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Probability of target attainment (PTA) analyses were conducted to support the recommended ceftolozane/tazobactam dosing regimens, adjusted for renal function, in patients with hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). Previously published population pharmacokinetic models describing the disposition of ceftolozane and tazobactam in plasma and epithelial lining fluid (ELF) in patients with HABP/VABP were used to simulate ceftolozane and tazobactam concentration-time profiles in plasma and ELF over the course of 14 days. The simulations were conducted for patients with normal renal function and for patients receiving adjusted doses for mild, moderate, and severe renal impairment. PTA was calculated using established pharmacokinetic/pharmacodynamic targets for ceftolozane and tazobactam. Across renal function groups, plasma PTA was 100% for ceftolozane and99% for tazobactam; ELF PTA was99% for ceftolozane and87% for tazobactam. These results provided support for the currently recommended ceftolozane/tazobactam dosing regimens for HABP/VABP, which were efficacious and well tolerated in the Ceftolozane-Tazobactam Versus Meropenem for Treatment of Nosocomial Pneumonia (ASPECT-NP) trial.

ASPECT-NP, a phase 3 trial of ceftolozane/tazobactam in hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), excluded patients with end-stage renal disease (ESRD). A modeling/simulation approach was undertaken to inform optimal dosing in this population, using previously developed ceftolozane and tazobactam population pharmacokinetic models informed by data from 16 clinical studies. Stochastic simulations were performed using NONMEM to support dose justification. Probability of target attainment (PTA) simulations in plasma and epithelial lining fluid were conducted using a 14-day treatment, with hemodialysis every other weekday for a high-dose (4X), middle-dose (3X), or low-dose (2X) regimen, where X was the recommended dose in patients with complicated intra-abdominal infection/complicated urinary tract infection and ESRD (500 mg/250 mg ceftolozane/tazobactam loading dose and 100 mg/50 mg ceftolozane/tazobactam maintenance dose administered by 1-hour infusion every 8 hours). PTA was determined using established pharmacokinetic/pharmacodynamic targets: ceftolozane, 30% of the interdose interval (8 hours) in which free ceftolozane concentration exceeded the minimum inhibitory concentration value of 4 µg/mL; tazobactam, 20% of the interdose interval in which free tazobactam concentration exceeded 1 µg/mL. Plasma PTA was90% for both agents for all 3 regimens. Plasma ceftolozane exposures at the high-dose regimen exceeded those from phase 3 study experience. Epithelial lining fluid PTA was90% for high- and middle-dose regimens but was80% for tazobactam on dialysis days at the low-dose regimen. For patients with HABP/VABP and ESRD requiring intermittent hemodialysis, the middle-dose regimen of 1.5 g/0.75 g ceftolozane/tazobactam loading + 300 mg/150 mg maintenance every 8 hours by 1-hour infusion is recommended.

Background The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function. Methods Baseline renal function was categorized as normal renal function (creatinine clearance 80–130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit. Results A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [− 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; − 2.6 [− 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; − 2.1 [− 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [− 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [− 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [− 8.7 to 19.0]). Conclusions C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

Many people infected with hepatitis C virus have comorbidities, including hypercholesterolemia, that are treated with statins. In this study, we evaluated the drug–drug interaction potential of the hepatitis C virus inhibitors elbasvir (EBR) and grazoprevir (GZR) with statins. Pitavastatin, rosuvastatin, pravastatin, and atorvastatin are substrates of organic anion-transporting polypeptide 1B, whereas rosuvastatin and atorvastatin are also breast cancer resistance protein substrates. Three open-label, phase I clinical trials in healthy adults were conducted with multiple daily doses of oral GZR or EBR/GZR and single oral doses of statins. Trial 1: GZR 200 mg plus pitavastatin 10 mg. Trial 2: Part 1, GZR 200 mg plus rosuvastatin 10 mg, then EBR 50 mg/GZR 200 mg plus rosuvastatin 10 mg; Part 2, EBR 50 mg/GZR 200 mg plus pravastatin 40 mg. Trial 3: EBR 50 mg/GZR 200 mg plus atorvastatin 10 mg. Neither GZR nor EBR pharmacokinetics were meaningfully affected by statins. Coadministration of EBR/GZR did not result in clinically relevant changes in the exposure of pitavastatin or pravastatin. However, EBR/GZR increased exposure to rosuvastatin (126%) and atorvastatin (94%). Coadministration of statins plus GZR or EBR/GZR was generally well tolerated. Although statins do not appreciably affect EBR or GZR pharmacokinetics, EBR/GZR can impact the pharmacokinetics of certain statins, likely via inhibition of breast cancer resistance protein but not organic anion-transporting polypeptide 1B. Coadministration of EBR/GZR with pitavastatin or pravastatin does not require adjustment of either dose of statin, whereas the dose of rosuvastatin and atorvastatin should be decreased when coadministered with EBR/GZR.

An exposure–efficacy analysis of the phase 3 ASPECT-NP trial was performed to evaluate the relationship between plasma exposure of ceftolozane and tazobactam and efficacy endpoints (primary: 28-day all-cause mortality; key secondary: clinical cure at test-of-cure visit) in adult participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). Participants ( N = 231) from the ceftolozane/tazobactam treatment group in the intention-to-treat population who had pharmacokinetic data available and relevant baseline lower respiratory tract (LRT) pathogen(s) susceptibility data were included.

