Bevirimat 3-O-(3',3'-dimethylsuccinyl)-betulinic acid is a novel inhibitor of HIV-1 maturation. This study was performed to investigate the pharmacokinetics and safety of bevirimat during repeated ...dosing in healthy volunteers.
The study was a 10-day, randomised, double-blind, placebo-controlled, dose escalation study. A total of 48 healthy male volunteers, aged 19-54 years, took part in the study. Treatment was administered for 10 days in six escalating dose cohorts (n = 8 in each cohort; 6 bevirimat, 2 placebo). The doses of bevirimat given in each successive cohort were 25 mg, 50 mg, 75 mg (with 150 mg loading dose), 100 mg, 150 mg and 200mg. Safety follow-up was performed 28 days after the first dose. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Plasma bevirimat levels were measured from blood samples collected pre-dose on days 1-10 and then at approximately 48-hour intervals until 21 days after dosing started. On days 1 and 10, further blood samples were obtained at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours after dosing. Urine samples were collected in the morning on days 1, 5 and 11 and at the end of the study for the measurement of cortisol and 6beta-hydroxycortisol. The pharmacokinetic parameters of bevirimat were estimated using non-compartmental methods.
Dose proportionality of exposure to bevirimat, assessed by the maximum plasma concentration and the area under the plasma concentration-time curve.
The mean terminal elimination half-life of bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour. Bevirimat showed approximately 4-fold greater accumulation on day 10 compared with day 1, and the degree of accumulation was similar with all doses. Maximum plasma concentrations ranged from 8 to 58 microg/mL at day 10. Testing for dose-proportionality showed that exposure to bevirimat was proportional to the dose, both after a single dose and after repeat dosing for 10 days. Measurement of the urinary 6beta-hydroxycortisol/cortisol ratio indicated that bevirimat did not affect cytochrome P450 3A activity. Repeated dosing with bevirimat for 10 days was well tolerated. There was no increase in adverse events observed for bevirimat compared with placebo, and no serious adverse events occurred. No clinically relevant changes in vital signs, physical examination or clinical laboratory evaluations were observed.
Bevirimat shows dose-proportional pharmacokinetics during repeated dosing for 10 days. Its accumulation is approximately 4-fold greater on day 10 compared with day 1. Repeated dosing with bevirimat is well tolerated. These properties make bevirimat potentially suitable for inclusion in highly active antiretroviral therapy regimens.
Abstract Background: Bevirimat, an inhibitor of HIV-1 maturation, is currently in clinical development for the treatment of HIV-1 infection. It undergoes glucuronidation via uridine diphosphate ...glucuronosyltransferases (UGTs). The protease inhibitor atazanavir is a potent inhibitor of UGT1A1. Because of this inhibition, high atazanavir plasma levels are associated with increases in plasma bilirubin. Objectives: The purposes of this study were to assess the pharmacokinetic (PK) properties and tolerability profiles of bevirimat administered as monotherapy and in combination with atazanavir. Methods: This was an open-label, parallel-group study in healthy volunteers. Nonsmoking men and women aged 18 to 60 years were eligible for inclusion in the study. After being stratified in a 1:1 ratio by sex, subjects were randomly assigned to 1 of 2 groups to receive bevirimat 200 mg/d for 14 days or atazanavir 400 mg/d on days 1 through 21 and bevirimat 200 mg/d on days 8 through 21. Bevirimat PK properties were assessed on day 14 in the monotherapy group and on day 21 in the combination group. Atazanivir PK properties were assessed on days 7 and 21 in the combination group. Serum bilirubin was assessed daily. Tolerability was assessed by monitoring of adverse events using physical examination and clinical laboratory evaluation, including recording of vital signs and electrocardiography throughout the study. Results: A total of 48 healthy volunteers (24 men, 24 women; mean age, 33 years; mean weight, 83.6 kg; mean body mass index, 27.8 kg/m2 ) were included in the study. There were no significant between-group effects on the PK properties with respect to geometric least squares mean ratios of Cmax and AUC0–τ (95.9 90% CI, 84.5–108.8 and 92.0 90% CI, 80.5– 105.2, bevirimat monotherapy vs bevirimat + atazanivir, respectively; and 93.9 90% CI, 82.3–107.1 and 94.1 90% CI, 78.2–113.1, atazanivir monotherapy vs