Drug Interactions

Effect of Faldaprevir on Raltegravir Pharmacokinetics in Healthy Volunteers

The Journal of Clinical Pharmacology 2015, 55(4) 384–391 © 2014, The American College of Clinical Pharmacology DOI: 10.1002/jcph.418

David Joseph, BSc1, Peter Rose, MD2, Natalja Strelkowa, PhD2, Armin Schultz, MD, PhD3, Jeanette Garcia, MHS1, Mabrouk Elgadi, PhD4, and Fenglei Huang, PhD, FCP1

Abstract Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor and an inhibitor of UDP-glucuronosyltransferase-1A1 (UGT1A1), which is involved in raltegravir clearance. Raltegravir, an HIV integrase inhibitor, may be used in combination with HCV treatment in HCV/HIV co-infected patients. In this open-label, 2-period, fixed-sequence study, 24 healthy volunteers (12 males) received faldaprevir 240 mg and raltegravir 400 mg in 2 treatment schedules (A and B) separated by a washout phase of
7 days: (A) twice-daily raltegravir (Days 1–3), once-daily raltegravir (Day 4); (B) twice-daily raltegravir and twice-daily faldaprevir (loading dose, Day 1), twice-daily raltegravir and once-daily faldaprevir (Days 2–5), once-daily raltegravir and once-daily faldaprevir (Day 6). Pharmacokinetics and safety were assessed over 132 hours post-dosing. Compared with raltegravir alone, co-administration with faldaprevir led to 2.7-fold and 2.5-fold increases in raltegravir geometric mean AUCt,ss and Cmax,ss, respectively, and a similar increase in raltegravir glucuronide metabolite exposure. No serious adverse events (AEs) were reported and no subject discontinued due to AEs. Faldaprevir and raltegravir co-administration was well tolerated and resulted in a moderate increase in raltegravir exposure.

Keywords clinical trials, drug interactions, HIV/AIDS, infectious diseases, pharmacokinetics and drug metabolism, virology

Hepatitis C virus (HCV) infection is increasingly prevalent among HIV-positive individuals in Europe and the US.1–3 Complications associated with HCV infection, including hepatocellular carcinoma and liver cirrhosis, are common causes of death in HCV/HIV co-infected patients with access to combination antiretroviral therapy (cART).4 Clearance of HCV infection after treatment with pegylated interferon a-2a and ribavirin has been shown to reduce mortality in HCV/HIV co-infected individuals.5–7 Therefore, it is important to effectively treat chronic HCV infection in HIV/HCV co-infected patients. Several directacting antivirals have been/or are being assessed in HCV/ HIV co-infected individuals, including the HCV protease inhibitors telaprevir, boceprevir, and simeprevir and the NS5B polymerase inhibitor sofosbuvir.8–11 However, the treatment of HCV in this population is complicated by the potential for drug interactions between antiviral and the antiretroviral regimens. Drug interactions have limited the use of telaprevir and boceprevir in HCV/HIV co-infected individuals as both agents exhibit strong CYP3A4 interactions and are not recommended for use with a number of antiretrovirals.12–14 Simeprevir is also metabolized by CYP3A4 and is not recommended for use with any HIV protease inhibitors (boosted or unboosted) or with efavirenz.15 Sofosbuvir is a substrate of drug transporter Pglycoprotein (P-gp) and is not recommended for use with tipranavir/ritonavir.16 The evaluation of potential interactions with commonly used antiretroviral agents is an

important consideration in the development of any new antiviral agent for the treatment of HCV infection. Faldaprevir is a potent HCV NS3/4A protease inhibitor, administered orally with or without food, once daily.17 The efficacy and safety of faldaprevir in combination with pegylated interferon a-2a and ribavirin have been established in clinical studies in treatment-naïve and treatment-experienced patients mono-infected with HCV genotype-118–23 and in patients with HCV genotype-1 and HIV co-infection.24 In a clinical drug-drug interaction study in healthy volunteers, faldaprevir dosed once daily at 120 mg was a weak inhibitor of CYP3A4 and a P-gp inhibitor.25 Faldaprevir was found to be an inhibitor of UDP-glucuronosyltransferase-1A1 (UGT1A1) in rhesus monkey and human liver microsomes.26 Based on the characteristics of inhibition, interactions with

