Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Neuropharmacology wikipedia , lookup
Discovery and development of cyclooxygenase 2 inhibitors wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Drug interaction wikipedia , lookup
HIV vaccine wikipedia , lookup
Discovery and development of HIV-protease inhibitors wikipedia , lookup
HIV/AIDS MAJOR ARTICLE Pharmacokinetic Interactions Between the Hepatitis C Virus Protease Inhibitor Boceprevir and Ritonavir-Boosted HIV-1 Protease Inhibitors Atazanavir, Darunavir, and Lopinavir Ellen G. J. Hulskotte,1 Hwa-Ping Feng,2 Fengjuan Xuan,2 Marga G. J. A. van Zutven,1 Michelle A. Treitel,2 Eric A. Hughes,2 Edward O’Mara,2 Stephen P. Youngberg,3 John A. Wagner,2 and Joan R. Butterton2 1 Merck Sharp & Dohme Corp, Oss, The Netherlands; 2Merck Sharp & Dohme Corp, Whitehouse Station, New Jersey, and 3Celerion, Lincoln, Nebraska Background. Boceprevir represents a new treatment option for hepatitis C (HCV)–infected patients, including those with HCV/human immunodeficiency virus coinfection; however, little is known about pharmacokinetic interactions between boceprevir and antiretroviral drugs. Methods. A randomized, open-label study to assess the pharmacokinetic interactions between boceprevir and ritonavir-boosted protease inhibitors (PI/r) was conducted in 39 healthy adults. Subjects received boceprevir (800 mg, 3 times daily) for 6 days and then received PI/r as follows: atazanavir (ATV) 300 mg once daily, lopinavir (LPV) 400 mg twice daily, or darunavir (DRV) 600 mg twice daily, each with ritonavir (RTV) 100 mg on days 10–31, plus concomitant boceprevir on days 25–31. Results. Boceprevir decreased the exposure of all PI/r, with area under the concentration–time curve [AUC] from time 0 to the time of the last measurable sample geometric mean ratios of 0.65 (90% confidence interval [CI], .55–.78) for ATV/r; 0.66 (90% CI, .60–.72) for LPV/r, and 0.56 (90% CI, .51–.61) for DRV/r. Coadministration with boceprevir decreased RTV AUC during a dosing interval τ (AUCτ) by 22%–36%. ATV/r did not significantly affect boceprevir exposure, but boceprevir AUCτ was reduced by 45% and 32% when coadministered with LPV/r and DRV/r, respectively. Overall, treatments were well tolerated with no unexpected adverse events. Conclusions. Concomitant administration of boceprevir with PI/r resulted in reduced exposures of PI and boceprevir. These drug–drug interactions may reduce the effectiveness of PI/r and/or boceprevir when coadministered. Keywords. pharmacokinetics; boceprevir; atazanavir; lopinavir; darunavir. One of the most common comorbidities for patients with hepatitis C virus (HCV) infection is coinfection with human immunodeficiency virus (HIV). HCV infection is typically more aggressive in patients with Received and accepted 2 November 2012; electronically published 15 November 2012. Presented in part: 19th Conference on Retroviruses and Opportunistic Infections, Seattle, Washington, 5–8 March 2012. Correspondence: Ellen Hulskotte, PhD, Department of Clinical Pharmacology, Merck Research Laboratories, MSD, PO Box 20, 53410 BH Oss, The Netherlands ([email protected]). Clinical Infectious Diseases 2013;56(5):718–26 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/cid/cis968 718 • CID 2013:56 (1 March) • HIV/AIDS HIV coinfection [1, 2], with poor response to treatment [3, 4]. Treatment for HCV monoinfection has advanced with the availability of targeted therapies, such as boceprevir (BOC), a potent, orally administered, ketoamide serine protease inhibitor (PI) of the HCV nonstructural protein 3 [5–7]. However, little is known about drug–drug interactions (DDIs) between BOC and commonly prescribed antiretroviral therapies such as the HIV PIs atazanavir (ATV), lopinavir (LPV), and darunavir (DRV) [8]. These HIV PIs are inhibitors of, and primarily metabolized by, CYP3A4 [9, 10], and are generally given in combination with low-dose ritonavir (RTV). Used as a pharmacokinetic enhancer, RTV is a potent inhibitor of CYP3A4 and CYP2D6 (to a lesser extent), and also inhibits several uptake and efflux transporters (such as organic anion-transporting polypeptide and P-glycoprotein) [11, 12]. Moreover, BOC also inhibits CYP3A4/5, raising the possibility that addition of BOC to RTV-boosted HIV PIs (PI/r) could exacerbate CYP3A4 inhibition. The current study was designed to investigate the effect of steady-state BOC on the exposure of RTV-boosted ATV, LPV, and DRV and vice versa in healthy volunteers, to provide additional guidance for the treatment of HCV/HIV-coinfected patients. MATERIALS AND METHODS Subjects This was a single-center, randomized, open-label