Novel therapeutics for pulmonary arterial hypertension (PAH) with improved safety/tolerability profiles are needed to address continued high rates of morbidity/mortality.This Phase 1 study evaluated efficacy/safety of inhaled single-dose MK-5475, an investigational, small-molecule stimulator of soluble guanylate cyclase designed for inhaled delivery via a dry-powder inhaler device, in participants with PAH (Clinicaltrials.gov: NCT03744637). Eligible participants were 18-70 years of age; body mass index ≤35 kg/mMK-5475 was generally well tolerated without systemic side effects on blood pressure or heart rate up to 24 h post dose. With respect to the primary pharmacodynamic outcome, mean reductions in pulmonary vascular resistance ranged from 21% to 30% across 120 μg and 360 μg doses.Treatment with inhaled single-dose MK-5475 showed rapid and sustained reductions in pulmonary vascular resistance and increases in pulmonary blood volume. MK-5475 was generally well tolerated versus placebo without vasodilatory systemic side effects. The promising pulmonary selectivity and favorable safety/tolerability profile of MK-5475 seen in this study of adult participants with PAH lays the foundation for further clinical development.

Ceftolozane/tazobactam (C/T) is a combination of a novel cephalosporin with tazobactam, recently approved for the treatment of hospital‐acquired and ventilator‐associated pneumonia. The plasma pharmacokinetics (PK) of a 3‐g dose of C/T (2 g ceftolozane and 1 g tazobactam) administered via a 1‐hour infusion every 8 hours in adult patients with nosocomial pneumonia (NP) were evaluated in a phase 3 study (ASPECT‐NP; NCT02070757). The present work describes the development of population PK models for ceftolozane and tazobactam in plasma and pulmonary epithelial lining fluid (ELF). The concentration‐time profiles of both agents were well characterized by 2‐compartment models with zero‐order input and first‐order elimination. Consistent with the elimination pathway, renal function estimated by creatinine clearance significantly affected the clearance of ceftolozane and tazobactam. The central volumes of distribution for both agents and the peripheral volume of distribution for tazobactam were approximately 2‐fold higher in patients with pneumonia compared with healthy participants. A hypothetical link model was developed to describe ceftolozane and tazobactam disposition in ELF in healthy participants and patients with pneumonia. Influx (from plasma to the ELF compartment) and elimination (from the ELF compartment) rate constants were approximately 97% lower for ceftolozane and 52% lower for tazobactam in patients with pneumonia versus healthy participants. These population PK models adequately described the plasma and ELF concentrations of ceftolozane and tazobactam, thus providing a foundation for further modeling and simulation, including the probability of target attainment assessments to support dose recommendations of C/T in adult patients with NP.

Purpose The burden of hepatitis C virus infection is particularly high in Asian countries, and new treatments are urgently needed. The purpose of this study was to characterize the pharmacokinetics (PK) and safety of the fixed-dose combination tablet of elbasvir/grazoprevir in healthy Chinese participants. Patient and Methods In this Phase I, single-site, open-label, 3-period study in healthy Chinese adults, participants received a single tablet of elbasvir 50 mg/grazoprevir 100 mg, followed by blood sampling for up to 96 hrs (http://www.chinadrugtrials.org.cn/ CTR20160034; Protocol PN071). Participants then received 1 tablet daily for 10 days, followed by a minimum 10-day washout, after which participants received a single dose of 2 tablets (elbasvir 100 mg/grazoprevir 200 mg). Elbasvir and grazoprevir PK were assessed following single and multiple doses. Safety and tolerability were also evaluated. Results Twelve participants (50% male) were enrolled in and completed the study. Following single-dose oral administration of elbasvir 50 mg/grazoprevir 100 mg or elbasvir 100 mg/grazoprevir 200 mg, the median Tmax was 3-4 hrs and elimination half-life was 18 hrs (elbasvir) and 30 hrs (grazoprevir). Multiple-dose administration resulted in AUC0-24 accumulation ratios of 1.58 (elbasvir) and 2.35 (grazoprevir). Both elbasvir 50 mg/grazoprevir 100 mg and 100 mg/200 mg regimens were generally well tolerated. Conclusion Single-dose administration of elbasvir 50 mg/grazoprevir 100 mg or 100 mg/200 mg and once-daily administration of elbasvir 50 mg/grazoprevir 100 mg for 10 days has been adequately characterized, with PK values within the expected range, and was generally well tolerated in healthy Chinese male and female participants.

Tedizolid phosphate is an oxazolidinone antibacterial agent approved for the treatment of Gram-positive acute bacterial skin and skin structure infections (ABSSSIs) in patients aged ≥12 years. To support the use of tedizolid phosphate in adolescents with ABSSSIs, a population pharmacokinetic (PK) model, developed using adult and pediatric data, was updated to include PK data from a phase 3 clinical trial (PN012) that evaluated the safety and efficacy of once-daily oral or intravenous 200-mg tedizolid phosphate treatment in adolescents (12 to

Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug-drug interactions. We evaluated the pharmacokinetic interaction of the direct-acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open-label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration-time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV-coinfected people.

Tazobactam/ceftolozane is a combination of a β-lactamase inhibitor and a cephalosporin antibiotic, with recommended dosage for patients with normal renal function of tazobactam 0.5 g/ceftolozane 1 g administered as a 1-h intravenous infusion every 8 h. The doses in patients with moderate and severe renal impairment are recommended to be reduced by half and 1/4th, respectively. The dose in patients undergoing dialysis is a single loading dose of 750 mg followed after 8 h by a 150 mg maintenance dose. In order to evaluate pharmacokinetics (PK) in Japanese patients, individual Bayes PK parameters were derived using the previously developed population PK models. Furthermore, attainment of PK/pharmacodynamic target in Japanese patients was calculated to confirm the recommended dosage. Based on PK data from 200 Japanese patients in the phase 3 studies, including patients with mild and moderate renal impairment, individual tazobactam/ceftolozane PK parameters were derived. No clinically relevant difference was observed in tazobactam/ceftolozane exposures between Japanese and non-Japanese patients. All Japanese patients achieved a target percent of time that free ceftolozane concentrations are above the minimum inhibitory concentration (MIC) of 30% for MICs of up to 8 μg/mL. Also for tazobactam, all Japanese patients achieved a target percent of time that the free tazobactam concentration exceeds a threshold concentration (1 μg/mL) of 20%. The results suggest that the doses will be efficacious in the Japanese population. The results indicate that the recommended dose in patients with normal renal function or renal impairment is appropriate in Japanese patients.

