Journal of clinical pharmacology
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Randomized Controlled Trial Multicenter Study
Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for Treatment of Anemia in Chronic Kidney Disease: A Placebo-Controlled Study of Pharmacokinetic and Pharmacodynamic Profiles in Hemodialysis Patients.
Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, was evaluated in a phase 1b study in patients with end-stage renal disease with anemia on hemodialysis. Seventeen patients, on epoetin-alfa maintenance therapy with stable hemoglobin levels ≥10 g/dL, had epoetin-alfa discontinued on day 3 and were enrolled in this double-blind placebo-controlled study. Two cohorts were randomized 3:1 (roxadustat: placebo). ⋯ Roxadustat induced transient elevations of endogenous erythropoietin that peaked between 7 and 14 hours after dosing and returned to baseline by 48 hours after dosing. Peak median endogenous erythropoietin levels were 96 mIU/mL and 268 mIU/mL for the 1- and 2-mg/kg doses, respectively, within physiologic range of endogenous erythropoietin responses to hypoxia at high altitude or after blood loss. No serious adverse events were reported, and there were no treatment- or dose-related trends in adverse event incidence.
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Multicenter Study Clinical Trial
Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib in Adult Patients With Advanced Solid Tumors or Relapsed/Refractory Lymphoma With Varying Degrees of Hepatic Dysfunction.
This clinical trial was designed to evaluate the effect of moderate or severe hepatic impairment on the single-dose pharmacokinetics (PK) of the investigational anticancer agent, alisertib, in adult patients with advanced solid tumors or lymphoma. Patients with normal hepatic function (total bilirubin and alanine transaminase [ALT] ≤ upper limit of normal [ULN]), moderate hepatic impairment (1.5 × ULN < total bilirubin ≤ 3 × ULN, with any ALT) or severe hepatic impairment (total bilirubin > 3 × ULN, with any ALT), received a single 50-mg oral dose of alisertib. Blood samples for PK were collected up to 168 hours postdose. ⋯ The geometric least-squares mean ratios (90% confidence intervals) for unbound alisertib area under the curve extrapolated to infinity for moderate/severe impairment groups versus the normal hepatic function group was 254% (184%, 353%). Patients with moderate or severe hepatic impairment have approximately 150% higher unbound alisertib exposures compared with patients with normal hepatic function. An approximately 60% reduction of the starting dose of alisertib in patients with moderate/severe hepatic impairment is recommended based on pharmacokinetic considerations.
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Multicenter Study
Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment.
Mirogabalin (DS-5565) is a novel preferentially selective α2 δ-1 ligand being developed for the treatment of diabetic peripheral neuropathic pain and postherpetic neuralgia. The current multicenter open-label study determined the effect of varying degrees of renal impairment on the pharmacokinetics and safety of a single dose of mirogabalin 5 mg in Japanese subjects. A total of 30 subjects (6 subjects per renal function category [normal, mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]) were enrolled and completed the study. ⋯ It was also tolerated in subjects with ESRD but with a higher incidence of TEAEs. The most frequently reported TEAEs were dizziness (ESRD, n = 3), somnolence (ESRD, n = 2), and vomiting (ESRD, n = 2). Based on these data, a mirogabalin dose adjustment will be considered in Japanese subjects with moderate to severe renal impairment and those with ESRD.
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Randomized Controlled Trial Multicenter Study
Parent-Metabolite Pharmacokinetic Modeling and Pharmacodynamics of Veliparib (ABT-888), a PARP Inhibitor, in Patients With BRCA 1/2-Mutated Cancer or PARP-Sensitive Tumor Types.
Veliparib (ABT-888) is a novel oral poly-ADP-ribose polymerase (PARP) inhibitor that is being developed for the treatment of hematologic malignancies and solid tumors. Although the pharmacokinetics of veliparib have been studied in combination with cytotoxic agents, limited information exists regarding the pharmacokinetics (PK) of chronically dosed single-agent veliparib in patients with either BRCA 1/2-mutated cancer or PARP-sensitive tumors. The objectives of the current analysis were to characterize the population pharmacokinetics of veliparib and its primary, active metabolite, M8, and to evaluate the relationship between veliparib and M8 concentrations and poly-ADP-ribose (PAR) level observed in peripheral blood mononuclear cells (PBMCs). ⋯ Creatinine clearance(CLCR ) and lean body mass (LBM) were identified as significant predictors of veliparib CLR /F and central volume of distribution, respectively. For a typical subject (LBM, 48 kg; CLCR , 95 mL/min), total clearance (CLR /F + CLNR /F), and central and peripheral volume of distribution for veliparib were estimated as 17.3 L/h, 98.7 L, and 48.3 L, respectively. At least 50% inhibition of PAR levels in PBMCs was observed at dose levels ranging from 50 to 500 mg.
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Randomized Controlled Trial Multicenter Study
Pharmacokinetics and Pharmacodynamics of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis.
The characterization of the pharmacokinetic (PK) and pharmacodynamic (PD) properties in pediatric patients is essential in supporting the recommended dosage of canakinumab in the relevant population. Here the PK and PD properties of canakinumab-a monoclonal antibody-in pediatric patients with systemic juvenile idiopathic arthritis (SJIA) are presented. Blood samples were obtained from 4 phase 2/3 clinical studies in patients with SJIA. ⋯ Compared to other indications, IL-1β production rate was higher and clearance was slower in patients with SJIA. Low immunogenicity incidence of 3.1% was observed, and none of the patients had neutralizing antibodies. In conclusion, the PK/PD findings further support dose selection of canakinumab in patients with SJIA.