study conducted in accordance with principles of good clinical practice and approved by the appropriate institutional review board (Celerion IRB, Lincoln, Nebraska). All subjects provided written informed consent. Healthy male and female subjects aged 19–55 years with a body mass index 18–32 kg/m2 were enrolled. Subjects were required to have no clinically significant disease or abnormal results on physical examination or laboratory tests and were negative for hepatitis B virus surface antigen, HCV antibodies, and HIV. Females who were breastfeeding or of childbearing potential and males with partners intending to become pregnant within 3 months were excluded. Study Design Following an overnight fast, all subjects received BOC 800 mg (4 × 200-mg capsules) every 8 hours for 6 days (Figure 1). Blood samples for BOC pharmacokinetic analysis were collected predose on the mornings of days 4, 5, and 6, and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose on day 6. On the morning of day 10, all subjects initiated PI/r treatment: part 1, 300 mg ATV (Reyataz)/100 mg RTV once daily; part 2, 400 mg LPV/100 mg RTV (Kaletra) twice daily; part 3, 600 mg DRV/100 mg RTV (Prezista) twice daily. PI/r therapy was continued from the morning of day 10 until the morning of day 31; in addition, all subjects received concomitant BOC 800 mg every 8 hours from days 25 to 31. Blood samples for assessment of PI/r pharmacokinetics were taken predose on days 10, 18, 23, 28, and 29, and postdose on days 24 and 30 at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours, and also at 24 hours postdose in patients receiving ATV/r (ATV/r only). Additional blood samples to assess BOC pharmacokinetics were collected predose on days 29 and 30 and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose on day 31. Both BOC and the HIV-PI/r were taken following food intake. On each pharmacokinetic sampling day (days 6, 24, 30, and 31), subjects received a standard breakfast of 860 kcal (46 g fat, 36 g protein, 75 g carbohydrates, 2 g fiber) with observed dosing after an overnight fast of at least 8 hours. The morning dose was taken with 240 mL of water 30 minutes after starting breakfast. Water was restricted 1 hour before and after dosing, and all subjects fasted for 4 hours after the morning dose. The use of other medications must have been related to an adverse event (AE) or to the subject’s medical history. Acetaminophen ( paracetamol) and hormonal contraceptives (except those containing drospirenone) were allowed. Assessments The following pharmacokinetic variables were evaluated for BOC, RTV, and the HIV PIs: AUClast (area under the concentration–time curve from time 0 to the time of the last measurable sample); AUCτ (area under the concentration–time curve during a dosing interval τ); Cmax (maximum observed plasma concentration); Tmax (time to maximum observed plasma concentration); Cmin (minimum observed plasma concentration); Cl/F (apparent total body clearance); and t½ (terminal phase half-life). The t½ was determined by linear regression of the terminal phase of the log-linear concentration–time profiles; reportable t½ required fitting to at least 3 points in the terminal phase, excluding Cmax. Cl/F was calculated as dose/AUCτ. For safety monitoring, all AEs were recorded, along with severity, relationship to study drug, and outcome. Assays Plasma concentrations of all analytes were determined using validated liquid chromatography with tandem mass spectrometric detection (PPD, Middleton, Wisconsin). Boceprevir concentrations were determined as the sum of concentrations of 2 enantiomers of BOC, SCH 534128 and SCH 534129. Concentrations of SCH 629144, an inactive metabolite of BOC, were obtained as the sum of concentrations of 4 stereoisomers, SCH 783004, SCH 783005, SCH 783006, and SCH 783007. The overall lower limit of quantification (LLOQ) for BOC was 4.80 ng/mL, and the overall LLOQ for SCH 629144 was 2.50 ng/mL. The LLOQ for HIV PIs and RTV was 10 ng/mL. Determination of Sample Size A sample size of 10 volunteers per treatment arm was deemed adequate based on a within-subject standard deviation of logtransformed Cmax and AUC of BOC of 25% and 20%, respectively, and of log-transformed AUC of the ATV/r, LPV/r, and DRV/r of 18%, 14%, and 19%, respectively (data on file). The sample size calculation was based on the ability to show equivalence of the Cmax and AUC between HIV-PI/r alone and with BOC, using a 90% confidence interval (CI) of .70–1.43 for the geometric mean ratio (GMR) of the HIV-PI/r and 0.50–2.00 for the GMR of BOC, with two 1-sided tests, and a significance level (α) of .1 and