To describe the phase 1 and population pharmacokinetic investigations that support dosing recommendations for elbasvir/grazoprevir (EBR/GZR) in hepatitis C virus-infected people with advanced chronic kidney disease. This was an open-label, two-part, multiple-dose trial (MK-5172 PN050; NCT01937975) in 24 non–HCV-infected participants with end-stage renal disease (ESRD) or severe renal impairment who received once-daily EBR 50 mg and GZR 100 mg for 10 days. Population pharmacokinetic analyses from the phase 3 C-SURFER study (PN052, NCT02092350) were also conducted. When comparing haemodialysis (HD) and non-HD days in participants with ESRD, geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for EBR and GZR AUC0–24 were 1.14 (1.08–1.21) and 0.97 (0.87–1.09). When comparing ESRD and healthy participants, GMRs (90% CIs) for EBR and GZR AUC0–24 were 0.99 (0.75–1.30) and 0.83 (0.56–1.22) on HD days, and 0.86 (0.65–1.14) and 0.85 (0.58–1.25) on non-HD days. GMRs (90% CIs) for AUC0–24 in participants with severe renal impairment relative to healthy controls were 1.65 (1.09–2.49) for GZR and 1.86 (1.38–2.51) for EBR. In population modelling of data from C-SURFER, absolute geometric means of steady-state EBR AUC0–24 were 2.78 and 3.07 μM*h (HD and non-HD recipients) and GZR AUC0–24 were 1.80 and 2.34 μM*h (HD and non-HD recipients). EBR/GZR represents an important treatment option for HCV infection in people with severe renal impairment and those with ESRD. No dosage adjustment of EBR/GZR is required in people with any degree of renal impairment, including those receiving dialysis.

Background Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection. Objectives To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir. Methods Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg. Results The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir. Conclusions Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people.

Many people infected with hepatitis C virus have comorbidities, including hypercholesterolemia, that are treated with statins. In this study, we evaluated the drug-drug interaction potential of the hepatitis C virus inhibitors elbasvir (EBR) and grazoprevir (GZR) with statins. Pitavastatin, rosuvastatin, pravastatin, and atorvastatin are substrates of organic anion-transporting polypeptide 1B, whereas rosuvastatin and atorvastatin are also breast cancer resistance protein substrates.Three open-label, phase I clinical trials in healthy adults were conducted with multiple daily doses of oral GZR or EBR/GZR and single oral doses of statins. Trial 1: GZR 200 mg plus pitavastatin 10 mg. Trial 2: Part 1, GZR 200 mg plus rosuvastatin 10 mg, then EBR 50 mg/GZR 200 mg plus rosuvastatin 10 mg; Part 2, EBR 50 mg/GZR 200 mg plus pravastatin 40 mg. Trial 3: EBR 50 mg/GZR 200 mg plus atorvastatin 10 mg.Neither GZR nor EBR pharmacokinetics were meaningfully affected by statins. Coadministration of EBR/GZR did not result in clinically relevant changes in the exposure of pitavastatin or pravastatin. However, EBR/GZR increased exposure to rosuvastatin (126%) and atorvastatin (94%). Coadministration of statins plus GZR or EBR/GZR was generally well tolerated.Although statins do not appreciably affect EBR or GZR pharmacokinetics, EBR/GZR can impact the pharmacokinetics of certain statins, likely via inhibition of breast cancer resistance protein but not organic anion-transporting polypeptide 1B. Coadministration of EBR/GZR with pitavastatin or pravastatin does not require adjustment of either dose of statin, whereas the dose of rosuvastatin and atorvastatin should be decreased when coadministered with EBR/GZR.

In the phase 3 ASPECT-NP trial (NCT02070757), ceftolozane/tazobactam (C/T) was noninferior to meropenem for treatment of Gram-negative ventilated hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (vHABP/VABP). Here, we report outcomes in participants from ASPECT-NP with renal impairment (RI). Participants were categorized by their baseline renal function as follows: normal renal function (NRF; creatinine clearance [CL(CR)], ≥80 ml/min), mild RI (CL(CR), >50 to

Our hollow-fiber infection model simulated the projected steady-state pharmacokinetics of ceftolozane and tazobactam in lung epithelial lining fluid of patients with pneumonia receiving 3 g of ceftolozane/tazobactam every 8 hours. Results confirmed the previously established in vitro activity of ceftolozane/tazobactam at and above approved breakpoints against multidrug-resistant Pseudomonas aeruginosa, regardless of Pseudomonas-derived cephalosporinase allele.

We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK-8742-P010 and MK-5172-P030) in non-hepatitis C virus (HCV)-infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R- and S-methadone AUC0-24 were 1.03 (90% confidence interval (CI), 0.92-1.15) and 1.09 (90% CI, 0.94-1.26) in the presence/absence of EBR; and 1.09 (90% CI, 1.02-1.17) and 1.23 (90% CI, 1.12-1.35) in the presence/absence of GZR. The GMRs for EBR and GZR AUC0-24 in participants receiving methadone relative to a healthy historical cohort not receiving methadone were 1.20 (90% CI, 0.94-1.53) and 1.03 (90% CI, 0.76-1.41), respectively. These results indicate that no dose adjustment is required for individuals with HCV infection receiving stable methadone therapy and the EBR/GZR fixed-dose regimen.

