. clinical dose. Similarly in rats, liver toxicity was not observed following 6 months of oral dosing at up to 4.8-fold above the exposure of the 400 mg b.i.d. clinical dose.
 
However, when raltegravir was administered to dogs in high doses as an IV bolus for 7 days at 100 mg/kg (23-fold greater than the AUC and 71-fold greater than the Cmax at the 400-mg b.i.d. clinical dose), body weight loss, minimal increases in serum urea nitrogen, increases in alanine aminotransferase (ALT) (up to +1967% compared to concurrent control), alkaline phosphatase (ALP) (up to +374% compared to concurrent control), and cholesterol, and very slight, multifocal tubular dilatation in the cortex of the kidneys was observed. There was no histomorphologic change in the liver to correlate with the increases in ALT or ALP. At the no observed effect level, safety margins were 6.5-fold and 24-fold the AUC and Cmax , respectively of the 400-mg b.i.d. clinical dose.
 
In conclusion, there was no evidence of hepatotoxicity following oral dosing of raltegravir to dogs for 1 year or rats for 6 months at 9-fold or 4.8-fold above clinical exposure, respectively. Although intravenous dosing resulted in increases in ALT and alkaline phosphatase in dogs, there were no histomorphologic changes in liver tissue which correlated with these liver enzyme elevations. Further, the high Cmax (71-fold above clinical Cmax) associated with liver enzyme elevations is not considered to be clinically relevant.
 
Carcinogenicity
Carcinogenicity studies in mice and rats are currently ongoing. The in-life phase of these studies is scheduled to be completed by the end of 2007. The study design and dose selection for these studies were reviewed and approved by the FDA Executive Carcinogenicity Assessment Committee. As noted in Section 4.4, raltegravir was negative in all genetic toxicology studies.
 
In rats, doses of 50, 150, and 300 mg/kg/day in males and 50, 300 and 600 mg/kg/day in females were selected for the carcinogenicity study. The chronic irritation and inflammation of the nose/nasopharynx observed in the 27-week oral toxicity study in rats has also been observed in early death rats on this ongoing 105-week carcinogenicity study. Histomorphologic changes consistent with drug irritation to the nose/nasopharynx include chronic inflammation and epithelial hyperplasia and metaplasia. Additionally, in the rat, 3 squamous cell carcinomas of the nose/nasopharynx were observed in high dose females and one chondrosarcoma was observed in one mid dose male rat. These neoplasms are considered to represent the expected consequence of chronic irritation and inflammation. Since these neoplasms likely resulted from continuous local deposition of the drug formulation on the nasal mucosa, the relevance of this observation to oral dosing in patients is expected to be minimal. A 26-week toxicokinetic study in rats was conducted in parallel with the ongoing main carcinogenicity study. Results from this study indicate that at 300-600 mg/kg/day in females and 150 to 300 mg/kg/day in males, systemic exposure is approximately 10.3-fold greater (females) or 1.7-fold greater (males) the AUC at the 400-mg b.i.d. clinical dose.
 
In mice, doses of 50, 250, and 400 mg/kg/day in females and 50, 100 and 250 mg/kg/day in males were selected for the carcinogenicity study. The dose selection was based on a 14 week study where mortality was evident at ≥500 mg/kg/day. Additionally, physical signs, decreases in body weight gains and histomorphologic changes in the stomach and esophagus were seen at 500 mg/kg/day. No neoplasms of the nose or nasopharynx have been observed in the ongoing mouse carcinogenicity study. However histomorphologic changes of chronic irritation and inflammation in the nose and nasopharynx, similar to the rat, have been observed. A 27-week toxicokinetic study in mice was conducted in parallel with the ongoing main carcinogenicity study. Results from this study indicate that at the high dose, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure is approximately 2-fold greater (females) or equal to (males) the AUC at the 400 mg b.i.d. clinical dose.
 
Non-clinical Pharmacokinetics and Toxicology Conclusions
Raltegravir is a low (dog) to intermediate (rat) clearance compound, with a short plasma half-life (≦1.6 hr). The glucuronidation of raltegravir is catalyzed mainly by UGT1A1 with minor contribution from UGT1A9 and UGT1A3. Therefore, raltegravir may be subject to drug-drug interactions when co-administered with drugs that are known to be UGT1A1 inducers or inhibitors.
 