1

Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany 3 CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany 4 Boehringer Ingelheim Ltd/Ltée, Burlington, ON, Canada 2

Submitted for publication 5 August 2014; accepted 20 October 2014. Corresponding Author: Fenglei Huang, PhD, FCP, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, Ridgefield, CT 06877 Email: [email protected]

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drugs that are glucuronidated by UGT1A1 are possible.26 Such interactions could also be influenced by UGT1A1 variants associated with reduced enzyme function, such as UGT1A1 * 28 (present as a homozygous polymorphism in 5%–25% of the population, depending on ethnicity).26–28 Raltegravir is an HIV integrase strand transfer inhibitor that is commonly used as a component of cART regimen and is recommended as a first-line treatment option for HIV.29–31 The major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation,32 and raltegravir has been shown to be a P-gp substrate.33 The primary objective of this trial was to investigate the effect of faldaprevir on the steady-state pharmacokinetics of raltegravir. An additional objective was to assess the safety and tolerability of faldaprevir co-administered with raltegravir.

Methods This was a Phase I, open-label, 2-period, fixed-sequence trial in healthy adult volunteers. The study was conducted in accordance with the requirements of the International Conference on Harmonisation (ICH), Harmonised Tripartite Guideline for Good Clinical Practice (GCP), and local legislation. The study protocol was reviewed and approved by the local Independent Ethics Committee (Ethik-Kommission bei der Landesärztekammer BadenWürttemberg, Stuttgart, Germany) and all volunteers provided written informed consent prior to participation. Faldaprevir 240 mg and raltegravir 400 mg were administered during 2 treatment sequences (Figure S1). Treatment sequence A comprised raltegravir 400 mg twice daily on Days 1–3 and raltegravir 400 mg once daily on Day 4. Treatment sequence B comprised raltegravir 400 mg twice daily and faldaprevir 240 mg twice daily (loading dose) on Day 1, raltegravir 400 mg twice daily and faldaprevir 240 mg once daily on Days 2–5, raltegravir 400 mg once daily and faldaprevir 240 mg once daily on Day 6. All subjects received treatments A and B in the sequence AB, separated by a washout period of at least 7 days. All study medications were administered under the supervision of the investigating physician or a designee at the trial center. Blood samples were collected at predetermined time points for pharmacokinetic analyses (Figure S1): during treatment A, samples for raltegravir analysis were taken on Day 1, 30 minutes before the first dose; on Day 3, within 10 minutes before the first and second dose; and on Day 4, within 10 minutes before the first dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; during treatment B, samples for raltegravir analysis were taken on Day 5, within 10 minutes before the first and second dose; and on Day 6, within 10 minutes before the first dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours post-dose.

385 An exploratory pharmacogenomic analysis was included to investigate the association between genetic variations in UGT1A1 and the pharmacokinetics of raltegravir. A blood sample for pharmacogenomic testing was taken at Visit 2. Genomic DNA was extracted from blood samples using standard molecular genetics methods and analyzed by standard genotyping technologies to detect the presence of the UGT1A1*28 allele, associated with reduced glucuronidation. Plasma concentrations of faldaprevir were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS, Tandem Laboratories, Salt Lake City, Utah) with a lower limit of quantification (LLOQ) of 10 ng/mL as previously described with slight modifications.34 Plasma concentrations of raltegravir and raltegravir-glucuronide were determined by LC-MS/MS (PPD, Middleton, Wisconsin). A method was validated for measuring raltegravir and raltegravir beta-D-glucuronide in human plasma (K3 EDTA). Samples were analyzed using a 50.0 mL aliquot volume and an online solid-phase extraction procedure followed by liquid LC-MS/MS. Raltegravir concentrations were calculated with a 1/2 linear regression over a concentration range of 1.00– 1,000 ng/mL using raltegravir-2H6 as an internal standard. Raltegravir beta-D-glucuronide concentrations were calculated with a 1/2 quadratic regression over a concentration range of 1.00–1,000 ng/mL using raltegravir-d3 beta-D-glucuronide as an internal standard. An API 5000 was operated in the selected reaction monitoring mode under optimized conditions for detection of raltegravir, raltegravir beta-D-glucuronide, raltegravir2H6, and raltegravir-d3 beta-D-glucuronide negative ions formed by electrospray ionization. The interassay accuracy (% bias) and interassay precision (%CV) was from 2.2% to 5.0% and from 2.0% to 10.6%, respectively, for raltegravir; and from 2.3% to 4.5% and 4.7% to 11.1%, respectively, for raltegravir beta-D-glucuronide. For both raltegravir and raltegravir beta-D-glucuronide, the LLOQ was 1.0 ng/mL. Safety and tolerability were assessed by collection of adverse event (AE) data, physical examinations, clinical laboratory tests, vital signs, and 12-lead electrocardiogram (ECG). Pharmacokinetic analyses of faldaprevir, raltegravir, and raltegravir-glucuronide were conducted by noncompartmental techniques using WinNonlin software version 5.2 (Pharsight, Mountain View, California) as previously described.34 Statistical analysis was carried out 1 with SAS Version 9.2 (SAS Institute Inc., Cary, North Carolina). Drug interaction potential, 2-sided 90% confidence intervals (CIs) for the adjusted geometric mean ratios were calculated for the primary pharmacokinetic parameters (AUCt,ss and Cmax,ss) for raltegravir and raltegravir-glucuronide using an analysis of variance (ANOVA) model. The sample size estimation was based on the reported variability of Cmax,ss of raltegravir;