bevirimat + atazanivir, respectively). Bevirimat was not associated with any significant changes from baseline in serum bilirubin concentrations, whereas 7-day atazanavir monotherapy was associated with a ~5-fold increase. Coadministration was not associated with significant bilirubin concentration elevations compared with the administration of atazanavir alone. Dosing was discontinued in 4 subjects (atazanavir-induced hyperbilirubinemia, 3; atazanavir-induced rash, 1). In addition, 17 subjects (35.4%) experienced treatment-emergent adverse events including: ocular icterus, 5; headache, 5; unconjugated blood bilirubin increases, 4; diarrhea, 3; upper respiratory tract infection, 3; and yellow skin, 3. Conclusions: In this study, there were no significant differences in PK properties in atazanavir or bevirimat administered as monotherapy or in combination in this small, select group of healthy volunteers. The coadministration of bevirimat and atazanavir was reasonably well tolerated. Bevirimat did not significantly increase serum bilirubin concentrations and had no significant effect on atazanavir-induced hyperbilirubinemia, potentially providing a further option in the management of HIV-1 infection following evaluation in HIV-infected patients.
Osimertinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), undergoes significant hepatic elimination. In this phase 1 study, we assessed the effects of mild and moderate ...hepatic impairment on the pharmacokinetics (PK) of osimertinib in patients with malignant solid tumors. In part A, patients with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, according to the Child-Pugh classification, received a single 80 mg oral dose of osimertinib. Standard PK measures were assessed. In part B, patients could continue osimertinib treatment if deemed clinically appropriate. We compared these study results with a population PK analysis including other osimertinib clinical studies. Geometric mean osimertinib plasma concentrations were lower in patients with mild (
= 7) or moderate hepatic impairment (
= 5) versus normal hepatic function (
= 10):
was reduced to 51% and 61%, respectively; area under the curve was reduced to 63% and 68%, respectively. PK results for the metabolites were similar. No apparent differences in the safety profile were found between patients with normal hepatic function and patients with mild or moderate hepatic impairment. Comparison of these study results with National Cancer Institute-Organ Dysfunction Working Group criteria from population PK analysis showed osimertinib exposure was not affected by hepatic impairment. No dose adjustment is required for osimertinib when treating patients with mild or moderate hepatic impairment. No apparent differences in the safety of osimertinib were found between patients with normal hepatic function and mild or moderate hepatic impairment.
CRS3123 is a novel small molecule that potently inhibits methionyl-tRNA synthetase of
, inhibiting
toxin production and spore formation. CRS3123 has been evaluated in a multiple-ascending-dose ...placebo-controlled phase 1 trial. Thirty healthy subjects, ages 18 to 45 years, were randomized into three cohorts of 10 subjects each, receiving either 200, 400, or 600 mg of CRS3123 (8 subjects per cohort) or placebo (2 subjects per cohort) by oral administration twice daily for 10 days. CRS3123 was generally safe and well tolerated, with no serious adverse events (SAEs) or severe treatment-emergent adverse events (TEAEs) reported. All subjects completed their assigned treatment and follow-up visits, and there were no trends in systemic, vital sign, or laboratory TEAEs. There were no QTcF interval changes or any clinically significant changes in other electrocardiogram (ECG) intervals or morphology. CRS3123 showed limited but detectable systemic uptake; although absorption increased with increasing dose, the increase was less than dose proportional. Importantly, the bulk of the oral dose was not absorbed, and fecal concentrations were substantially above the MIC
value of 1 μg/ml at all dosages tested. Subjects receiving either of the two lower doses of CRS3123 exhibited minimal disruption of normal gut microbiota after 10 days of twice-daily dosing. CRS3123 was inactive against important commensal anaerobes, including
, bifidobacteria, and commensal clostridia. Microbiome data showed favorable differentiation compared to other CDI therapeutics. These results support further development of CRS3123 as an oral agent for the treatment of CDI. (This study has been registered at Clinicaltrials.gov under identifier NCT02106338.).