The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single-dose trial in healthy participants. Trial 2 was a multiple-dose trial in participants on BUP/NAL maintenance therapy. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC0-∞ were 0.98 (0.89-1.08), 0.97 (0.86-1.09), and 0.88 (0.78-1.00) in the presence/absence of EBR; 0.98 (0.81-1.19), 1.13 (0.97-1.32), and 1.10 (0.82-1.47) in the presence/absence of GZR. The GMRs (90% CI) for EBR and GZR AUC0-∞ in the absence/presence of BUP/NAL were 1.22 (0.98-1.52) and 0.86 (0.63-1.18). In conclusion, no dose adjustment for BUP/NAL, EBR, or GZR is required for patients with HCV infection receiving EBR/GZR and BUP/NAL maintenance therapy.

The combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection. To evaluate the pharmacokinetics and safety of single-dose elbasvir 50 mg in participants with hepatic impairment. Participants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study. Blood samples were collected to assess pharmacokinetics. Safety and tolerability were assessed throughout the study. Thirty-four participants were enrolled: eight with mild hepatic impairment, 11 with moderate hepatic impairment, seven with severe hepatic impairment, and eight healthy matched controls. Participants with mild, moderate, and severe hepatic impairment demonstrated a numeric, but not statistically significant, decrease in elbasvir exposure compared with controls, with a mean 39, 28, and 12% decrease in area under the concentration–time curve from time 0 extrapolated to infinity, as well as a 42, 31, and 42% decrease in maximum plasma concentration (C max), respectively. The observed median time to C max was similar in participants with hepatic impairment and controls. Single-dose administration of elbasvir was well tolerated. The pharmacokinetics of elbasvir after a single, oral 50-mg dose were not clinically meaningfully altered in non–HCV-infected participants with mild, moderate, or severe hepatic dysfunction. However, since elbasvir is currently available only as part of a fixed-dose combination with grazoprevir, the fixed-dose combination should not be administered to patients with moderate or severe hepatic impairment, due to the significantly increased plasma grazoprevir exposures in those populations.

Concomitant proton pump inhibitor (PPI) use reduces plasma concentrations of certain nonstructural protein 5A inhibitors, which are key components of modern hepatitis C infection (HCV) treatments. These reduced concentrations may decrease efficacy, leading to challenging treatment failures due to the development of resistance-associated substitutions. This post-hoc analysis assessed 12-week sustained viral response (SVR12) and pharmacokinetics of fixed-dose combination elbasvir/grazoprevir (EBR/GZR) in patients with HCV infection and self-reported PPI use. Data were derived from six phase 3 EBR/GZR trials with treatment-naive or treatment-experienced genotype 1- or 4-infected patients, with or without compensated cirrhosis. Baseline PPI use was defined as ≥7 consecutive days of use between study days -7 and 7. Bivariate analyses assessed PPI use and factors associated with SVR12 with sex, age (continuous and dichotomous), cirrhosis status, prior treatment status, baseline HCV RNA (continuous and dichotomous), HCV genotype, and baseline resistance-associated substitutions as variables in the models. Overall, 12% (162/1,322) of EBR/GZR-treated patients reported baseline PPI use. Of those, 96% achieved SVR12. In patients without PPI use, 97% achieved SVR12. PPI use was not a predictive factor in achieving SVR12 based on a univariate analysis (P = 0.188). In the bivariate models, none of the interaction terms involving PPI use were statistically significant. There was no significant effect of PPI usage, regardless of adjustment for considered factors. The estimated area under the curve and maximum concentration values for EBR were comparable among patients with and without reported PPI use. Conclusion: These results demonstrate that PPI use with EBR/GZR had no clinically significant effect on SVR12 rates in genotype 1/4-infected patients with or without compensated cirrhosis. (clinicaltrials.gov identifiers: NCT02092350, NCT02105467, NCT02105662, NCT02105688, NCT02105701, NCT02358044) (Hepatology Communications 2017;1:757-764).

Use of agents to suppress gastric acid secretion is common among patients with hepatitis C virus (HCV) infection. The aims of this open-label, three-period, fixed-sequence study were to evaluate the effect of famotidine and pantoprazole on the pharmacokinetics and safety of elbasvir/grazoprevir fixed-dose combination (FDC) in 16 healthy subjects. Elbasvir and grazoprevir each exhibited similar pharmacokinetics following single-dose administration of elbasvir/grazoprevir with or without famotidine or pantoprazole. Geometric mean ratios (GMRs) of grazoprevir AUC(0,∞), Cmax , and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 0.89-1.17. Similarly, GMRs of elbasvir AUC(0,∞), Cmax , and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 1.02-1.11. These results indicate that gastric acid-reducing agents do not modify the pharmacokinetics of elbasvir or grazoprevir in a clinically relevant manner and may be coadministered with elbasvir/grazoprevir in HCV-infected patients without restriction.