with at least 80% power. To allow for dropouts, 13 subjects were enrolled in each study arm. HIV/AIDS • CID 2013:56 (1 March) • 719 Table 1. RESULTS Patient Demographics Subject Disposition Boceprevir + RTV/PI Study Atazanavir/RTV (n = 13) Lopinavir/RTV (n = 13) Darunavir/RTV (n = 13) 4 (31) 9 (69) 5 (38) 8 (62) 5 (38) 6 (62) 9 (69) 4 (31) 9 (69) 4 (31) 13 (100) 0 4 (31) 2 (15) 9 (69) 11 (85) 13 (100) 36.3 (7.4) 33.1 (11.0) 37.3 (13.3) 27.5 (3.8) 26.3 (3.1) 25.2 (3.4) Sex, No. (%) Female Male Boceprevir/Atazanavir/Ritonavir Pharmacokinetics Race, No. (%) White Nonwhite Ethnicity, No. (%) Hispanic/ Latino Non-Hispanic/ Latino Age, y, mean (SD) BMI, kg/m2, mean (SD) Thirty-nine subjects were enrolled and randomized to ATV/r (n = 13), LPV/r (n = 13), or DRV/r (n = 13) treatment. Baseline demographics were generally similar across treatment arms (Table 1). 0 Abbreviations: BMI, body mass index; PI, protease inhibitor; RTV, ritonavir; SD, standard deviation. Statistical Analyses A mixed-effects model including factors for subject and treatment was employed. The GMRs and associated 90% CIs for log-transformed AUCs were analyzed, extracting the effect due to treatment as fixed effect and subject as random effect. The resulting 2-sided 90% CI for the true mean difference in AUC0-last values was then exponentiated to obtain the CI for true GMR. Mean ATV concentrations were lower at all time points in the presence of BOC than with ATV/r alone (Figure 2A). Cmax, AUClast, and AUCτ for ATV were lower in subjects receiving BOC plus ATV/r compared with ATV/r alone: at steady state, ATV AUC0-last, Cmax, and Cmin values were reduced by 35%, 25%, and 49%, respectively (Tables 2 and 3). Geometric mean ATV Cmin was decreased from 693 ng/mL to 333 ng/mL in the presence of BOC. By contrast, BOC pharmacokinetics were largely unchanged in the presence of ATV/r; ATV/r had little effect on BOC exposure and Cmax (Tables 2 and 3). An approximate 18% decrease in BOC Cmin was seen upon coadministration with ATV/r (Table 3). Ritonavir AUCτ and Cmax were reduced by 36% and 27%, respectively, in the presence of BOC and ATV, compared with ATV alone (Table 3, Figure 3). Boceprevir/Lopinavir/Ritonavir Pharmacokinetics Mean LPV concentrations were lower at all time points in the presence of BOC and RTV than with RTV alone (Figure 2B). Geometric mean ratios for LPV AUC0-last, Cmax, and Cmin were reduced 34%, 30%, and 43%, respectively, in the presence of BOC plus LPV/r, compared with LPV/r alone. Geometric Figure 1. Study design for boceprevir/ritonavir/human immunodeficiency virus protease inhibitor coadministration. Abbreviations: ATV, atazanavir; bid, twice daily; BOC, boceprevir; DRV, darunavir; HIV, human immunodeficiency virus; LPV, lopinavir; PI, protease inhibitor; PK, pharmacokinetic; qd, once daily; RTV, ritonavir; tid, 3 times daily. 720 • CID 2013:56 (1 March) • HIV/AIDS in the presence of BOC (Table 2), with GMR of DRV AUC0last, Cmax, and Cmin reduced by 44%, 36%, and 59%, respectively, when coadministered with BOC plus RTV compared with RTV alone. Geometric mean DRV Cmin decreased from 3222 ng/mL to 1321 ng/mL with BOC coadministration (Table 5). Boceprevir exposure was markedly reduced when coadministered with DRV/r (Table 2). GMRs for BOC were reduced by 32% for AUCτ, 25% for Cmax, and 35% for Cmin when administered with DRV/r (Table 5). Ritonavir exposure was reduced by 27% and Cmax by 13% in subjects receiving BOC plus DRV/r compared with those receiving DRV alone (Table 5, Figure 3). Safety Figure 2. Mean (standard deviation) plasma concentration–time profiles for ritonavir-boosted atazanavir (A), lopinavir (B ), and darunavir (C ) alone and in combination with boceprevir. Abbreviations: ATV, atazanavir; BOC, boceprevir; DRV, darunavir; LPV, lopinavir; MD, multiple dose; RTV, ritonavir. mean LPV Cmin was decreased from 6730 ng/mL to 3805 ng/ mL by the presence of BOC. Coadministration of BOC with LPV/r reduced BOC concentrations (Table 2). Overall, BOC AUCτ, Cmax, and Cmin GMRs decreased between 45% and 57% when BOC was coadministered with LPV/r (Table 4). Geometric least-squares mean BOC Cmin decreased from 92 ng/mL to 40 ng/mL with LPV/r coadministration. Ritonavir AUCτ and Cmax were reduced by 22% and 12%, respectively, in the presence of BOC and LPV compared with LPV alone (Table 4, Figure 3). Boceprevir/Darunavir/Ritonavir Pharmacokinetics Mean DRV concentrations were lower at all time points in the BOC plus DRV/r treatment arm than with DTV/r alone (Figure 2C). Darunavir Cmax, AUC0-last, and AUCτ were lower There were no deaths, severe/serious AEs, or clinically relevant changes in