386 assuming a geometric coefficient of variation (gCV) of 50% and a sample size of 24 subjects, the precision of the 2-sided 90%CI would be approximately 1.84.

Results Subjects A total of 25 healthy subjects were entered into the study, 24 subjects (12 males and 12 females) were treated, and 23 subjects completed the trial according to protocol. One subject was unable to swallow the raltegravir tablet and was therefore not treated. One subject withdrew consent for personal reasons and discontinued from the study after Day 4 of Treatment A. All 24 treated subjects were of white race. Mean age was 40.8 years (standard deviation [SD] 8.8 years), mean weight was 78.8 kg (SD 11.5 kg), and mean body mass index was 26.0 (SD 3.3). Pharmacokinetics Geometric mean plasma concentration-time profiles for raltegravir administered alone or with faldaprevir are shown in Figure 1 (for Day 4 of Treatment A and Day 6 of Treatment B). Plasma pharmacokinetics of raltegravir and raltegravir-glucuronide following administration of raltegravir with or without faldaprevir are summarized in Table 1. At steady-state faldaprevir exposure, geometric mean Cmax,ss, AUCt,ss, and C12,ss of raltegravir increased approximately 148%, 173%, and 121%, respectively, relative to raltegravir administered alone. These increases were accompanied by decreases in geometric mean CL/Fss and Vz/Fss of raltegravir. Similarly, after faldaprevir co-administration, geometric mean Cmax,ss, AUCt,ss, and C12,ss of raltegravir-glucuronide increased approximately 198%, 246%, and 431%, respectively, relative to raltegravir administered alone. The geometric mean metabolite-to-parent ratio (raltegravir-glucuronide to raltegravir) for AUCt,ss decreased approximately 9% when raltegravir was administered with faldaprevir relative to raltegravir administered alone. Clear increases in AUCt,ss and Cmax,ss

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values for both raltegravir and raltegravir-glucuronide when administered with faldaprevir were seen for most subjects (Figure 2). According to the statistical analysis using ANOVA method, the co-administration of raltegravir with faldaprevir led to an approximately 2.7-fold increase in geometric mean AUCt,ss of raltegravir (adjusted geometric mean ratio [%]: 272.1; 90%CI 199.7–370.7; gCV 67.9%) and an approximately 2.5-fold increase in geometric mean Cmax,ss of raltegravir (adjusted geometric mean ratio [%]: 245.7; 90%CI 168.5–358.4; gCV 87.1%) compared with raltegravir administered alone. Similar increases in geometric mean AUCt,ss (adjusted geometric mean ratio [%]: 246.0; 90%CI 184.5–328.2; gCV 62.4%) and Cmax,ss (adjusted geometric mean ratio [%]: 194.8; 90%CI 144.7–262.4; gCV 64.7%) were observed for the metabolite raltegravir-glucuronide. Effect of UGT1A1 Genotype Raltegravir pharmacokinetics, when raltegravir was administered alone, were comparable across subgroups based on UGT1A1 genotype (Table 2). Increases in raltegravir Cmax,ss, AUCt,ss, and C12,ss when raltegravir was administered with faldaprevir were 122%, 163%, and 135%, respectively, in subjects homozygous for the wildtype UGT1A1*1/*1 genotype (N ¼ 7); 117%, 139%, and 115% in subjects with a heterozygous UGT1A1*1/*28 genotype (possibly reduced activity; N ¼ 12); and 270%, 279%, and 122% in subjects homozygous for the UGT1A1*28/*28 genotype (reduced activity; N ¼ 5). Safety Twenty-three subjects were administered all 7 doses of 240 mg faldaprevir (total dose: 1,680 mg) and all 18 doses of 400 mg raltegravir (total dose: 7,200 mg). The subject who discontinued for personal reasons after Treatment A received 7 doses of 400 mg raltegravir (total dose: 2,800 mg) and no faldaprevir. Of the 24 treated subjects, 18 (75.0%) reported at least 1 AE during the treatment