The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (n = 10) and the potential two-way pharmacokinetic interactions of elbasvir (n = 30) or grazoprevir (n = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC0-24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC0-24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC0-24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir. ispartof: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY vol:63 issue:4 ispartof: location:United States status: published

Tedizolid phosphate, the prodrug of the active antibiotic tedizolid, is an oxazolidinone for the treatment of acute bacterial skin and skin structure infections. Studies in a mouse thigh infection model demonstrated that tedizolid has improved potency and pharmacokinetics/pharmacodynamics (PK/PD) compared with those of linezolid. Subsequent studies showed that the efficacy of tedizolid was enhanced in immunocompetent (IC) mice compared with neutropenic (immunosuppressed [IS]) mice, with stasis at clinically relevant doses being achieved only in the presence of granulocytes. The tedizolid label therefore contains a warning about its use in neutropenic patients. This study reevaluated the PK/PD of tedizolid and linezolid in the mouse thigh infection model in IC and IS mice using a methicillin-resistant Staphylococcus aureus (MRSA) strain (ATCC 33591) and a methicillin-susceptible S. aureus (MSSA) strain (ATCC 29213). The antistaphylococcal effect of doses ranging from 1 to 150 mg/kg of body weight tedizolid (once daily) or linezolid (twice daily) was determined at 24, 48, and 72 h after initiating treatment. In IC mice, stasis was achieved in the absence of antibiotics, and both tedizolid and linezolid reduced the burden further beyond a static effect. In IS mice, tedizolid achieved stasis against MRSA ATCC 33591 and MSSA ATCC 29213 at 72 h at a human clinical dose of 200 mg, severalfold lower than that in earlier studies. Linezolid achieved a static effect against MRSA ATCC 33591 in IS mice at a dose lower than that used clinically. This study demonstrates that, with time, both tedizolid and linezolid at clinically relevant exposures achieve stasis in neutropenic mice with an MRSA or MSSA thigh infection.

Treatment of individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) requires careful consideration of potential drug-drug interactions. The pharmacokinetic interaction of the HCV fixed-dose combination treatment of elbasvir/grazoprevir (EBR/GZR) when coadministered with the fixed-dose combination HIV treatment of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (EVG/COB/TDF/FTC) was evaluated in 22 healthy adults. In period 1, oral doses of EVG/COB/TDF/FTC (150 mg/150 mg/300 mg/200 mg) were administered once daily for 7 days. In period 2, oral doses of EBR/GZR (50 mg/100 mg) were administered once daily for 10 days. In period 3, oral doses of EVG/COB/TDF/FTC were coadministered with EBR/GZR once daily for 10 days. The pharmacokinetics of EVG/COB/TDF/FTC were not clinically meaningfully altered by concomitant EBR/GZR administration. Geometric mean ratios (90%CIs) for area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24 ) in the presence/absence of EBR/GZR were 1.1 (1.0, 1.2) for elvitegravir; 1.1 (1.0, 1.1) for emtricitabine; 1.2 (1.1, 1.2) for tenofovir; and 1.5 (1.4, 1.6) for cobicistat. In comparison, the AUC0-24 of elbasvir was ∼2 times higher and the AUC0-24 of grazoprevir was ∼5 times higher following concomitant administration of EVG/COB/TDF/FTC and EBR/GZR. Geometric mean ratios (90%CI) for AUC0-24 in the presence/absence of EVG/COB/TDF/FTC were 2.2 (2.0, 2.4) for elbasvir and 5.4 (4.5, 6.4) for grazoprevir. Coadministration of EVG/COB/TDF/FTC and EBR/GZR was generally well tolerated in healthy adults in this study. Nevertheless, because of the increased GZR exposure that occurs with coadministration of EVG/COB/TDF/FTC and EBR/GZR, coadministration of this combination is not recommended in those coinfected with HIV and HCV.

We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK‐8742‐P010 and MK‐5172‐P030) in non‐hepatitis C virus (HCV)‐infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R‐ and S‐methadone AUC0‐24 were 1.03 (90% confidence interval (CI), 0.92–1.15) and 1.09 (90% CI, 0.94–1.26) in the presence/absence of EBR; and 1.09 (90% CI, 1.02–1.17) and 1.23 (90% CI, 1.12–1.35) in the presence/absence of GZR. The GMRs for EBR and GZR AUC0‐24 in participants receiving methadone relative to a healthy historical cohort not receiving methadone were 1.20 (90% CI, 0.94–1.53) and 1.03 (90% CI, 0.76–1.41), respectively. These results indicate that no dose adjustment is required for individuals with HCV infection receiving stable methadone therapy and the EBR/GZR fixed‐dose regimen.

Intravenous opioid use is a common route of hepatitis C virus (HCV) infection; consequently, the prevalence of HCV is high among patients on methadone or buprenorphine/naloxone. The authors evaluated the pharmacokinetic interaction of boceprevir with methadone or buprenorphine/naloxone in patients on stable maintenance therapy. This was a two-center, open-label, fixed-sequence study in 21 adult volunteers on stable maintenance therapy. Oral methadone (20–150 mg once daily) or sublingual buprenorphine/naloxone (8/2–24/6 mg once daily) was administered alone or in combination with boceprevir (800 mg every 8 h) on days 2–7. Pharmacokinetic sampling occurred before and up to 24 h after the dose on days 1 and 7. Coadministration of boceprevir reduced the area under the concentration-time curve during a dosing interval τ (AUC τ ) and maximum observed plasma (or serum) concentration (C max) of R-methadone (geometric mean ratios (GMRs) [90 % confidence intervals (CIs)], 0.85 [0.74, 0.96] and 0.90 [0.71, 1.13]) and S-methadone (GMRs [90 % CIs], 0.78 [0.66, 0.93] and 0.83 [0.64, 1.09]). Boceprevir increased the AUC τ and C max of buprenorphine (GMRs [90 % CIs], 1.19 [0.91, 1.58] and 1.18 [0.93, 1.50]) and naloxone (GMRs [90 % CIs], 1.33 [0.90, 1.93] and 1.09 [0.79, 1.51]). Boceprevir exposure upon methadone or buprenorphine/naloxone coadministration was not clinically different from historical controls and there was no evidence of opioid withdrawal or excess. There was no clinically meaningful impact of boceprevir on methadone or buprenorphine pharmacokinetics, suggesting that methadone/buprenorphine dose adjustments are not required upon coadministration with boceprevir. Individual patients may differ in their clinical experience and clinicians should maintain vigilance when coadministering these medications.

