Single-dose pharmacokinetics of BMS-986177/JNJ-70033093 in participants with mild or moderate hepatic impairment compared to healthy participants

Background According to the scientific evidence accumulated to date (ie, genetic, epidemiological, preclinical, clinical), the modulation of Factor XI (FXI) function may provide a novel mechanism for systemic anticoagulation without increasing the risk of clinically significant bleeding in a variety of conditions predisposing patients to a high risk of thrombotic or bleeding events. BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) is a small molecule that inhibits the active form of FXI (FXIa) with high affinity and selectivity. Depending on the indication, BMS-177/JNJ-3093 may provide benefit to patients as add-on or potentially replacement therapy to the current standard of care antithrombotic agents. Patients with hepatic impairment may have an increased risk of bleeding when using existing antithrombotic agents and therefore may benefit from drugs with an improved safety profile. Purpose To assess the effect of mild or moderate hepatic impairment on the pharmacokinetic (PK) properties of BMS-177/JNJ-3093. Methods This was a multicenter, open-label, non-randomized, single-dose study. A single 60-mg oral dose of BMS-177/JNJ-3093 was administered to 9 participants with mild hepatic impairment (Child-Pugh class A), 8 participants with moderate hepatic impairment (Child-Pugh class B), and 9 healthy participants with normal hepatic function. Healthy participants were matched to participants with hepatic impairment in each Child-Pugh class with regard to body weight. To assess the effects of hepatic impairment on BMS-177/JNJ-3093 PK, an analysis of variance was performed on the natural log-transformed Cmax, AUC(INF), and AUC(0-T) with hepatic function group as a fixed effect. Results BMS-177/JNJ-3093 was well tolerated when administered as an oral dose of 60 mg in participants with mild or moderate hepatic impairment and healthy participants with normal hepatic function. There were no deaths, serious adverse events (AEs), severe AEs, bleeding AEs, or discontinuations due to an AE reported during the study. The geometric mean ratios (GMRs) (90% CI) comparing mild hepatic impairment to normal hepatic function were 1.180 (0.735, 1.895) and 1.168 (0.725, 1.882) for total BMS-177/JNJ-3093 maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC(INF)), respectively. The GMRs (90% CI) comparing moderate hepatic impairment to normal hepatic function were 1.140 (0.699, 1.857) and 0.996 (0.609, 1.628) for total BMS-177/JNJ-3093 Cmax and AUC(INF), respectively. Overall, levels of activated partial thromboplastin time (aPTT) increased in an exposure-related manner following single oral doses of 60 mg BMS-177/JNJ-3093 in all groups. Conclusion BMS-177/JNJ-3093 was well tolerated in the normal healthy participants and those with mild or moderate hepatic impairment. The observed changes indicate that a dose adjustment in these populations may not be necessary. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This work was sponsored by Bristol-Myers Squibb and Janssen Research & Development, LLC

An Open-Label Study of the Impact of Hepatic Impairment on the Pharmacokinetics and Safety of Single Oral and Intravenous Doses of Omadacycline

ABSTRACT Omadacycline is a once-daily oral or intravenous (i.v.) aminomethylcycline antibiotic approved in the United States for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults. Omadacycline pharmacokinetics were characterized in 18 patients with hepatic impairment and 12 matched healthy subjects. Patients with hepatic impairment received i.v. omadacycline at 100 mg (mild hepatic impairment) or 50 mg (moderate and severe hepatic impairment) and oral omadacycline at 300 mg (mild hepatic impairment) or 150 mg (moderate hepatic impairment); oral omadacycline was not evaluated in those with severe hepatic impairment. Safety monitoring included the collection of adverse events (AEs), performance of laboratory tests, determination of vital signs, and performance of electrocardiograms. Omadacycline exposures were similar in patients with hepatic impairment and healthy subjects following i.v. or oral administration, with the geometric mean ratios for the area under the concentration-time curve and the maximum drug concentration ranging from 0.79 to 1.42. Omadacycline was safe and well tolerated. Overall, 13/30 (43.3%) participants experienced an AE; those occurring in more than 1 participant included headache (13.3%), nausea (6.7%), infusion-site pain (6.7%), contusion (6.7%), and dizziness (6.7%), with no differences based on the degree of hepatic impairment or the route of administration. Asymptomatic increases in heart rate were observed; none was considered an AE. These findings suggest that no omadacycline dose adjustment is warranted in patients with hepatic impairment.