Raltegravir is not genotoxic in a battery of in vitro assays in bacteria and mammalian cells or in vivo in mice designed to detect mutagenicity, direct DNA damage, or clastogenicity. Raltegravir was well tolerated in chronic toxicology studies in rats and dogs at 1.6-fold and 9-fold above the expected exposure of the 400 mg b.i.d. dose in patients. Therefore, the results of these nonclinical toxicity studies support the registration of raltegravir for the treatment of HIV-1 infection.
 
Clinical Pharmacology Program Overview
Eighteen (18) studies were completed to characterize the safety, tolerability, and pharmacokinetics (PK) of raltegravir. Studies were conducted in healthy subjects (including females, individuals of different races), and in special populations (patients with renal and hepatic insufficiency). Since raltegravir is primarily metabolized by UGT1A1, an additional study is presently ongoing examining the effect of UGT1A1 polymorphisms on raltegravir pharmacokinetics.
 
Raltegravir was generally well tolerated up to 1600 mg administered as single doses and 800 mg administered every 12 hours (q12 hr) for up to 10 days in healthy subjects. There were no reports of serious clinical or laboratory adverse experiences in the 18 Phase I studies presented. All adverse experiences were generally transient in nature and mild to moderate in intensity. No clinically important abnormalities were noted in routine blood and urine chemistry panels, complete blood count, electrocardiograms, and physical examinations including vital signs. In the thorough QTc study, a single supratherapeutic dose of raltegravir did not prolong the QTc interval; assay sensitivity was verified in this study, as the positive control (moxifloxacin) demonstrated an increase in the placebo-adjusted mean change-from-baseline QTc.
 
Additional information on the influence of a variety of demographic factors (gender, age, body mass index [BMI], hepatic function, renal function, race, and HIV infection status) were obtained from a composite PK analysis performed using pooled Phase I and Phase II data and from a population PK model-based covariate analysis performed using pooled Phase I and Phase II data (see Section 6.1 for a description of Phase II).
 
Pharmacokinetic Profile of Raltegravir
Following fasted oral administration of raltegravir, AUC0-∞ of raltegravir was doseproportional over the dose range from 100 to 1600 mg, indicating that the plasma clearance and the bioavailability of raltegravir are independent of the dose administered. Plasma Cmax also increased dose-proportionally over this dose range. Plasma C12hr increased dose-proportionally from 100 to 800 mg, but slightly less than dose-proportionally when assessed over the broader dose range 100 to 1600 mg. The apparent terminal t1/2 of raltegravir is approximately 9 hours with a shorter _-phase half-life (∼1 hour) accounting for much of the AUC. Typical concentration-time profiles following single dose administration of raltegravir are shown in Figure 2. This elimination profile coupled with trough concentrations exceeding the pharmacokinetic trough target of 33 nM support the use of a twice-daily dosing regimen for raltegravir. After multiple-dose administration, there was some evidence of higher plasma C12hr values indicating a slight degree of accumulation (20 to 60%). The overall low degree of accumulation resulted in relatively rapid achievement of steady state, demonstrated to be within 2 days.
 
In patients on 400 mg twice daily monotherapy, raltegravir drug exposures were characterized by a geometric mean AUC0-12hr of 14.3 _M•hr and C12hr of 142 nM.
 
Arithmetic Mean Raltegravir Plasma Concentration Profiles Following Single-Dose Administration of 100, 200, 400, 800, or 1600 mg to Healthy Male and Female Subjects (N=20; inset: semilog scale)
 

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Absorption
Raltegravir was rapidly absorbed, with a Tmax of ∼3 hours at the dose of 400 mg in the fasted state. A definitive bioavailability study was not conducted; however, ADME results indicate that the absolute bioavailability of raltegravir is at least 32%. For the final market composition formulation used in all Phase II and Phase III studies, the extent of absorption, as assessed by AUC0-∞, was similar in the fed (high-fat meal) and fasted states, although food appeared to slow the rate and extend the duration of absorption; this resulted in approximately a 34% decrease in Cmax, an 8.5-fold increase in plasma C12hr, and a 7.3 hr delay in Tmax. A cross-study comparison of multiple-dose pharmacokinetics suggests that the magnitude of the food effect is diminished following multiple-dosing and when administered with a standard, rather than high-fat, meal. Food also appears to increase pharmacokinetic variability somewhat over the fasted state and, consequently, a similar lower range of individual C12hr values was observed in the cross-study comparison, suggesting that food does not consistently increase C12hr values. In the Phase II and Phase III development program, raltegravir was dosed without regard to food, and demonstrated comparable potent efficacy in all studies at a range of doses (100- 600 mg b.i.d.) that brackets the proposed dose of 400 mg b.i.d. Dose selection is discussed in Section 7.2.2 and was based pharmacokinetic, safety, and efficacy data.
 