Purpose This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals. Methods This study was a 2-part, parallel-arm, open-label trial. In part 1, single-dose PK variables of elbasvir 10/50/100 mg and grazoprevir 50/100/200 mg were evaluated in 10 participants per drug. In part 2, 10-day multiple-dose PK variables of elbasvir 50 mg and grazoprevir 100 mg administered once daily alone and in combination were evaluated in 12 participants. Summary and inferential statistics of the PK parameters are reported. Elbasvir and grazoprevir PK parameters were also compared between Chinese participants and historical data from white participants. Findings Single-dose elbasvir and grazoprevir median Tmax were 2.9 to 4.0 and 1.9 to 3.0 hours after administration, respectively. Elbasvir AUC0–∞ and Cmax increased in a dose-proportional manner (slope estimate [90% CI], 0.92 [0.84–1.01] and 0.98 [0.86–1.09], respectively), whereas grazoprevir AUC0–∞ and Cmax increased in a greater-than-dose-proportional manner (slope estimate [90% CI], 1.42 [1.27–1.57] and 1.96 [1.64–2.29]). After repeated administration, the accumulation ratios for AUC0–24, 24-hour concentration, and Cmax were 1.55, 1.57, and 1.38 for elbasvir and 2.03, 1.23, and 2.51 for grazoprevir. Co-administration of elbasvir 50 mg and grazoprevir 100 mg once daily did not have a clinically relevant effect on the PK variables of either drug. Median Tmax after co-administration versus alone was 3.0 hours versus 3.0 hours for elbasvir and 3.1 hours versus 3.0 hours for grazoprevir. Geometric mean ratios (90% CI) for elbasvir and grazoprevir AUC0–24 (Chinese/white participants) were 1.58 (1.03–2.42) and 1.21 (0.76–1.92). Elbasvir and grazoprevir, administered alone or concomitantly, were well tolerated. Implications In healthy Chinese individuals, administration of elbasvir and grazoprevir, alone or concomitantly, was generally well tolerated, with a thoroughly characterized PK profile. Elbasvir and grazoprevir exposures may trend higher in Chinese healthy participants relative to white healthy participants. Protocol number MK-5172 PN022.

Elbasvir (EBR)/grazoprevir (GZR) may be coadministered with immunosuppressant drugs in posttransplant people who are infected with hepatitis C virus. The aim of the present study was to assess the safety and pharmacokinetic interactions between EBR and GZR and single doses of cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and prednisone. This was a 4-part, open-label study in 58 healthy volunteers. Participants received single doses of cyclosporine 400 mg, tacrolimus 2 mg, MMF 1 g, or prednisone 40 mg alone or in the presence of once-daily EBR 50 mg/GZR 200 mg. Multiple oral doses of EBR + GZR had no significant effect on cyclosporine. However, in the presence of cyclosporine, the 24-hour area under the concentration-time curve of GZR was increased by approximately 15-fold (geometric mean ratio [90%CI] 15.21 [12.83; 18.04]); the concentration of EBR was increased approximately 2-fold in the presence of cyclosporine. Coadministration of EBR/GZR and tacrolimus did not affect the pharmacokinetics of EBR or GZR, but resulted in an increase in tacrolimus AUC (geometric mean ratio [90%CI] 1.43 [1.24; 1.64]). There were no clinically relevant interactions between EBR/GZR and either MMF or prednisone. Data from the present study indicate that EBR/GZR may be coadministered in people receiving tacrolimus, MMF, and prednisolone. EBR/GZR is contraindicated in people receiving cyclosporine because the significantly higher concentrations of GZR may increase the risk of transaminase elevations.

The purpose of this study was to examine drug interactions between boceprevir, a hepatitis C virus NS3/4A protease inhibitor, and a combined oral contraceptive containing ethinyl estradiol (EE) and norethindrone (NE). A single-center, open-label study was conducted in 20 healthy female volunteers. In three consecutive 28-day treatment periods, subjects received EE/NE (0.035 mg/1 mg; 21 days on, 7 days off). During period 3, subjects also received boceprevir (800 mg three times daily) for 28 days. Coadministration of boceprevir with EE/NE did not affect NE AUC0–24 but slightly reduced NE C max. Geometric mean ratios (GMRs) for NE AUC0–24 and C max with EE/NE alone and EE/NE plus boceprevir were 0.96 (90 % confidence interval (CI), 0.87–1.06) and 0.83 (90 % CI, 0.76–0.90). Coadministration of boceprevir with EE/NE reduced EE AUC0–24 and C max by 26 and 21 %, with GMRs of 0.74 (90 % CI, 0.68–0.80) and 0.79 (90 % CI, 0.75–0.84). Boceprevir had no effect on mid-cycle luteinizing hormone (LH), follicle-stimulating hormone (FSH), or sex hormone-binding globulin levels, and progesterone concentrations remained