hematology, blood pressure, pulse rate, oral body temperature, or electrocardiogram parameters. In the ATV/r group, 1 subject stopped treatment because of an increase in total bilirubin (7.6 mg/dL; 4.75 × upper limit of normal) with apparent jaundice, blurred vision, and dizziness after receiving ATV/r for 5 days. A second subject withdrew consent for personal reasons. In total, 80 AEs were reported by 10 of 13 subjects, with 72 categorized as possibly/probably drug related. The most common drug-related AE was dysgeusia (n = 8). All AEs were mild in intensity except for 1 report of elevated bilirubin and another of dyspepsia, both of moderate intensity. In the LPV/r group, a total of 129 AEs were reported by 12 of 13 subjects, with 104 considered to be possibly/probably drug related. There were no treatment discontinuations, and the most common drug-related AEs were dysgeusia (n = 10) and headache (n = 5). All AEs were of mild intensity except for 1 case of headache of moderate intensity. In the DRV/r group, a total of 111 AEs were reported across all 13 subjects, with 80 considered to be possibly/probably drug related. Two subjects in the DRV/r group discontinued because of an AE (abdominal cramp, n = 1; nausea, n = 1; both moderate intensity), and all subjects reported at least 1 possible/probable drug-related AE (most commonly dysgeusia [n = 12] and dizziness [n = 5]). All AEs were of mild intensity except the cases of abdominal cramping and nausea leading to treatment discontinuation. DISCUSSION Data from the present study indicate that coadministration with BOC reduces the concentrations of RTV and RTVboosted ATV, LPV, and DRV. Boceprevir reduced mean trough concentrations of ATV/r, LPV/r, and DRV/r by 49%, 43%, and 59%, respectively. Mean reductions in HIV PI exposure ranged from 34% to 44%, and PI Cmax decreased from 25% to 36%. RTV exposure was also reduced in the presence HIV/AIDS • CID 2013:56 (1 March) • 721 722 • Table 2. Pharmacokinetic Parameters for Boceprevir, and Ritonavir-Boosted Atazanavir, Lopinavir and Darunavir, Geometric Means CID 2013:56 (1 March) Treatment Cmax (ng/mL) AUClast (ng × h/mL) AUCτ (ng × h/mL) Cmin (ng/mL) t½ (h) CL/F (L/h) Tmax a (h) ATV/RTV + BOC ATV PK • ATV/RTV alone 3606 (37.7) n = 12 39 932 (31.9) n = 12 36 202 (31.3) n = 8 693 (52.8) n = 12 11.1 (26.5) n = 8 138 (31.2) n = 8 4.0 (2.0–8.0) n = 12 ATV/RTV + BOC BOC PK 2641 (22.9) n = 11 25 762 (18.1) n = 11 24 272 (13.1) n = 9 333 (48.9) n = 11 10.2 (39.6) n = 9 206.0 (13.1) n = 9 4.0 (3.0–7.9) n = 11 HIV/AIDS BOC alone 1450 (36.7) n = 13 5615 (22.8) n = 13 4835 (26.1) n = 13 106 (40.4) n = 13 2.9 (67.8) n = 12 2758 (26.1) n = 13 4.0 (3.0–6.0) n = 13 BOC + ATV/RTV RTV PK 1400 (27.7) n = 11 5270 (25.0) n = 11 4687 (23.8) n = 11 86 (33.1) n = 11 3.6 (88.0) n = 9 2845 (23.8) n = 11 4.0 (2.0–6.0) n = 11 ATV/RTV alone 1474 (31.7) n = 12 9269 (33.9) n = 12 9274 (33.9) n = 12 35.8 (80.6) n = 12 5.0 (17.2) n = 12 180 (33.9) n = 12 4.0 (2.0–4.0) n = 12 1049 (25.6) n = 11 5807 (30.4) n = 11 5857 (29.5) n = 11 22.7 (41.6) n = 8 4.6 (27.6) n = 11 285 (29.5) n = 11 4.0 (3.0–4.0) n = 11 13 305 (18.8) n = 13 9375 (23.1) n = 13 117 200 (24.0) n = 13 77 082 (23.1) n = 13 108 953 (22.0) n = 8 77 436 (23.2) n = 13 6,730 (40.0) n = 13 3805 (33.7) n = 13 9.0 (45.8) n = 8 5.5 (35.3) n = 13 61 (22.0) n = 8 86 (23.2) n = 13 4.0 (3.0–8.0) n = 13 4.0 (2.0–6.0) n = 13 1767 (47.4) n = 13 878 (55.2) n = 13 6513 (65.1) n = 13 3677 (64.9) n = 13 6040 (61.9) n = 13 3315 (62.7) n = 13 2.8 (86.6) n = 10 2.3 (76.8) n = 12 2207 (61.9) n = 13 4023 (62.6) n = 13 4.0 (3.0–4.0) n = 13 4.0 (0.5–6.0) n = 13 990 (44.1) n = 13 869 (60.1) n = 13 5518 (33.8) n = 13 4258 (43.9) n = 13 5360 (33.0) n = 12 4268 (43.9) n = 13 155 (51.4) n = 13 91 (54.8) n = 13 3.1 (25.2) n = 12 2.8 (25.5) n = 13 311 (33.1) n = 12 391 (43.9) n = 13 4.0 (3.0–6.0) n = 13 4.0 (3.0–6.0) n = 13 8086 (23.4) n = 11 60 271 (24.6) n = 11 59 943 (19.8) n = 5 3222 (32.1) n = 10 9.3 (30.2) n = 5 167 (19.8) n = 5 3.0 (2.0–4.0) n = 11 5192 (25.0) n = 11 33 511 (22.2) n = 11 33 319 (23.2) n = 10 1321 (26.3) n = 11 5.9 (32.1) n = 10 300 (23.2) n = 10 3.0 (1.0–4.0) n = 11 1564 (29.1) n = 12 5940 (22.8) n = 12 5352 (21.2) n = 12 95 (36.6) n = 12 3.6 (54.7) n = 11 2491 (21.2) n = 12 3.5 (3.0–6.0) n = 12 1161 (20.1) n = 11 4149 (22.0) n = 11 3600 (17.0) n = 11 62 (25.8) n = 11 5.1 (60.9) n = 8 3603 (17.0) n = 11 3.0 (1.0–4.0) n = 11 776 (36.9) n = 11 4816 (31.0) n = 11 4829 (30.9) n = 11 155 (28.6) n = 11 3.7 (19.6) n = 11 345 (30.9) n = 11 4.0 (2.0–6.0) n = 11 678 (53.6) n = 11 3552 (36.8) n = 11 3375 (33.3) n = 10 86 (31.1) n = 11 4.0 (20.1) n = 10 494 (33.3) n = 10 4.0 (3.0–6.0) n = 11 ATV/RTV + BOC LPV/RTV + BOC LPV PK LPV/RTV alone LPV/RTV + BOC BOC PK BOC alone BOC + LPV/RTV 92 (115.6) n = 13 40 (123.7) n = 12 RTV PK LPV/RTV alone LPV/RTV + BOC DRV/RTV + BOC DRV PK DRV/RTV alone DRV/RTV + BOC BOC PK BOC alone BOC + DRV/RTV RTV PK DRV/RTV alone DRV/RTV + BOC All data, except for Tmax, are presented as geometric mean (coefficient of variance). For some of the subjects, AUCτ, t½, and Cl/F could not be reported because there was insufficient number of points after Cmax to define the terminal phase. Abbreviations: ATV, atazanavir; AUClast, area under the concentration–time curve to the last measureable sample; AUCτ, area under the concentration–time curve during a dosing interval τ; BOC, boceprevir; Cmax, maximum observed plasma concentration; Cmin, minimum observed plasma concentration; Cl/F, apparent clearance; DRV, darunavir; LPV, lopinavir; PK, pharmacokinetics; RTV, ritonavir; t½, apparent terminal halflife; Tmax, time to maximum observed plasma concentration. a Data presented as median (range). Table 3. Pharmacokinetic Interactions Among Boceprevir, Atazanavir, and Ritonavir PK Parameter No. ATV PK 90% CI rMSEa (BOC + ATV/RTV)/(ATV/RTV) AUC0-lastb,c (ng × h/mL) Cmax b (ng/mL) 12 12 Cmin b (ng/mL) 12 BOC PK AUCτ b (ng × h/mL) GMR 13 Cmax b (ng/mL) 13 Cmin b (ng/mL) RTV PK 13 0.65 0.75 (.55–.78) (.64–.88) 0.23 0.21 0.51 (.44–.61) 0.22 (BOC + ATV/RTV)/(BOC) 0.95 (.87–1.05) 0.93 (.80–1.08) 0.12 0.20 0.82 (.68–.98) 0.25 (BOC + ATV/RTV)/(ATV/RTV) AUCτ b (ng × h/mL) 12 0.64 (.58–.72) 0.14 Cmax b (ng/mL) Cmin b (ng/mL) 12 12 0.73 0.55 (.64–.83) (.45–.67) 0.17 0.21 Abbreviations: ATV, atazanavir; AUC0-last, area under the concentration–time curve to the last measurable sample; AUCτ, area under the concentration– time curve during a dosing interval τ; BOC, boceprevir; CI, confidence interval; Cmax, maximum observed plasma concentration; Cmin, minimum observed plasma concentration; GMR, geometric least-squares mean ratio; PK, pharmacokinetics; RTV, ritonavir. a rMSE: Square root of conditional mean squared error (residual error) from the linear mixed-effect model. rMSE*100% approximates the within-subject coefficient of variation (%CV) on the raw scale. b Back-transformed least-squares mean and CI from linear mixed-effect model performed on natural log-transformed values. c Statistical comparison was conducted using AUC0-last as several subjects did not have reportable AUCτ. As the actual sampling time point did not deviate >1% from the dosing interval τ, AUC0-last accurately represented AUCτ. of HIV PIs and BOC (22%–36%). Furthermore, although BOC exposure was unchanged by ATV/r coadministration, BOC AUCτ was reduced by 45% and 32% by LPV/r and DRV/r, respectively. A previous DDI study between BOC and RTV alone indicated that the exposure of BOC (400 mg every 8 hours) was reduced by 19% when coadministered with RTV (100 mg once daily; AUCτ GMR, 0.81 [90% CI, .73–.91]), with an associated 27% reduction in BOC Cmax (GMR, 0.73 [90% CI, .57–.93]) [13]. The observed pharmacokinetic interactions cannot be explained solely by a CYP3A4/5-mediated interaction or a reduction of RTV levels by BOC leading to a decrease in the RTV-mediated boosting of the HIV PI concentrations. In addition to potently inhibiting CYP3A, RTV inhibits several uptake and efflux transporters and can induce various drugmetabolizing enzymes, including CYP3A [9, 10]. Boceprevir and the HIV PIs evaluated in this study inhibit some of the same drug-metabolizing enzymes and transporters [11, 12]. Because of the complex enzyme-transporter interplay and potential mechanisms of interaction among the 3 components (HIV PI, RTV, and BOC), it is not possible to isolate the relative contribution of each pathway to the observed interactions. In addition, the role of protein displacement or altered Figure 3. Mean (standard deviation) plasma concentration–time profiles for ritonavir in combination with atazanavir (A), lopinavir (B ), or darunavir (C ) in the presence and absence of boceprevir. Abbreviations: ATV, atazanavir; BOC, boceprevir; DRV, darunavir; LPV, lopinavir; MD, multiple dose; RTV, ritonavir. absorption cannot be excluded. Exposure of the inactive ketoreduced metabolite of BOC, SCH 629144 (a product of aldoketo-reductase-mediated metabolism), was increased by all HIV PIs/r by approximately 1- to 2-fold (data on file). As the HIV PIs and RTV inhibit both drug-metabolizing enzyme and uptake/efflux transporter systems, our data do not clarify whether the increase in SCH 629144 levels is due to increased keto-reduced metabolite formation, reduced elimination of SCH 629144, or a combination