Figure 1. Geometric mean plasma concentration-time profiles over a 12-hour period for raltegravir (A) and raltegravir-glucuronide (B) when raltegravir was administered alone or with faldaprevir. FDV, faldaprevir; QD, once daily; RAL, raltegravir.

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Table 1. Steady-State Pharmacokinetics of Raltegravir and Raltegravir-Glucuronide After Administration of Raltegravir Alone or With Faldaprevir RAL Alone (N ¼ 24) Pharmacokinetic Parameter, Geometric Mean (gCV%) AUCt,ss, ng  h/mL Cmax,ss, ng/mL C12,ss, ng/mL t1/2,ss, hours CL/Fss, mL/min Vz/Fss, L Ratio AUCt,ss M/P

RAL 4,070 1,300 37.0 4.03 1,640 571 0.824

RAL þ FDV (N ¼ 23)

RAL-Glucuronide

(92.9) (115) (42.9) (74.1) (92.9) (204) (41.0)

3,360 764 32.0 2.48 1,990 427

(90.5) (103) (59.5) (37.8) (90.5) (153)

RAL 11,100 3,220 81.9 3.03 602 158 0.748

(78.7) (108) (59.1) (33.7) (78.7) (103) (32.6)

RAL-Glucuronide 8,290 1,510 138 2.53 804 176

(59.2) (70.5) (56.6) (28.2) (59.2) (81.3)

AUCt,ss, area under the plasma concentration-time curve at steady state over the uniform dosing interval t; CL/Fss, apparent clearance of the analyte in plasma at steady state following oral administration; Cmax,ss, maximum plasma concentration at steady state; C12,ss, concentration of the analyte in plasma at the end of the uniform dosing interval t; gCV, geometric coefficient of variation; FDV, faldaprevir; M/P, metabolite to parent; RAL, raltegravir; t1/2,ss, terminal half-life of the analyte in plasma at steady state; Vz/Fss, apparent volume of distribution during the terminal phase lz at steady state following oral administration.

phase of the study (Table 3). The incidence of AEs was higher during the combined treatment with raltegravir and faldaprevir than during treatment with raltegravir alone (17 subjects, 73.9% vs. 7 subjects, 29.2%). In particular, gastrointestinal disorders were more frequent during the combined treatment than during raltegravir alone (11 subjects, 47.8% vs. 3 subjects, 12.5%). The most

frequently reported AEs in the treatment period with raltegravir alone were headache (12.5%), flatulence (8.3%), and dizziness (8.3%), and the most frequently reported AEs in the treatment period with raltegravir and faldaprevir were nausea (26.1%), headache (21.7%), fatigue (21.7%), diarrhea (13.0%), and vomiting (8.7%). All but 1 AE (mild vomiting) were assessed by the

Figure 2. Individual (solid lines) and geometric mean (dashed lines) AUCt,ss (ngh/mL) (panels A and B) and Cmax,ss (ng/mL) (panels C and D) for raltegravir and raltegravir–glucuronide when raltegravir was administered alone or with faldaprevir. AUCt,ss, area under the plasma concentration-time curve at steady state over the uniform dosing interval t; Cmax,ss, maximum plasma concentration at steady state; FDV, faldaprevir; RAL, raltegravir.