Distribution
Raltegravir is approximately 83% bound to human plasma protein and is minimally distributed into red blood cells (blood-to-plasma partitioning ratio of 0.6). The pharmacokinetics of raltegravir following IV administration were not evaluated and, therefore, the absolute volume of distribution cannot be determined. No data are available regarding human central nervous system (CNS) or brain penetration. Available data in animals suggest a limited penetration of raltegravir to the CNS as tissue-to-plasma radioactivity concentration ratios were 0.016 for brain in the rat tissue distribution studies and a model of brain penetration in wild-type mice with active P-glycoprotein (P-gp) demonstrated brain concentrations below the limit of quantitation. Raltegravir was shown to be a substrate of human P-gp in vitro, which may limit CNS penetration in humans as well. Studies in lactating rats determined a milk-to-plasma concentration ratio of ∼3, consistent with substantial excretion of raltegravir into milk.
 

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Tenofovir is an antiretroviral agent eliminated primarily by a combination of glomerular filtration and active tubular excretion. A drug-drug interaction study was conducted with tenofovir and raltegravir demonstrating that raltegravir had no substantial effect on tenofovir pharmacokinetics. Multiple-dose coadministration of tenofovir and raltegravir led to a slight decrease in peak serum concentrations of tenofovir (tenofovir Cmax GMR [raltegravir and tenofovir/ tenofovir] (90% CI) = 0.77 (0.69, 0.85)), with less of an effect on tenofovir AUC (tenofovir AUC0-24hr GMR (90% CI) = 0.90 (0.82, 0.99)) and no effect on C24 hr (tenofovir C24hr GMR (90% CI) = 0.87 (0.74, 1.02)). The effect of raltegravir on tenofovir is similar to the reported effect of rifampin on tenofovir. No dose adjustment is recommended for tenofovir in the presence of rifampin, implying that the effect of raltegravir is unlikely to be of clinical importance.
 
Both atazanavir alone and in combination with ritonavir were investigated in Phase I. Additional data on this interaction was also obtained from the Phase II population PK data. As anticipated, raltegravir plasma levels were increased with coadministration, consistent with inhibition of UGT1A1. The increases, however, were on the whole modest (30 to 70% increases in AUC; Table 1) and not considered clinically meaningful, because the upper bounds of the 90% CIs for AUC (2.02, 1.78, and 1.64, respectively) were similar to or less than the defined upper bound of clinical significance of 2.0 (See Section 10.1). Of note, concomitant use of raltegravir and atazanavir was well tolerated in the Phase II and Phase III studies. Based on these data, atazanavir may be coadministered with raltegravir without adjustment in the dose of raltegravir.
 
The effect of tenofovir on raltegravir pharmacokinetics was evaluated in a Phase I interaction study and in a Phase II study. The results from both studies are consistent with a modest effect of tenofovir on raltegravir (∼40 to 50% increase in AUC) that is similar in magnitude to the atazanavir effect. The mechanism of this interaction is unknown. This effect is not clinically significant, because the upper bounds of the 90% CIs for AUC (1.94 and 1.79, respectively) were less than the defined upper bound of clinical significance of 2.0 (See Section 10.1). The effect of tenofovir on C12hr was somewhat inconsistent in the two studies, with no effect in the Phase I study and a modest increase in the Phase II study, but the effect in either study would not be judged clinically meaningful. Of note, concomitant use of raltegravir and tenofovir was well tolerated in the Phase II and III studies. Based on these data, tenofovir disoproxil fumarate may be coadministered with raltegravir without dose adjustment.
 
Ritonavir (100 mg twice-daily) had no effect on the pharmacokinetics of raltegravir, despite the potential for induction of UGT1A1 by ritonavir. Due to the multiple effects of ritonavir on enzymes and transporters, a balance of competing effects of induction and inhibition cannot be ruled out. Based on these data, ritonavir may be coadministered with raltegravir without dose adjustment.
 
