pharmacokinetics; boceprevir; atazanavir; lopinavir; darunavir.

Transcription

1 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. Butterton 2 1 Merck Sharp & Dohme Corp, Oss, The Netherlands; 2 Merck Sharp & Dohme Corp, Whitehouse Station, New Jersey, and 3 Celerion, 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 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 (AUC τ ) by 22% 36%. ATV/r did not significantly affect boceprevir exposure, but boceprevir AUC τ 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 Presented in part: 19th Conference on Retroviruses and Opportunistic Infections, Seattle, Washington, 5 8 March Correspondence: Ellen Hulskotte, PhD, Department of Clinical Pharmacology, Merck Research Laboratories, MSD, PO Box 20, BH Oss, The Netherlands (ellen.hulskotte@merck.com). Clinical Infectious Diseases 2013;56(5): The Author Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please journals.permissions@oup.com. DOI: /cid/cis968 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 718 CID 2013:56 (1 March) HIV/AIDS

2 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 years with a body mass index kg/m 2 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: AUC last (area under the concentration time curve from time 0 to the time of the last measurable sample); AUC τ (area under the concentration time curve during a dosing interval τ); C max (maximum observed plasma concentration); T max (time to maximum observed plasma concentration); C min (minimum observed plasma concentration); Cl/F (apparent total body clearance); and t ½ (terminal phase half-life). The t ½ was determined by linear regression of the terminal phase of the log-linear concentration time profiles; reportable t ½ required fitting to at least 3 points in the terminal phase, excluding C max. Cl/F was calculated as dose/auc τ. 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 and SCH Concentrations of SCH , an inactive metabolite of BOC, were obtained as the sum of concentrations of 4 stereoisomers, SCH , SCH , SCH , and SCH The overall lower limit of quantification (LLOQ) for BOC was 4.80 ng/ml, and the overall LLOQ for SCH 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 C max 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 C max and AUC between HIV-PI/r alone and with BOC, using a 90% confidence interval (CI) of for the geometric mean ratio (GMR) of the HIV-PI/r and 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

3 Table 1. Patient Demographics RESULTS Atazanavir/RTV (n = 13) Boceprevir + RTV/PI Study Lopinavir/RTV (n = 13) Darunavir/RTV (n = 13) Sex, No. (%) Female 4 (31) 5 (38) 5 (38) Male 9 (69) 8 (62) 6 (62) Race, No. (%) White 9 (69) 9 (69) 13 (100) Nonwhite 4 (31) 4 (31) 0 Ethnicity, No. (%) Hispanic/ 4 (31) 2 (15) 0 Latino Non-Hispanic/ 9 (69) 11 (85) 13 (100) Latino Age, y, mean 36.3 (7.4) 33.1 (11.0) 37.3 (13.3) (SD) BMI, kg/m 2, mean (SD) 27.5 (3.8) 26.3 (3.1) 25.2 (3.4) 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 AUC 0-last values was then exponentiated to obtain the CI for true GMR. Subject Disposition 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). Boceprevir/Atazanavir/Ritonavir Pharmacokinetics Mean ATV concentrations were lower at all time points in the presence of BOC than with ATV/r alone (Figure 2A). C max, AUC last, and AUC τ for ATV were lower in subjects receiving BOC plus ATV/r compared with ATV/r alone: at steady state, ATV AUC 0-last,C max, and C min values were reduced by 35%, 25%, and 49%, respectively (Tables 2 and 3). Geometric mean ATV C min 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 C max (Tables 2 and 3). An approximate 18% decrease in BOC C min was seen upon coadministration with ATV/r (Table 3). Ritonavir AUC τ and C max 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 AUC 0-last, C max, and C min 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

4 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 C min 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 AUC τ,c max, and C min GMRs decreased between 45% and 57% when BOC was coadministered with LPV/r (Table 4). Geometric least-squares mean BOC C min decreased from 92 ng/ml to 40 ng/ml with LPV/r coadministration. Ritonavir AUC τ and C max 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 C max, AUC 0-last, and AUC τ were lower in the presence of BOC (Table 2), with GMR of DRV AUC 0- last, C max, and C min reduced by 44%, 36%, and 59%, respectively, when coadministered with BOC plus RTV compared with RTV alone. Geometric mean DRV C min 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 AUC τ, 25% for C max, and 35% for C min when administered with DRV/r (Table 5). Ritonavir exposure was reduced by 27% and C max by 13% in subjects receiving BOC plus DRV/r compared with those receiving DRV alone (Table 5, Figure 3). Safety 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 C max decreased from 25% to 36%. RTV exposure was also reduced in the presence HIV/AIDS CID 2013:56 (1 March) 721