of both. The findings from this study do not indicate whether the reduced drug exposures observed in healthy volunteers will impact clinical efficacy. The lower limit of the 90% CI for the effect of BOC on ATV, LPV, and DRV fell below the bounds of .70–1.43 generally used to indicate clinically relevant effects HIV/AIDS • CID 2013:56 (1 March) • 723 Table 4. Pharmacokinetic Interactions Among Boceprevir, Lopinavir, and Ritonavir PK Parameter No. LPV PK GMR 90% CI rMSEa (BOC + LPV/RTV)/(LPV/RTV) Table 5. Pharmacokinetic Interactions Among Boceprevir, Darunavir, and Ritonavir PK Parameter No. DRV PK 13 13 0.66 0.70 (.60–.72) (.65–.77) 0.13 0.12 AUC0-last b,c (ng × h/mL) Cmax b (ng/mL) 11 11 Cmin b (ng/mL) 13 0.57 (.49–.65) 0.19 Cmin b (ng/mL) 10 13 Cmax b (ng/mL) 13 Cmin b (ng/mL) RTV PK 13 AUCτ b (ng × h/mL) b Cmax (ng/mL) Cmin b (ng/mL) (BOC + LPV/RTV)/(BOC) 0.55 (.49–.61) 0.15 BOC PK AUCτ b (ng × h/mL) 12 0.15 Cmax b (ng/mL) 12 0.43 (.36–.53) 0.27 (BOC + LPV/RTV)/(BOC) Cmin b (ng/mL) RTV PK 12 0.50 (.45–.55) 90% CI rMSEa (BOC + DRV/RTV)/(DRV/RTV) AUC0-last b,c (ng × h/mL) Cmax b (ng/mL) BOC PK AUCτ b (ng × h/mL) GMR 0.56 0.64 (.51–.61) (.58–.71) 0.12 0.13 0.41 (.38–.45) 0.11 (BOC + DRV/RTV)/(BOC) 0.68 (.65–.72) 0.072 0.75 (.67–.85) 0.16 0.65 (.56–.76) 0.20 (BOC + DRV/RTV)/(BOC) 12 0.78 (.71–.87) 0.15 AUCτ b (ng × h/mL) 11 0.73 (.68–.79) 0.092 13 13 0.88 0.58 (.72–1.07) (.52–.65) 0.28 0.16 Cmax b (ng/mL) Cmin b (ng/mL) 11 11 0.87 0.55 (.76–1.00) (.52–.59) 0.18 0.077 Abbreviations: AUC0-last, area under the concentration–time curve to the last measurable sample; AUCτ, area under the concentration–time curve during a dosing interval τ; BOC, boceprevir; CI, confidence interval; Cmax, maximum observed plasma concentration; Cmin, minimum observed plasma concentration; GMR, geometric least-squares mean ratio; LPV, lopinavir; PK, pharmacokinetics; RTV, ritonavir. Abbreviations: AUC0-last, area under the concentration–time curve to the last measurable sample; AUCτ, area under the concentration–time curve during a dosing interval τ; BOC, boceprevir; CI, confidence interval; Cmax, maximum observed plasma concentration; Cmin, minimum observed plasma concentration; DRV, darunavir; GMR, geometric least-squares mean ratio; PK. pharmacokinetics; RTV, ritonavir. a rMSE: Square root of conditional mean squared error (residual error) from the linear mixed-effect model. rMSE*100% approximates the within-subject %CV on the raw scale. a b Back-transformed least-squares mean and CI from linear mixed–effect model performed on natural log-transformed values. b Back-transformed least-squares mean and CI from linear mixed-effect model performed on natural log-transformed values c Statistical comparison was conducted using AUC0-last as several subjects did not have reportable AUCτ. As the actual sampling time point did not deviate >1% from the dosing interval τ, AUC0-last accurately represented AUCτ. c Statistical comparison was conducted using AUC0-last as several subjects did not have reportable AUCτ. As the actual sampling time point did not deviate >1% from the dosing interval τ, AUC0-last accurately represented AUCτ. for this class of compounds [14–16]. For BOC, the 90% CIs were within the clinically relevant range of .5–2.0 for the interaction with ATV/r and DRV/r, but not for LPV/r. Furthermore, compromised liver function resulting from HCV infection should be considered when translating these results to patients, as liver function may impact drug metabolism and therapeutic levels [17]. Data regarding the use of BOC-based treatment for HCV genotype 1 infection in patients coinfected with HIV are currently limited [18]. The pharmacokinetic interactions observed in healthy volunteer studies do not appear to have a substantial clinical impact in patients with HIV/HCV coinfection. Interim data from treatment-naive patients with HCV genotype 1 infection and HIV coinfection suggest that sustained virologic response (SVR) 12 rates (undetectable HCV-RNA 12 weeks posttreatment) are significantly higher in patients receiving BOC plus peginterferon/ribavirin (PR) than in those receiving placebo plus PR alone (61% vs 27%) [19]. In this study, 28 of 34 patients receiving PR and 45 of 61 patients receiving BOC plus PR received concomitant ATV/r, LPV/r, or DRV/r, and SVR rates were generally similar between these patients and those receiving alternative HIV antiviral therapy. It is possible that SVR rates may have been even higher with other background antiretroviral medications that did not affect BOC levels. However, there is no reported correlation between BOC exposure and SVR rates in either monoinfected