Abstract
Background
OLO is a novel antifungal active vs. Aspergillus (including azole-resistant strains), resistant moulds (e.g., Lomentospora prolificans), and dimorphic moulds. Information on ...absolute bioavailability and effect of food upon the pharmacokinetics (PK) of OLO when administered as a 30 mg tablet, including feasibility of alternative enteral delivery, is required for appropriate guidance on dosing.
Methods
Healthy male and female subjects in Cohorts A and B (6/cohort; high carbohydrate /low fat meals at 8 and 24 h for Cohort A and low carbohydrate/high fat meals for Cohort B ) participated in 3 treatment periods; single doses of 150 mg OLO as a 2-h IV infusion, a fasted PO dose (after overnight fast), and a fed single PO dose (30 min after starting a high fat breakfast). Healthy subjects in Cohort C participated in 2 treatment periods and received fasted single doses of 150 mg OLO either PO as intact tablets or via NG tube (tablets dispersed in water). PK sampling was performed for 120 h after each dose, with at least 10 days between dosing occasions per subject.
Results
The absolute bioavailability of a fasted single PO dose of OLO was found to be 67%. Administering OLO in the presence of food resulted in slight reduction in overall exposure, with an approximate 30% reduction in Cmax (Table 1). Multiple post-dose OLO peaks were observed for most subjects regardless of dose route or fed state; peaks typically coincided with meal times (Figure).
OLO systemic exposure was similar for intact tablets given PO and tablets dispersed in water given via NG tube (Table).
Statistical Analysis of Olorofim PK parameters for Cohorts A, B and C
Conclusion
OLO (30 mg tablet) has good oral bioavailability and based upon the minimal impact of a high-fat breakfast upon overall exposure, can be administered with or without food. No dose adjustment is needed if switching from oral dosing with intact tablets to dosing tablet in water via NG tube.
Disclosures
Karen Cornelissen, PhD, F2G: Employee Paul A. Newell, MB BS, AstraZeneca: Stocks/Bonds|F2G: Stocks/Bonds John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant Samuel Israel, MBBS, Labcorp: Eemployee James Bush, MB ChB, PhD, Labcorp: Employee (Salaried)|Labcorp: Stocks/Bonds.
Abstract
Background
OLO is a novel antifungal active vs. Aspergillus (including azole-resistant strains), resistant moulds (e.g., Lomentospora prolificans), and dimorphic moulds. In preclinical PKPD ...studies, a plasma level ≥ 0.2 µg/mL was required for efficacy similar to mould-active azoles.
Methods
Patients in Study 32 (N=100) received OLO (30 mg tablets) guided either by therapeutic drug monitoring (TDM) based on baseline bodyweight and OLO pre-dose plasma levels (180 to 300 mg/day x 1 d to load then 120 to 240 mg/day, given BID or TID as appropriate) or a fixed dose (150 mg BID for 1d then 90 mg BID). For each subject, OLO PK profiles were determined over 1 or 2 dosing intervals, an additional 8 to 9 scheduled pre-dose samples were taken during the initial 84 days and every 1-3 months thereafter. Food intake was not constrained.
Results
Geometric mean steady-state OLO PK parameters in the 90 evaluable subjects were similar between the TDM and fixed dosing groups (Table). Mean OLO pre-dose concentrations were similar over time for all 100 patients regardless of group and regimen; drug concentration variability was slightly greater when TDM was not utilized (Figure).
Pre-dose levels were greater than the Cmin observed over a dosing interval in most subjects (range of pre-dose: Cmin ratio of 1 to 15.8). which may be due to food-triggered release from a deep compartment such as the liver. Exposures exceeding the PD target (≥ 0.2 µg/mL) were consistently achieved.