Population Pharmacokinetics and Exposure-Safety Of Lenalidomide In Patients With Multiple Myeloma, Myelodysplastic Syndromes and Mantle Cell Lymphoma

Introduction Lenalidomide (LEN) has been approved for the treatment of multiple myeloma (MM: dose 25mg/day, in combination with dexamethasone), myelodysplastic syndromes (MDS: 10 mg/day), and mantle cell lymphoma (MCL: 25 mg/day). In patients with these 3 types of hematologic malignancies, grade 3/4 neutropenia and thrombocytopenia are the most common dose-limiting adverse events (AEs) associated with LEN treatment. Renal function has been used to guide the starting dose of LEN in these patients as renal excretion is the primary route for LEN clearance. However, questions remain whether other intrinsic factors (e.g., race, age, body weight, gender, mild hepatic impairment) should also be considered in determining LEN dose, and how hematologic AEs are related to LEN exposure. The aim of this study was to quantitatively assess the effect of various intrinsic factors on LEN clearance and to explore the exposure-response relationship for severe neutropenia and thrombocytopenia in patients with MM, MDS, and MCL. Methods Single- and multiple-dosing concentration data of LEN were pooled from 7 clinical studies yielding a total of 147 patients: 68 with MM, 25 with MDS, 24 with MCL, and 30 with renal impairment and without a malignant condition. In the entire analysis population, 39% of the patients had normal renal function (creatinine clearance [CrCl] ≥ 90 mL/min), 31% had mild renal impairment (RI) (CrCl = 60-89 mL/min, 26% had moderate to severe RI (CrCl = 15-59mL/min), and 4% of the patients were on hemodialysis. The LEN dose level studied was 5 mg [N = 6], 10 mg [N = 41], 25 mg [N = 80], or 50 mg [N = 20], respectively. Non-linear, mixed effects' modeling was used to develop a population pharmacokinetic (PK) model for LEN. Subsequently, Bayesian post-hoc population PK model parameters were used to generate LEN steady state area under the plasma concentration-time curve (AUC) and was analyzed via logistic regression to determine the probability of experiencing grade 3/4 neutropenia or thrombocytopenia during the treatment (N = 116). Results Plasma LEN concentrations were adequately described by a 2-compartment population PK model with first order absorption and elimination. LEN exhibited linear and time invariant PKs with moderate variability. The baseline CrCl was predictive of the apparent LEN clearance (CL/F). Inclusion of renal function (CrCl and hemodialysis) into the PK model explained 24% of the inter-individual variability in CL/F. The typical value of LEN CL/F at a CrCl level of 80 mL/min was 10.26 L/h, and each 10-mL/min decrease in CrCl resulted in approximately a 10% decrease in CL/F. Age (39-85 years), body weight (33-135 kg), gender, race (white [N=110]; Asian [N=27]; and other [N=10]), and mild hepatic impairment (total bilirubin > 1 to ≤ 1.5× upper level of normal [ULN] or alanine aspartate transaminase >ULN, N = 16) had no effect on LEN CL/F. All LEN PK parameters were comparable among MM, MDS, and MCL patients. Including all treatment cycles up to one year, and after adjusting for disease and baseline neutrophil or platelet counts, LEN AUC was a significant predictor of the probability experiencing Grade 3/4 thrombocytopenia (odds ratio [OR] = 3.337, 95%CI = 1.183 to 9.415) and it was also associated with an increased probability experiencing Grade 3/4 neutropenia (OR = 1.978, 95%CI = 0.999 to 3.917). However, these relationships were not apparent during the first treatment cycle. Conclusion Creatinine clearance is the only significant and clinically important predictor of LEN CL/F; race (White vs Asian), age, body weight, gender, and mild hepatic impairment had no effect. Also no difference in LEN disposition was observed between MM, MDS, and MCL patients. LEN AUC was a significant predictor of the probability of experiencing grade 3/4 thrombocytopenia and neutropenia. Disclosures: Chen: Celgene Corporation: Employment, Equity Ownership. Ette:Anoxis Corporation: Consultancy. Zhou:Celgene Corporation: Employment, Equity Ownership. Weiss:Celegene Corporation: Employment, Equity Ownership. Palmisano:Celgene Corporation: Employment, Equity Ownership.