Purpose The safety, tolerability, and pharmacokinetic (PK) interactions of MK-0646 in combination with cetuximab and irinotecan were investigated in Japanese patients with advanced colorectal cancer. Methods Twenty patients were treated in the following study arms in combination with cetuximab and irinotecan: A [MK-0646 (10 mg/kg) weekly starting on Day 22], B [MK-0646 (15 mg/kg) on Day 8, followed by 7.5 mg/kg every 2 weeks], or C [MK-0646 (10 mg/kg) on Day 1 and weekly starting on Day 22]. Dose limiting toxicities (DLTs) were evaluated during a prespecified 4-week period in arms A and B. Full PK sampling was performed to evaluate the PK interactions. Results One of the 6 evaluable patients in arm A developed a DLT (grade 3 hyperglycemia); no DLTs occurred in the 6 patients in arm B. Common treatment-related adverse events included leukopenia, neutropenia, dermatitis acneiform, paronychia, nausea, stomatitis, diarrhea, and decreased appetite. The co-administration of cetuximab and irinotecan with MK-0646 increased the MK-0646 AUC0–168h by 25 %, with MK-0646 accumulation from the previous dose contributing to the observed increase. The co-administration of MK-0646 with cetuximab and irinotecan did not affect the PK of cetuximab and irinotecan, but reduced the Cmax (from 16.8 to 13.0 ng/mL) and the AUC0–24h (by 13 %) of SN-38, the active metabolite of irinotecan. Conclusions The triple combination of MK-0646, cetuximab, and irinotecan was well tolerated in Japanese patients with advanced colorectal cancer. These results indicate a minimal potential for PK interactions between MK-0646 and cetuximab and between MK-0646 and irinotecan/SN-38.

Boceprevir is a potent orally administered inhibitor of hepatitis C virus and a strong, reversible inhibitor of CYP3A4, the primary metabolic pathway for many 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Thus, the aim of the present study was to investigate drug-drug interactions between atorvastatin or pravastatin and boceprevir. We conducted a single-center, open-label, fixed-sequence, one-way-crossover study with 20 healthy adult volunteers. Subjects received single-dose atorvastatin (40 mg) or pravastatin (40 mg) on day 1, followed by boceprevir (800 mg three times daily) for 7 to 10 days. Repeat single doses of atorvastatin or pravastatin were administered in the presence of steady-state boceprevir. Atorvastatin exposure increased in the presence of boceprevir, with atorvastatin area under the concentration-time curve from time zero to infinity after single dosing (AUC inf ) increasing 2.3-fold (90% confidence interval [CI], 1.85, 2.90) and maximum observed concentration in plasma ( C max ) 2.7-fold (90% CI, 1.81, 3.90). Pravastatin exposure was slightly increased in the presence of boceprevir, with pravastatin AUC inf increasing 1.63-fold (90% CI, 1.03, 2.58) and C max 1.49-fold (90% CI, 1.03, 2.14). Boceprevir exposure was generally unchanged when the drug was coadministered with atorvastatin or pravastatin. All adverse events were mild and consistent with the known safety profile of boceprevir. The observed 130% increase in AUC of atorvastatin supports the use of the lowest possible effective dose of atorvastatin when coadministered with boceprevir, without exceeding a maximum daily dose of 40 mg. The observed 60% increase in pravastatin AUC with boceprevir coadministration supports the initiation of pravastatin treatment at the recommended dose when coadministered with boceprevir, with close clinical monitoring.

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 (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.

The hepatitis C virus protease inhibitor boceprevir is a strong inhibitor of cytochrome P450 3A4 and 3A5 (CYP3A4/5). Cyclosporine and tacrolimus are calcineurin inhibitor immunosuppressants used to prevent organ rejection after liver transplantation; both are substrates of CYP3A4. This two-part pharmacokinetic interaction study evaluated boceprevir with cyclosporine (part 1) and tacrolimus (part 2). In part 1, 10 subjects received single-dose cyclosporine (100 mg) on day 1, single-dose boceprevir (800 mg) on day 3, and concomitant cyclosporine/boceprevir on day 4. After washout, subjects received boceprevir (800 mg three times a day) for 7 days plus single-dose cyclosporine (100 mg) on day 6. In part 2A, 12 subjects received single-dose tacrolimus (0.5 mg). After washout, they received boceprevir (800 mg three times a day) for 11 days plus single-dose tacrolimus (0.5 mg) on day 6. In part 2B, 10 subjects received single-dose boceprevir (800 mg) and 24 hours later received boceprevir (800 mg) plus tacrolimus (0.5 mg). Coadministration of boceprevir with cyclosporine/tacrolimus was well tolerated. Concomitant boceprevir increased the area under the concentration-time curve from time 0 to infinity after single dosing (AUCinf) and maximum observed plasma (or blood) concentration (Cmax) of cyclosporine with geometric mean ratios (GMRs) (90% confidence interval [CI]) of 2.7 (2.4-3.1) and 2.0 (1.7-2.4), respectively. Concomitant boceprevir increased the AUCinf and Cmax of tacrolimus with GMRs (90% CI) of 17 (14-21) and 9.9 (8.0-12), respectively. Neither cyclosporine nor tacrolimus coadministration had a meaningful effect on boceprevir pharmacokinetics. Conclusion: Dose adjustments of cyclosporine should be anticipated when administered with boceprevir, guided by close monitoring of cyclosporine blood concentrations and frequent assessments of renal function and cyclosporine-related side effects. Administration of boceprevir plus tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects. (HEPATOLOGY 2012;56:1622–1630)