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Table 2. Comparison of Steady-State Raltegravir Pharmacokinetic Parameters by UGT1A1 Genotype Pharmacokinetic Parameters, Geometric Mean (gCV%) UGT1A1 Genotype

Treatment

UGT1A1 * 1/*1 (n ¼ 7)

RAL alone RAL þ FDV RAL alone RAL þ FDV RAL alone RAL þ FDV

UGT1A1*1/*28 (n ¼ 12) UGT1A1*28/*28 (n ¼ 5)

Cmax,ss 1,090 2,420 1,530 3,320 1,130 4,180

AUCt,ss

(149) (141) (95.6) (100) (146) (108)

3,730 9,800 4,600 11,000 3,430 13,000

(111) (105) (90.1) (69.7) (95.4) (88.7)

C12,ss 37.5 88.0 36.9 79.5 36.4 80.7

(49.7) (32.2) (35.2) (57.9) (61.4) (102)

AUCt,ss, area under the plasma concentration-time curve at steady state over the uniform dosing interval t; Cmax,ss, maximum plasma concentration at steady state; gCV, geometric coefficient of variation; FDV, faldaprevir; RAL, raltegravir.

investigator as drug-related. The majority of AEs were of mild intensity, 1 AE was rated as moderate (flatulence), and no AE was rated as severe. No serious AEs, protocolspecified significant AEs, or other significant AEs according to ICH E3 occurred. None of the reported AEs required therapy, all subjects recovered from their AEs by the end of the trial, and no subject discontinued the trial due to an AE. There were no clinically relevant findings with respect to vital signs (systolic and diastolic blood pressures, pulse rate). During treatment with raltegravir alone, no notable increase in mean bilirubin was observed. During the treatment period with raltegravir and faldaprevir, mean total bilirubin increased from 0.6 mg/dL at baseline to 1.8 mg/dL on Day 5, mean direct bilirubin increased from 0.2 mg/dL at baseline to 0.6 mg/dL on Day 5, and mean indirect bilirubin increased from 0.5 mg/dL at baseline to 1.9 mg/dL on Day 5. Individual total bilirubin values greater than 2-fold upper limit of normal were observed for 12 of 23 subjects during this period. At the end-ofstudy visit the values had decreased to baseline. No increase from baseline to last value on treatment was

observed for mean values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Discussion The treatment of HCV infection in patients co-infected with HIV is complicated by drug interactions and the potential for increased toxicities. The present study evaluated co-administration of the HCV protease inhibitor faldaprevir and the HIV integrase inhibitor raltegravir in 24 healthy adult subjects. Faldaprevir resulted in an approximately 2.7-fold increase in the calculated adjusted geometric mean AUCt,ss for raltegravir and an approximately 2.5-fold increase in the calculated adjusted geometric mean Cmax,ss for raltegravir. Similar increases in the calculated adjusted geometric mean AUCt,ss and Cmax,ss for raltegravir-glucuronide were observed. As exposure to both raltegravir and its metabolite raltegravir– glucuronide were almost equally increased after coadministration of raltegravir with faldaprevir, the observed drug-drug interaction was more likely due to the interaction of faldaprevir with transporters (ie, P-gp),

Table 3. Summary of Adverse Events n (%)

RAL Alone

RAL þ FDV

Total Treated

Number of subjects Any AE Serious AEs Severe AEs AEs leading to discontinuation AEs by system organ classa Gastrointestinal disordersb Nervous system disordersc General disorders and administration site conditionsd Renal and urinary disorderse

24 (100.0) 7 (29.2) 0 0 0

23 (100.0) 17 (73.9) 0 0 0

24 (100) 18 (75.0) 0 0 0

3 (12.5) 4 (16.7) 1 (4.2) 0

11 (47.8) 7 (30.4) 5 (21.7) 1 (4.3)

12 (50.0) 9 (37.5) 5 (20.8) 1 (4.2)

a

More than 1 AE can occur in a single subject. Gastrointestinal disorders: nausea, diarrhea, vomiting, flatulence, abdominal discomfort, abdominal pain upper, abdominal pain, dry mouth. c Nervous system disorders: headache, dizziness, syncope, tremor. d General disorders and administration site conditions: fatigue, feeling of relaxation. e Renal and urinary disorders: chromaturia. AE, adverse event; FDV, faldaprevir; RAL, raltegravir. b