PK parameters predicted by population PK modelling of Phase II data were in reasonable agreement with observed data (Table).
Table: OLO Systemic Exposure at Steady-State median (5th – 95th percentiles)
1 based on 90 mg BID
Conclusion
OLO is a novel mechanism oral antifungal with broad-spectrum mould activity. When administered as a fixed dose (90 mg BID), adequate exposure for efficacy against invasive mycoses is achieved, without the need to confirm by TDM
Disclosures
Karen Cornelissen, PhD, F2G: Employee James G. Wright, PhD, F2G: Advisor/Consultant Andrew Cristinacce, MSc by Research, F2G: Advisor/Consultant Roger Bruggemann, Pharm, PhD, Amplyx: Advisor/Consultant|Astellas: Advisor/Consultant|Cidara: Advisor/Consultant|Gilead: Advisor/Consultant|Gilead: Grant|Mindipharma: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Grant Johan A. Maertens, MD PhD, F2G Ltd: Advisor/Consultant|Gilead Sciences Ltd: Advisor/Consultant|Mundipharma: Advisor/Consultant|Pfizer Inc: Advisor/Consultant George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Sharon C. Chen, PhD MBBS, F2G PTy Ltd: Grant/Research Support|MSD Australia: Grant/Research Support John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant.
The effect of proton pump inhibitors (PPIs) on the pharmacokinetics and pharmacodynamics of clopidogrel was assessed in two healthy volunteer crossover studies.
Study 1: subjects received clopidogrel ...alone (300-mg loading dose, then 75 mg/day for 28 days) and two of three PPIs (omeprazole 80 mg, esomeprazole 40 mg or lansoprazole 60 mg) plus clopidogrel for 29 days in three treatment periods (randomized treatment sequence assignment). Study 2: subjects received clopidogrel alone (75 mg/day for 9 days) and clopidogrel alone for 4 days followed by clopidogrel plus fixed-combination esomeprazole 20 mg/low-dose acetylsalicylic acid (ASA) 81 mg for 5 days in two treatment periods (randomized treatment sequence assignment). Pharmacokinetic effects were estimated by measuring active metabolite of clopidogrel, and pharmacodynamic effects by inhibition of adenosine diphosphate (ADP)-induced platelet aggregation.
There was a relative decrease of up to 50 % in exposure to the active metabolite of clopidogrel with the different PPIs (study 1), and close to 40 % with esomeprazole/low-dose ASA (study 2), compared with clopidogrel alone. There was an absolute decrease of up to 17 % in inhibition of ADP-induced platelet aggregation with co-administration of different PPIs, compared with clopidogrel alone; however, no differences in platelet inhibition were observed during co-administration with the esomeprazole/low-dose ASA fixed-dose combination.
Omeprazole, esomeprazole and lansoprazole decreased systemic exposure to the active metabolite of clopidogrel in healthy volunteers, leading to modest decreases in its antiplatelet effect. However, no apparent differences in platelet inhibition were observed when esomeprazole was co-administered with low-dose ASA as a fixed-dose combination.
Summary
We consider the problem of quantifying the degree of association between pairs of discrete event time series, with potential applications in forensic and cybersecurity settings. We focus in ...particular on the case where two associated event series exhibit temporal clustering such that the occurrence of one type of event at a particular time increases the likelihood that an event of the other type will also occur nearby in time. We pursue a non‐parametric approach to the problem and investigate various score functions to quantify association, including characteristics of marked point processes and summary statistics of interevent times. Two techniques are proposed for assessing the significance of the measured degree of association: a population‐based approach to calculating score‐based likelihood ratios when a sample from a relevant population is available, and a resampling approach to computing coincidental match probabilities when only a single pair of event series is available. The methods are applied to simulated data and to two real world data sets consisting of logs of computer activity and achieve accurate results across all data sets.
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