Dataset Information

Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment.

ABSTRACT: Cenicriviroc, a dual CCR2/CCR5 antagonist, is being evaluated for treatment of nonalcoholic steatohepatitis and liver fibrosis (CENTAUR; NCT02217475). As it is metabolized by the liver, cenicriviroc was investigated in hepatic-impaired participants for pharmacokinetic changes. Participants with mild-to-moderate hepatic impairment (HI) (Child-Pugh class A (N = 7) or B (N = 8)) and matched controls (N = 15) received cenicriviroc 150 mg once daily for 14 days. Serial blood samples were obtained on Days 1 and 14. Safety, tolerability, and effects on CCR2/CCR5 ligands, cytokines, and bacterial translocation biomarkers were evaluated. Cenicriviroc exposures were increased by moderate HI (AUC0-? 55%, Cmax 29% higher) but were not with mild HI (AUC0-? 38%, Cmax 40% lower). Cenicriviroc was well tolerated. Rapid and potent CCR2/CCR5 blockade was observed, not associated with increases in hepatic inflammation or bacterial translocation biomarkers. Study findings suggest that cenicriviroc 150 mg can be used in patients with mild-to-moderate HI.

SUBMITTER: Lefebvre E

PROVIDER: S-EPMC5351328 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment.

Lefebvre E E Gottwald M M Lasseter K K Chang W W Willett M M Smith P F PF Somasunderam A A Utay N S NS

Clinical and translational science 20160512 3

Cenicriviroc, a dual CCR2/CCR5 antagonist, is being evaluated for treatment of nonalcoholic steatohepatitis and liver fibrosis (CENTAUR; NCT02217475). As it is metabolized by the liver, cenicriviroc was investigated in hepatic-impaired participants for pharmacokinetic changes. Participants with mild-to-moderate hepatic impairment (HI) (Child-Pugh class A (N = 7) or B (N = 8)) and matched controls (N = 15) received cenicriviroc 150 mg once daily for 14 days. Serial blood samples were obtained o ...[more]

PMID: 27169903

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Project description:Clinical management of neuropathic pain is unsatisfactory, mainly due to its resistance to the effects of available analgesics, including opioids. Converging evidence indicates the functional interactions between chemokine and opioid receptors and their influence on nociceptive processes. Recent studies highlight that the CC chemokine receptors type 2 (CCR2) and 5 (CCR5) seem to be of particular interest. Therefore, in this study, we investigated the effects of the dual CCR2/CCR5 antagonist, cenicriviroc, on pain-related behaviors, neuroimmune processes, and the efficacy of opioids in rats after chronic constriction injury (CCI) of the sciatic nerve. To define the mechanisms of action of cenicriviroc, we studied changes in the activation/influx of glial and immune cells and, simultaneously, the expression level of CCR2, CCR5, and important pronociceptive cytokines in the spinal cord and dorsal root ganglia (DRG). We demonstrated that repeated intrathecal injections of cenicriviroc, in a dose-dependent manner, alleviated hypersensitivity to mechanical and thermal stimuli in rats after sciatic nerve injury, as measured by von Frey and cold plate tests. Behavioral effects were associated with the beneficial impact of cenicriviroc on the activation/influx level of C1q/IBA-1-positive cells in the spinal cord and/or DRG and GFAP-positive cells in DRG. In parallel, administration of cenicriviroc decreased the expression of CCR2 in the spinal cord and CCR5 in DRG. Concomitantly, we observed that the level of important pronociceptive factors (e.g., IL-1beta, IL-6, IL-18, and CCL3) were increased in the lumbar spinal cord and/or DRG 7 days following injury, and cenicriviroc was able to prevent these changes. Additionally, repeated administration of this dual CCR2/CCR5 antagonist enhanced the analgesic effects of morphine and buprenorphine in neuropathic rats, which can be associated with the ability of cenicriviroc to prevent nerve injury-induced downregulation of all opioid receptors at the DRG level. Overall, our results suggest that pharmacological modulation based on the simultaneous blockade of CCR2 and CCR5 may serve as an innovative strategy for the treatment of neuropathic pain, as well as in combination with opioids.

Project description:Purpose The aim of this study was to describe the clinical course and outcomes of four lung transplant recipients in the CD10 trial (NCT04343651): use of leronlimab (PRO 140), a novel humanized IgG4,κ monoclonal antibody to CCR5, for the treatment of mild-moderate COVID-19 illness. Methods Four eligible lung transplant recipients with positive SARS-CoV2 PCR testing and mild-moderate illness received placebo or 1-2 weekly 700mg subcutaneous doses of leronlimab. Demographics, laboratory, radiologic, and clinical outcomes were reviewed. Results Between March and May 2020, three single-lung transplant recipients received leronlimab and one received placebo for mild-moderate disease. The total median age was 63.5 years (range 59.0-73.0) with equal male and female participants. The median duration between transplant and COVID-19 diagnosis was 409 days (range 149-631). Three patients (75%) required hospitalization for a median of 3 days (range 2-4); however, none required mechanical ventilation or positive pressure support. Baseline median CRP and CD4/CD8 counts were 4.4 mg/dL (range 1.3-15.3) and 1.16 (range 0.73-1.84) respectively, and normalized after one week of therapy. Abnormal imaging findings at the time of diagnosis were identified in native lungs (Figure 1). Baseline median FEV1, FVC, and 6MWT were 2.07 L (range 0.76-3.4), 2.73 L (range 1.46-4.09), and 402 m (range 247-496) with median change in baseline of -1.7%, -2.8%, and 3.8% respectively as of full clinical recovery through September 1, 2020. There were no episodes of acute rejection, by clinical evaluation or biopsy, or other known adverse events noted after leronlimab administration. Conclusion No definitive adverse events, disruptions of immunosuppression, or episodes of acute rejection or BOS were identified following leronlimab administration in a small series of lung transplant patients. Leronlimab may prove a safe and effective therapy for the restoration of immune homeostasis associated with COVID-19 illness in the future.

Dataset Information

Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment.

Publications

Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment.

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