patients in previous phase 3 trials or in HIV/HCV-coinfected patients [20]. Treatment failure (HCV RNA <2 log decline at week 12 or detectable at week 24) was higher in the placebo arm (41% vs 9%). All patients had HIV RNA levels <50 copies/mL and a CD4 cell count >200 cells/μL at baseline. During the study, 4 of 34 patients (12%) receiving placebo and 3 of 64 patients (5%) receiving BOC experienced HIV viral rebound (>50 copies/mL at 2 consecutive visits) [19]. It may be that the potentially adverse impact of a BOC-boosted PI drug–drug interaction was mitigated by a beneficial anti-HIV effect of peginterferon alfa. An important caveat is that this was a small study with 64 of 98 patients receiving BOC. Further studies are needed to confirm these findings and better define the role of BOC in this setting. Currently, BOC is not approved for treatment of HIV/HCV-coinfected patients. Guidelines are emerging that pertain to treatment of the coinfected population and are likely to evolve as more data become available [8, 18, 21, 22]. 724 • CID 2013:56 (1 March) • HIV/AIDS rMSE: Square root of conditional mean squared error (residual error) from the linear mixed-effect model. rMSE*100% approximates the within-subject %CV on the raw scale. Drug–drug interactions between BOC and other antiretroviral therapies have also been studied. Boceprevir had no impact on the exposure of the integrase inhibitor raltegravir [23]. Boceprevir also had no notable effect on the AUC or renal clearance of tenofovir, although tenofovir Cmax was increased by 32% [24]. Efavirenz AUC0–24 and Cmax were increased by 20% and 11%, respectively, in the presence of BOC [24], whereas etravirine AUCτ, Cmax, and Cmin were reduced by 23%, 24%, and 29%, respectively, in the presence of BOC [25]. Tenofovir had no clinically relevant effect on BOC pharmacokinetics, increasing BOC AUC and Cmax by 8% and 5%, respectively [24]. When coadministered with efavirenz, BOC AUC and Cmax were decreased 8% and 19%, respectively, and Cmin was decreased 44% [24]. When coadministered with etravirine, BOC AUCτ and Cmax were increased 10%, while C8hours was decreased 12% by etravirine [25]. Clinicians must consider the additive effects of interactions with other concomitantly administered drugs when determining the clinical impact of combination drug use. In addition to small sample size, limitations of the current study may also include use of a fixed-sequence design rather than a randomized crossover design. As LPV, DRV, and RTV have the potential to induce CYP450 enzymes [14, 26, 27], a crossover design would require an extra washout period of 2 weeks to restore enzyme levels to baseline, extending study duration to over 6 weeks. To allow full enzyme induction, HIVPI/r treatment was initiated 21 days before blood sampling for assessment of BOC pharmacokinetics. The short half-life of BOC and the lack of induction seen in vitro and in vivo [28] suggest that the risk of carryover effects with the current design were minimal. In conclusion, concomitant administration of BOC with PI/r reduced exposures of the HIV PIs, RTV, and BOC. The current study raises no toxicity-related safety concerns; however, the drug–drug interactions may potentially reduce the effectiveness of these HIV therapies and/or of BOC. Additional data on concomitant administration in HCV/HIV-coinfected patients are needed to provide appropriate guidance for the treatment of these patients. Notes Acknowledgments. Bioanalytical support was provided by Bhavana Kantesaria (employee of Merck Sharp & Dohme Corp), and pharmacokinetic and statistical support was provided by Megan Kozisek of Celerion (assistance supported by Merck Sharp & Dohme Corp). Medical writing and/or editorial assistance were provided by Tim Ibbotson, PhD, and Santo D’Angelo, PhD, MS, of ApotheCom. This assistance was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. Financial support. This study was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. Potential conflicts of interest. S. P. Y. has a financial relationship within the last 12 months relevant to these data with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. M. T., E. A. H., H. P. F., F. X., E. O., J. W., and J. B. are current or former employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. E. H. and M. V. are current or former employees of Merck Sharp & Dohme, the Netherlands. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Monga HK, Rodriguez-Barradas MC, Breaux K, et al. Hepatitis C virus infection-related morbidity and mortality among patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 33:240–7. 2. Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001; 33:562–9. 3. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIVinfected patients: a randomized controlled trial. JAMA 2004; 292:2839–48. 4. Chung RT, Andersen J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; 351:451–9. 5. Malcolm BA, Liu R, Lahser F, et al. SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother 2006; 50:1013–20. 6. Bacon B, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1207–17. 7. Poordad F, McCone J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195–206. 8. US Department of Health and Human Services. Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2011. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdole scentGL.pdf. Accessed 25 November 2012. 9. Hartkoorn RC, Kwan WS, Shallcross V, et al. HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms. Pharmacogenet Genomics 2010; 20:112–20. 10. Liu L, Mugundu GM, Kirby BJ, Samineni D, Desai PB, Unadkat JD. Quantification of human hepatocyte cytochrome P450 enzymes and transporters induced by HIV protease inhibitors using newly validated LC-MS/MS cocktail assays and RT-PCR. Biopharm Drug Dispos 2012; 33:207–17. 11. Josephson F. Drug-drug interactions in the treatment of HIV infection: focus on pharmacokinetic enhancement through CYP3A inhibition. J Intern Med 2010; 268:530–9. 12. Annaert P, Ye ZW, Stieger B, Augustijns P. Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1. Xenobiotica 2010; 40:163–76. 13. VICTRELIS™ (boceprevir) tablets [ prescribing information]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp, May 2011. 14. Kaletra™ (lopinavir/ritonavir) tablets [ prescribing information]. North Chicago, IL: Abbott Laboratories, April 2012. 15. Prezista™ (darunavir) tablets [ prescribing information]. Raritan, NJ: Tibotec Therapeutics, Division of Ortho Biotech Products, June 2006. 16. Reyataz™ (atazanavir sulfate) capsules [ prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company, June 2003. 17. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008; 64:1147–61. 18. Thomas DL, Bartlett JG, Peters MG, Sherman KE, Sulkowski MS, Pham PA. Provisional guidance on the use of hepatitis C virus HIV/AIDS • CID 2013:56 (1 March) • 725 19. 20. 21. 22. 23. 726 protease inhibitors for treatment of hepatitis C in HIV-infected persons. Clin Infect Dis 2012; 54:979–83. Sulkowski M, Pol S, Cooper C. Boceprevir + pegylated interferon + ribavirin for the treatment of HCV/HIV-coinfected patients: End of treatment (week 48) interim results. Available at: http://retroconfer ence.org/static/webcasts/2012/. Accessed 25 November 2012. Wenning L, Flexner C, Liu R, et al. Assessment of boceprevir (VICTRELIS™) pharmacokinetic/pharmacodynamic relationships for sustained viral response (SVR) and occurrence of anemia: results in HCV/HIV coinfected patients and in combined mono- and co-infected patients. In: 63rd Annual Meeting of the American Association for the Study of Liver Disease, 9–13 November 2012, Boston, MA; abstract 707. Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society–USA panel. JAMA 2012; 308:387–402. European AIDS Clinical Society (EACS). Guidelines: clinical management and treatment of chronic hepatitis B and C coinfection in HIVinfected adults. Available at: http://www.europeanaidsclinicalsociety. org/images/stories/EACS-Pdf/EACSGuidelines-v6.0-English.pdf. Accessed 25 November 2012. de Kanter CT, Blonk MI, Colbers AP, Schouwenberg BJ, Burger DM. Lack of a clinically significant drug-drug interaction in healthy • CID 2013:56 (1 March) • HIV/AIDS 24. 25. 26. 27. 28. volunteers between the hepatitis C virus protease inhibitor boceprevir and the HIV integrase inhibitor raltegravir. Clin Infect Dis 2013; 56:298–304. Kasserra C, Hughes E, Treitel M, Gupta S, O’Mara E. Clinical pharmacology of boceprevir: metabolism, excretion, and drug-drug interactions. In: 18th Conference on Retroviruses and Opportunistic Infections, 27 February–2 March 2011, Boston, MA. Hammond K, Wolfe P, Burton J, et al. Pharmacokinetic interaction between boceprevir and etravirine in HIV/HCV seronegative volunteers. Rev Antiviral Ther Infect Dis 2012; 3:17. Foisy MM, Yakiwchuk EM, Hughes CA. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother 2008; 42:1048–59. Yeh RF, Gaver VE, Patterson KB, et al. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr 2006; 42:52–60. US Food and Drug Administration. FDA Antiviral Drugs Advisory Committee Meeting, Boceprevir capsules briefing document. 2011. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/Com mitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM 252343.pdf. Accessed 25 November 2012.