5 722 CID 2013:56 (1 March) HIV/AIDS Table 2. Pharmacokinetic Parameters for Boceprevir, and Ritonavir-Boosted Atazanavir, Lopinavir and Darunavir, Geometric Means Treatment C max (ng/ml) AUC last (ng h/ml) AUC τ (ng h/ml) C min (ng/ml) t ½ (h) CL/F (L/h) T a max (h) ATV/RTV + BOC ATV PK ATV/RTV alone 3606 (37.7) n = (31.9) n = (31.3) n = (52.8) n = (26.5) n = (31.2) n = ( ) n = 12 ATV/RTV + BOC 2641 (22.9) n = (18.1) n = (13.1) n = (48.9) n = (39.6) n = (13.1) n = ( ) n = 11 BOC alone 1450 (36.7) n = (22.8) n = (26.1) n = (40.4) n = (67.8) n = (26.1) n = ( ) n = 13 BOC + ATV/RTV 1400 (27.7) n = (25.0) n = (23.8) n = (33.1) n = (88.0) n = (23.8) n = ( ) n = 11 ATV/RTV alone 1474 (31.7) n = (33.9) n = (33.9) n = (80.6) n = (17.2) n = (33.9) n = ( ) n = 12 ATV/RTV + BOC 1049 (25.6) n = (30.4) n = (29.5) n = (41.6) n = (27.6) n = (29.5) n = ( ) n = 11 LPV/RTV + BOC LPV PK LPV/RTV alone (18.8) n = (24.0) n = (22.0) n = 8 6,730 (40.0) n = (45.8) n = 8 61 (22.0) n = ( ) n = 13 LPV/RTV + BOC 9375 (23.1) n = (23.1) n = (23.2) n = (33.7) n = (35.3) n = (23.2) n = ( ) n = 13 BOC alone 1767 (47.4) n = (65.1) n = (61.9) n = (115.6) n = (86.6) n = (61.9) n = ( ) n = 13 BOC + LPV/RTV 878 (55.2) n = (64.9) n = (62.7) n = (123.7) n = (76.8) n = (62.6) n = ( ) n = 13 LPV/RTV alone 990 (44.1) n = (33.8) n = (33.0) n = (51.4) n = (25.2) n = (33.1) n = ( ) n = 13 LPV/RTV + BOC 869 (60.1) n = (43.9) n = (43.9) n = (54.8) n = (25.5) n = (43.9) n = ( ) n = 13 DRV/RTV + BOC DRV PK DRV/RTV alone 8086 (23.4) n = (24.6) n = (19.8) n = (32.1) n = (30.2) n = (19.8) n = ( ) n = 11 DRV/RTV + BOC 5192 (25.0) n = (22.2) n = (23.2) n = (26.3) n = (32.1) n = (23.2) n = ( ) n = 11 BOC alone 1564 (29.1) n = (22.8) n = (21.2) n = (36.6) n = (54.7) n = (21.2) n = ( ) n = 12 BOC + DRV/RTV 1161 (20.1) n = (22.0) n = (17.0) n = (25.8) n = (60.9) n = (17.0) n = ( ) n = 11 DRV/RTV alone 776 (36.9) n = (31.0) n = (30.9) n = (28.6) n = (19.6) n = (30.9) n = ( ) n = 11 DRV/RTV + BOC 678 (53.6) n = (36.8) n = (33.3) n = (31.1) n = (20.1) n = (33.3) n = ( ) n = 11 All data, except for T max, are presented as geometric mean (coefficient of variance). For some of the subjects, AUCτ, t ½, and Cl/F could not be reported because there was insufficient number of points after C max to define the terminal phase. Abbreviations: ATV, atazanavir; AUC last, area under the concentration time curve to the last measureable sample; AUC τ, area under the concentration time curve during a dosing interval τ; BOC, boceprevir; C max, maximum observed plasma concentration; C min, minimum observed plasma concentration; Cl/F, apparent clearance; DRV, darunavir; LPV, lopinavir; PK, pharmacokinetics; RTV, ritonavir; t ½, apparent terminal halflife; T max, time to maximum observed plasma concentration. a Data presented as median (range).