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than metabolism of raltegravir by UGT1A1. The increased impact of faldaprevir on raltegravir exposure in subjects carrying alleles indicative of a reduced UGT1A1 function is consistent with this suggestion. Other possible mechanisms may also play a role in increasing the absorption or systemic bioavailability of raltegravir, for example, other drug transport proteins or intestinal absorption independent of transporter effects.32 Raltegravir plasma levels observed in this trial, both with and without faldaprevir, were comparable to previously published data from similar studies in HCV/ HIV co-infected patients.35–37 Analysis of the influence of UGT1A1 genotypes did not reveal any clear effect on the raltegravir pharmacokinetic parameters. This is in contrast to modestly increased plasma levels of raltegravir previously reported in a study in 30 individuals with the UGT1A1*28/*28 genotype.38 Possibly the high level of interindividual variation observed in our study, along with the relatively small number of patients homozygotic for the *28 genotype, may have prevented detection of any association between UTG1A1 genotype and raltegravir levels. In the clinical setting, pharmacokinetics of raltegravir have been shown to vary widely both within and between patients with no reported impact on safety.39–41 In this study no serious or severe AEs were reported and there were no discontinuations due to AEs. The most frequent AEs were consistent with the reported AE profiles previously described for both agents.18–23,32 Bilirubin elevations were observed in nearly all subjects during treatment with raltegravir and faldaprevir. Transient increases in total bilirubin (mainly driven by increases in indirect bilirubin) are a known effect of faldaprevir treatment and are not considered clinically relevant.26 The bilirubin elevations were not accompanied by increases in ALT or AST. Overall, the safety results suggest that faldaprevir and raltegravir are well tolerated when administered together and that the increased exposure to raltegravir is not sufficient to cause any safety concerns. Studies in patients with HIV/HCV co-infection further support a lack of any adverse clinical impact from moderately increased levels of raltegravir. In a Phase I study in HIV/HCV co-infected patients with advanced liver cirrhosis (Child-Pugh C score) raltegravir AUC0–12 and C12 were increased 1.72-fold and 6.58-fold, respectively; however, despite the higher exposure raltegravir was well tolerated with no safety issues identified.42 The STARTVerso4 Phase III study assessed the efficacy and safety of faldaprevir in combination with pegylated interferon a-2a and ribavirin in HIV/HCV co-infected patients, the majority of whom were receiving cART.24 Among 143 patients receiving raltegravir-based cART, plasma trough raltegravir levels were approximately 20%– 40% lower with faldaprevir 240 mg and comparable with

389 faldaprevir 120 mg compared to levels before initiation of faldaprevir.43 These data suggest that the magnitude of the interaction between faldaprevir and raltegravir was considerably less in HIV/HCV co-infected patients than was observed in healthy volunteers in this study. Consistent with the pharmacokinetic data, the safety and efficacy profiles of faldaprevir in patients who were on raltegravir-based cART regimens in STARTVerso4 were comparable to those who were not on raltegravir-based cART.24 In addition, current evidence suggests that raltegravir seems to have a wide therapeutic range. For example, co-administration with omeprazole led to an approximately 3-fold increase in exposure of raltegravir;44 however, as no unique safety signal was observed with concomitant use of raltegravir and proton inhibitors (ie, omeprazole) in Phase III studies, no dose adjustment of raltegravir is recommended when these 2 agents are given together.32 Thus, our data seem to confirm that faldaprevir may be safely co-administered with raltegravir 400 mg twice daily; however, given the wide inter- and intraindividual variability in raltegravir pharmacokinetics, further investigation may be needed to understand if the observed drug-drug interaction between raltegravir and faldaprevir is clinically relevant. In conclusion, co-administration of raltegravir 400 mg twice daily with faldaprevir 240 mg once daily in healthy subjects resulted in a moderate increase in raltegravir exposure but no unexpected AEs or safety concerns. These observations may be of relevance to the administration of raltegravir with other co-medications that inhibit UGT1A1 and/or P-gp. Acknowledgments The study was sponsored by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. Medical writing assistance, supported by Boehringer Ingelheim, was provided by Esther Race of Choice Healthcare Solutions during the preparation of this manuscript.

Declaration of Conflicting Interests DJ, PR, NS, JG, ME, and FH are employees of Boehringer Ingelheim. AS is an employee of CRS Clinical Research Services Mannheim GmbH.

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