Boceprevir is a potent, orally administered ketoamide inhibitor that targets the active site of the hepatitis C virus (HCV) non-structural (NS) 3 protease. The addition of boceprevir to peginterferon plus ribavirin resulted in higher rates of sustained virologic response (SVR) than for peginterferon plus ribavirin alone in phase III studies in both previously treated and untreated patients with HCV infection. Because boceprevir is metabolized by metabolic routes common to many other drugs, and is an inhibitor of cytochrome P450 (CYP) 3A4/5, there is a high potential for drug-drug interactions when boceprevir is administered with other therapies, particularly when treating patients with chronic HCV infection who are often receiving other medications concomitantly. Boceprevir is no longer widely used in the US or EU due to the introduction of second-generation treatments for HCV infection. However, in many other geographic regions, first-generation protease inhibitors such as boceprevir continue to form an important treatment option for patients with HCV infection. This review summarizes the interactions between boceprevir and other therapeutic agents commonly used in this patient population, indicating dose adjustment requirements where needed. Most drug interactions do not affect boceprevir plasma concentrations to a clinically meaningful extent, and thus efficacy is likely to be maintained when boceprevir is coadministered with the majority of other therapeutics. Overall, the drug-drug interaction profile of boceprevir suggests that this agent is suitable for use in a wide range of HCV-infected patients receiving concomitant therapies.

O005 RETREATMENT OF PATIENTS WHO FAILED 8 OR 12 WEEKS OF LEDIPASVIR/SOFOSBUVIR-BASED REGIMENS WITH LEDIPASVIR/SOFOSBUVIR FOR 24 WEEKS E. Lawitz, S. Flamm, J.C. Yang, P.S. Pang, Y. Zhu, E. Svarovskaia, J.G. McHutchison, D. Wyles, P. Pockros. Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, Feinberg School of Medicine, Northwestern University, Chicago, IL, Gilead Sciences, Foster City, CA, University of California, San Diego, CA, Scripps Clinic, La Jolla, CA, United States E-mail: jenny.yang@gilead.com

The Clp/Hsp 100 molecular chaperones are unusual in their ability to tease apart protein aggregates and complexes. Recent results make a good case that these chaperones bind substrates via PDZ-like domains; this may reflect a general strategy for manipulating the assembly state of substrate proteins.

The molecular chaperonins are essential proteins involved in protein folding, complex assembly, and polypeptide translocation. While there is abundant structural information about the machinery and the mechanistic details of its action are well studied, it is yet unresolved how chaperonins recognize a large number of structurally unrelated polypeptides in their unfolded or partially folded forms. To determine the nature of chaperonin-substrate recognition, we have characterized by NMR methods the interactions of GroEL with synthetic peptides that mimic segments of unfolded proteins. In previous work, we found using transferred nuclear Overhauser effect (trNOE) analysis that two 13 amino acid peptides bound GroEL in an amphipathic alpha-helical conformation. By extending the study to a variety of peptides with differing sequence motifs, we have observed that peptides can adopt conformations other than alpha-helix when bound to GroEL. Furthermore, peptides of the same composition exhibited significantly different affinities for GroEL as manifested by the magnitude of trNOEs. Binding to GroEL correlates well with the ability of the peptide to cluster hydrophobic residues on one face of the peptide, as determined by the retention time on reversed-phase (RP) HPLC. We conclude that the molecular basis of GroEL-substrate recognition is the presentation of a hydrophobic surface by an incompletely folded polypeptide and that many backbone conformations can be accommodated.

Background and Aims: Boceprevir is a potent, orally administered, ketoamide inhibitor of the hepatitis C virus (HCV) NS3 protease. HCV-related end-stage liver disease and hepatocellular carcinoma are frequent causes of liver transplantation. Sirolimus is a macrolide immunosuppressant frequently used for the prophylaxis of transplant rejection. This study was conducted to evaluate the pharmacokinetic interaction of boceprevir and sirolimus in healthy volunteers. Methods: In this open-label, 3-period, fixed-sequence trial, 12 subjects received single-dose sirolimus (2mg) in period 1 and boceprevir (800mg TID for 6 days) in period 2 with an intervening washout of 14 days. Period 3 immediately followed period 2 with no intervening washout: subjects received sirolimus (2mg SD) plus boceprevir (800mg TID) on day 1 and boceprevir (800mg TID) thereafter for 9 days. Blood samples were collected for the pharmacokinetic assessment of sirolimus and boceprevir. Safety assessments included electrocardiograms, vital signs, clinical laboratory tests, physical examination, and adverse event monitoring. Results: Twelve healthy volunteers were enrolled and 11 completed the trial. Coadministration of boceprevir and sirolimus was well tolerated. Boceprevir co-administration increased the geometric mean AUC0–∞ and Cmax of sirolimus by 8.1-fold and 4.8-fold, respectively, with the corresponding 90% CIs of (7.08, 9.32) for AUC0–∞ and (3.99, 5.88) for Cmax. The elimination half-life of sirolimus increased from 82.5 h to 98.3 h, and the apparent clearance decreased from 9.62 L/min to 1.18 L/min, respectively, with boceprevir coadministration. Sirolimus co-administration did not affect the pharmacokinetics of boceprevir (AUC0–8h and Cmax GMR [90%CI] of 1.0 [0.89, 1.01] and 0.9 [0.82, 1.07], respectively). Conclusions: Concomitant administration of boceprevir and sirolimus resulted in increased steady-state exposures of sirolimus in healthy subjects. The magnitude of the potential interaction between sirolimus and boceprevir in organ transplant patients is not known, but could potentially be higher and more variable than that seen in healthy volunteers. Dose adjustment of sirolimus and/or prolongation of the dosing interval should be anticipated when administered with boceprevir, and should be guided by close monitoring of sirolimus blood concentrations, and frequent assessment of renal function and sirolimus-related side effects.

The concept of a scanning probe microscope is quite straightforward — by dragging a probe that responds to structural features across a surface, one can generate an image of the surface using computer graphics.