Efavirenz and etravirine had a modest influence on the pharmacokinetic profile of raltegravir. There is evidence of a modest reduction in C12hr (21% and 34%, mean decrease, respectively), which is probably due to slight induction of UGT1A1; however, the point estimates and 90% CIs for these effects indicate that the magnitude of these effects are small and not likely to be clinically meaningful. Although the lower bound of the CI (0.34) for etravirine was less than 0.4 with a wide 90% CI, the lack of effect on the other raltegravir exposure parameters suggests that etravirine has only a slight effect on raltegravir pharmacokinetics that is unlikely to be clinically meaningful. Based on these data, efavirenz and etravirine may be coadministered with raltegravir without dose adjustment.
 
Based on data from a Phase I interaction study and an analysis of Phase III population PK data, ritonavir-boosted tipranavir decreased plasma levels of raltegravir. The interaction is consistent with a modest inductive effect of tipranavir on the metabolism of raltegravir, because, as described above, ritonavir alone had little effect on raltegravir pharmacokinetics. The raltegravir C12hr value was most impacted, with a mean decrease of approximately 51 to 55%. Smaller mean decreases were observed for AUC0-12hr (24 to 35 %) and Cmax (18%). Based on pharmacokinetic data alone, it is unclear if the effect of tipranavir on raltegravir is clinically significant; the point estimate for the effect on raltegravir C12hr in both analyses is close to the 60% reduction that is considered of potential significance. However, there are considerable clinical efficacy data available from the Phase III program which support that this interaction is not clinically significance (Section 7.3.5 and Section 10.1). Based on these data, tipranavir with low-dose ritonavir may be coadministered with raltegravir without dose adjustment. See Section 10.1 for additional discussion.
 
Rifampin, which is an overall broad potent inducer of drug metabolizing enzymes, decreased raltegravir C12hr by an average of 61%. Mean AUC0-∞ and Cmax values decreased by 40% and 38%, respectively. The observed interaction is consistent with a modest effect of even a very potent inducer on the metabolism of raltegravir. These alterations in pharmacokinetics with coadministered rifampin may be clinically significant, because the true decrease in raltegravir C12hr is likely greater than a 60% reduction (both the point estimate of the GMR and the lower bound of the 90% CI for C12hr fell below 0.4). In contrast to tipranavir, there is no clinical experience from the Phase III program with coadministration of rifampin and raltegravir. Since this appears to be a slightly greater decrease in exposure than with tripranavir, and no clinical experience is available from the Phase III program, it is conservative to suggest a dose adjustment. Based on these data, rifampin may be used with raltegravir, but a doubling of the raltegravir dose should be considered when coadministered with rifampin. To confirm this recommendation, a study is currently being conducted comparing the pharmacokinetics of 400-mg raltegravir dosed alone and 800-mg raltegravir dosed in combination with rifampin. The potential for interactions with phenytoin and phenobarbital was not evaluated in the clinical program for raltegravir; however, both drugs are strong inducers with inductive potential similar to rifampin. On the basis of the results with rifampin, a doubling of the raltegravir dose should be considered when coadministered with either phenytoin or phenobarbital.
 
Other drugs in the inducer class have less potent inductive activity than rifampin, and the evidence from studies such as the efavirenz interaction study support that no dose adjustment is needed when these drugs are used with raltegravir. On this basis, no dose adjustment is recommended for coadministration with nevirapine, rifabutin, glucocorticoids, St. John's Wort, and pioglitazone.
 
Gender, age, BMI, hepatic function, renal function, race, and HIV infection status do not have clinically meaningful effects on the pharmacokinetics of raltegravir. No dose adjustment is warranted on the basis of gender, age, BMI, hepatic function, renal function, race, and HIV infection status.
 
Efficacy
7.1 Overview

The pivotal (Protocols 018 and 019) and supportive (Protocols 004 and 005) studies provide evidence of the clinical efficacy of raltegravir used in combination with other ARTs in the treatment of HIV-infected patients. In this section, results of each of the individual studies are presented first (Section 7.2). The rationale for Phase III dose selection is explained (Section 7.2.2).
 
The Phase III studies, Protocol 018 and 019, were identical in terms of design. After preplanned testing confirmed the homogeneity of treatment effects, the data from these 2 studies were combined. The combined data from Protocols 018 and 019 comprise the bulk of the evidence supporting the proposed indication (Section 7.3).
 
The following provides an overview of the efficacy evidence from each of the individual studies as well as the combined data set from Protocols 018 and 019.
 
• In Protocol 004 (treatment-naive), raltegravir demonstrated similar potent efficacy across the range of doses 100-600 mg b.i.d. in combination with tenofovir and lamivudine. This efficacy was similar to that seen in a standard of care comparator arm, efavirenz 600 mg q.h.s in combination with tenofovir and lamivudine. The treatment effect was sustained through Week 48, and interestingly, patients receiving raltegravir experienced faster declines in HIV RNA levels than patients receiving efavirenz.
 