6 Table 3. Pharmacokinetic Interactions Among Boceprevir, Atazanavir, and Ritonavir PK Parameter No. GMR 90% CI rmse a ATV PK (BOC + ATV/RTV)/(ATV/RTV) AUC b,c 0-last (ng h/ml) (.55.78) 0.23 C b max (ng/ml) (.64.88) 0.21 C b min (ng/ml) (.44.61) 0.22 (BOC + ATV/RTV)/(BOC) AUC b τ (ng h/ml) ( ) 0.12 C b max (ng/ml) ( ) 0.20 C b min (ng/ml) (.68.98) 0.25 (BOC + ATV/RTV)/(ATV/RTV) AUC b τ (ng h/ml) (.58.72) 0.14 C b max (ng/ml) (.64.83) 0.17 C b min (ng/ml) (.45.67) 0.21 Abbreviations: ATV, atazanavir; AUC 0- last, area under the concentration time curve to the last measurable sample; AUC τ, area under the concentration time curve during a dosing interval τ; BOC, boceprevir; CI, confidence interval; C max, maximum observed plasma concentration; C min, 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 AUC 0-last as several subjects did not have reportable AUC τ. As the actual sampling time point did not deviate >1% from the dosing interval τ, AUC 0-last accurately represented AUC τ. of HIV PIs and BOC (22% 36%). Furthermore, although BOC exposure was unchanged by ATV/r coadministration, BOC AUC τ 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; AUC τ GMR, 0.81 [90% CI,.73.91]), with an associated 27% reduction in BOC C max (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 (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 levels is due to increased keto-reduced metabolite formation, reduced elimination of SCH , 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 generally used to indicate clinically relevant effects HIV/AIDS CID 2013:56 (1 March) 723

7 Table 4. Pharmacokinetic Interactions Among Boceprevir, Lopinavir, and Ritonavir PK Parameter No. GMR 90% CI rmse a LPV PK (BOC + LPV/RTV)/(LPV/RTV) AUC b,c 0-last (ng h/ml) (.60.72) 0.13 C b max (ng/ml) (.65.77) 0.12 C b min (ng/ml) (.49.65) 0.19 (BOC + LPV/RTV)/(BOC) AUC b τ (ng h/ml) (.49.61) 0.15 C b max (ng/ml) (.45.55) 0.15 C b min (ng/ml) (.36.53) 0.27 (BOC + LPV/RTV)/(BOC) AUC b τ (ng h/ml) (.71.87) 0.15 C b max (ng/ml) ( ) 0.28 C b min (ng/ml) (.52.65) 0.16 Abbreviations: AUC 0- last, area under the concentration time curve to the last measurable sample; AUC τ, area under the concentration time curve during a dosing interval τ; BOC, boceprevir; CI, confidence interval; C max, maximum observed plasma concentration; C min, minimum observed plasma concentration; GMR, geometric least-squares mean ratio; LPV, lopinavir; 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. 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 AUC 0-last as several subjects did not have reportable AUC τ. As the actual sampling time point did not deviate >1% from the dosing interval τ, AUC 0-last accurately represented AUC τ. for this class of compounds [14 16]. For BOC, the 90% CIs were within the clinically relevant range of 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. Table 5. Pharmacokinetic Interactions Among Boceprevir, Darunavir, and Ritonavir PK Parameter No. GMR 90% CI rmse a DRV PK (BOC + DRV/RTV)/(DRV/RTV) AUC b,c 0-last (ng h/ml) (.51.61) 0.12 C b max (ng/ml) (.58.71) 0.13 C b min (ng/ml) (.38.45) 0.11 (BOC + DRV/RTV)/(BOC) AUC b τ (ng h/ml) (.65.72) C b max (ng/ml) (.67.85) 0.16 C b min (ng/ml) (.56.76) 0.20 (BOC + DRV/RTV)/(BOC) AUC b τ (ng h/ml) (.68.79) C b max (ng/ml) ( ) 0.18 C b min (ng/ml) (.52.59) Abbreviations: AUC 0- last, area under the concentration time curve to the last measurable sample; AUC τ, area under the concentration time curve during a dosing interval τ; BOC, boceprevir; CI, confidence interval; C max, maximum observed plasma concentration; C min, 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. 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 AUC 0-last as several subjects did not have reportable AUC τ. As the actual sampling time point did not deviate >1% from the dosing interval τ, AUC 0-last accurately represented AUC τ. 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

8 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 C max was increased by 32% [24]. Efavirenz AUC 0 24 and C max were increased by 20% and 11%, respectively, in the presence of BOC [24], whereas etravirine AUC τ,c max, and C min 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 C max by 8% and 5%, respectively [24]. When coadministered with efavirenz, BOC AUC and C max were decreased 8% and 19%, respectively, and C min was decreased 44% [24]. When coadministered with etravirine, BOC AUC τ and C max were increased 10%, while C 8hours 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, HIV- PI/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. 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