• In Protocol 005 (treatment-experienced), raltegravir demonstrated similar potent efficacy across the range doses of 200-600 mg b.i.d. in combination with OBT. This efficacy is superior to that seen in patients receiving placebo in combination with OBT and is sustained through at least 24 weeks of double blind therapy. Analysis of the data from the open label portions of Protocol 005 suggest sustained efficacy at week 48 and week 72.
 
• Data from Protocol 004 and Protocol 005 provide the basis for the selection of the 400 mg b.i.d. dose of raltegravir carried forward into Phase III.
 
• The individual Phase III studies, Protocols 018 and 019 (treatment-experienced), each confirmed the superiority of raltegravir 400 mg b.i.d. in combination with OBT as compared to placebo, through at least Week 16 (100% of patients enrolled), with confirmatory data available for the ∼60% of patients who had reached Week 24 as of 13-Dec-06, the cut-off used for the original application. After the original application, Week 24 data for all patients was available, and was supplied to the FDA. With the agreement with the FDA, Week 24 data for all patients are also provided in this document, though these data were not reviewed by the FDA as part of the original application.
 
• The Protocol 018 and 019 combined data confirmed the superior antiretroviral effect of raltegravir 400 mg b.i.d. plus OBT versus placebo plus OBT. Sub-group analyses suggest that potent efficacy is seen in patients with: high HIV RNA levels; low CD4 cell counts; and high levels of resistance to currently licensed ARTs. Potent efficacy was seen in a diverse patient population regardless of hepatitis B and/or C virus co-infection, gender, race geographic region, or viral sub-type.
 
Efficacy in Individual Studies (Protocols 004, 005, 018, and 019)
 
7.2.1 Efficacy in Phase II Dose Ranging Studies (Protocols 004 and 005)
The Phase II dose-ranging studies support the dosing recommendation of raltegravir at 400 mg b.i.d. without regard to food, and in combination with other licensed ARTs.
 
In treatment-naive patients (raltegravir doses of 100, 200, 400, and 600 mg), 85 to 95% achieved HIV RNA <50 copies/mL at Week 24, which was sustained through at least Week 48 (Figure 6). Immunological benefits as measured by increases in CD4 cell counts were also demonstrated at all doses studied. At Week 48, in the raltegravir groups, CD4 cell counts increased by 271-336 cells/mm3, and in the efavirenz comparator arm, CD4 cell counts increased by 274 cells/mm3. The antiretroviral effects demonstrated for raltegravir were comparable to those demonstrated by the efavirenz-based regimen, one of the current standards of care for treatment-naive patients. Interestingly, the raltegravir regimens resulted in a more rapid reduction in viral load than the efavirenz-based regimen.
 
In treatment-experienced patients (Figure 7), 56% to 67% achieved HIV RNA <50 copies/mL at Week 24, the end of the double blind portion; this was sustained through at least Week 48. In the placebo arm, 13% achieved HIV RNA <50 copies/mL. Immunological benefits, as measured by increases in CD4 cell counts during the double blind portion, were also demonstrated at all doses studied. In the raltegravir arms, mean CD4 cell counts increased by 64-100 cells/mm3, and in the placebo comparator arm, mean CD4 cell counts increased by 17 cells/mm3. These results were also sustained through at least Week 48. The antiretroviral effect demonstrated for raltegravir was superior to that seen in the placebo group. Protocol 005 provides a stringent test of efficacy, because patients had extensive prior experience and limited treatment options (e.g., 71% of raltegravir-treated patients had GSS=0; 90% of patients had no active PI in the OBT; 26% of patients had prior enfuvirtide exposure). Appendix 1 presents the percentages of patients achieving HIV RNA <400 copies/mL over the same time period.
 
In Protocol 005, the durability of antiretroviral activity was also assessed using Time to Loss of Virological Response (TLOVR) (Figure 8). This analysis includes all data for patients randomized to raltegravir, and encompasses the 24-week double-blind portion of the study, the period between Week 24 and Week 48 representing a mix of double-blind data and open-label extension data, and the period beyond Week 48 during which all patients remaining in study were receiving raltegravir 400 mg b.i.d. Only 3 patients on raltegravir lost virologic response after Week 48, noting that the number of patients with data beyond Week 56 is small (n=13).
 

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