Jong-Soon Park

Effect of apolipoprotein E and A-IV phenotypes on the low density lipoprotein response to HMG CoA reductase inhibitor therapy

Our purpose was to assess the effect of apolipoprotein (apo) E and apo A-IV isoform variation on low density lipoprotein (LDL) cholesterol lowering response to the HMG CoA reductase inhibitor, pravastatin. Plasma samples were obtained from participants (apo E, n = 97; apo A-IV, n = 144) in the PLAC-I (Pravastatin Limitation of Atherosclerosis in Coronary Arteries Study-1). The mean LDL cholesterol reduction in these subjects who were randomized to pravastatin 40 mg/day was 28%. Subjects with the APOE*2 allele (n = 12) had significantly (P = 0.04) greater reductions at 36% than subjects homozygous for the APOE*3 allele (n = 66, 27%) or those with the APOE*4 allele (n = 19, 26%). No significant effect of apo A-IV phenotype on LDL cholesterol lowering in response to pravastatin was noted. A meta-analysis utilizing published data from 4 previously published studies as well as our own data with a total sample size of 625 subjects was carried out. This analysis indicates that the presence of the APOE*2 allele was associated with a significantly greater (P < 0.05) LDL-cholesterol lowering response at 37% than those subjects homozygous for the APOE*3 allele at 35%, while those with the APOE*4 allele had a significantly lower response (P < 0.05), at 33%. These data are consistent with the concept that apo E phenotype modulates the LDL cholesterol lowering response observed with the use of HMG CoA reductase inhibitors.

Lack of Effect of Food on the Oral Bioavailability of Irbesartan in Healthy Male Volunteers

This study was conducted to evaluate the effects of a high‐fat meal on the oral bioavailability of an 300‐mg irbesartan tablet in healthy male volunteers. Sixteen healthy young male volunteers participated in this single‐center, open‐label, single‐dose, crossover study. Each volunteer received a single 300‐mg irbesartan tablet under fasted conditions and 5 minutes after a high‐fat breakfast, with administrations separated by a 7‐day washout period. Serial blood samples were collected over a 72‐hour period, and plasma samples were analyzed for irbesartan using a validated high‐performance liquid chromatography/fluorescence procedure. Food had no statistically significant effects on the peak concentration (Cmax) and area under the concentration‐time curve (AUC) of irbesartan. The presence of food was associated with a slightly prolonged time to maximum concentration (tmax) and half‐life (t1/2), but the differences were not statistically significant. The results of this study indicate that food does not affect the bioavailability of irbesartan. Thus, irbesartan can be administered without regard to meals.

Evaluation of Immunogenicity of Nivolumab Monotherapy and Its Clinical Relevance in Patients With Metastatic Solid Tumors

Nivolumab is a fully human IgG4 monoclonal antibody targeting the programmed death‐1 (PD‐1) receptor that blocks interactions between PD‐1 and its ligands on tumor cells to prevent T‐cell exhaustion in patients with cancer. It has demonstrated efficacy in multiple tumor types, including melanoma, non‐small‐cell lung cancer, and renal cell carcinoma. This analysis assessed the immunogenicity of nivolumab and its impact on pharmacokinetics, safety, and efficacy in patients with solid tumors enrolled in 6 clinical studies. The incidence and prevalence of antidrug antibodies (ADAs) were determined by validated electrochemiluminescence assays in samples collected during nivolumab treatment and up to 100 days after the last dose. Confirmed positive samples from the 6 studies were also tested for presence of neutralizing antibodies (NAbs). Among 1086 nivolumab‐treated patients, 138 patients (12.7%) were ADA positive (relative to baseline), only 3 (0.3%) of whom were persistently positive for ADA, and 9 (0.8%) were NAb positive at 1 time point. The presence of ADAs was not associated with hypersensitivity, infusion reactions, or loss of efficacy and had minimal impact on nivolumab clearance. Additionally, the presence of NAbs was not associated with loss of efficacy. In conclusion, immunogenicity of nivolumab is not clinically meaningful.

Evaluation of continuous summary physical performance scores (CSPPS) in an elderly cohort

Background and aims: Physical performance is an important predictor of quality of life among the elderly. A valid and sensitive measure of physical performance is needed in order to evaluate possible interventions. The aim of this study was to examine the validity and reliability of the Continuous Summary Physical Performance Score (CSPPS) and its relationship to the Quartile Summary Physical Performance Score (QSPPS). Methods: This cross-sectional study of an elderly cohort from 5 centers in the US and Europe included men and women (>age 65) reporting at least two domains of disability. Subjects completed assessments of mobility and ability to perform activities of daily living (ADLs), the physical component of the SF-36, and a self-rating of physical performance. Timed physical performance tests were used to calculate the CSPPS and QSPPS. Results: 216 subjects took part (mean age=81 years). The distribution of CSPPS scores was similar for men and women, with a mean of 59.2 (SD 17.8), median of 64.3, and range from 1.3 to 91. Subjects with older age, higher degree of disability, and lower self-rated physical performance had lower CSPPS scores. The CSPPS had good test-retest reliability (r=0.92), and CSPPS and QSPPS are highly correlated (r=0.94, p<0.001). However, the QSPPS appears to lack the linearity, and the ranges of the CSPPS for each score of the QSPPS overlap substantially. Conclusions: In a cohort with moderate to severe disability, the CSPPS appears to be a valid, reproducible measure that can discriminate smaller yet clinically meaningful differences in physical function, as compared with the QSPPS.

Quantitative Characterization of the Exposure–Response Relationship for Cancer Immunotherapy: A Case Study of Nivolumab in Patients With Advanced Melanoma

To inform the benefit–risk assessment of nivolumab in patients with advanced melanoma, analyses of efficacy and safety exposure–response (E–R) relationships were conducted with data from patients with advanced melanoma enrolled in two clinical studies (phase I and phase III) who received nivolumab 0.1–10.0 mg/kg every 2 weeks. E‐R efficacy analyses were performed by relating the nivolumab time‐averaged concentration after the first dose (Cavg1) to two endpoints: RECIST objective response (OR) and overall survival (OS). E–R safety analyses characterized the relationship between nivolumab Cavg1 and the hazard of all‐causality adverse events leading to discontinuation or death (AE‐DC/D). Nivolumab exposure represented by Cavg1 was not a significant predictor of OR, OS, or the hazard of AE‐DC/D. E–R efficacy and safety relationships were relatively flat over the exposure range.

Beta-cell response to metformin-glibenclamide combination tablets (Glucovance) in patients with type 2 diabetes.

This exploratory double‐blind, randomised, 20‐week study evaluated the mechanism of action of metformin–glibenclamide combination tablets (Glucovance®) vs. metformin and glibenclamide in 50 type 2 diabetes patients inadequately controlled by diet and exercise. A glycaemic target of HbA1C 7.0% was used. Final HbA1C, fasting glucose and post‐oral glucose tolerance test (OGTT) glucose were similar between groups, although average doses of metformin and glibenclamide from combination tablets (708 and 3.5 mg) were lower than monotherapy doses (1500 and 6.6 mg). Second‐phase insulin during a hyperglycaemic clamp increased by 93% with combination tablets, 36% with metformin and 46% with glibenclamide. The insulin response post‐OGTT was more rapid with the combination tablets vs. glibenclamide. First‐phase insulin responses improved modestly in all groups, possibly due to reduced glucotoxicity. Changes in insulin sensitivity were minor. Larger β‐cell responses between combination tablets and glibenclamide may reflect more rapid glibenclamide absorption.

Nivolumab Exposure–Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non–Small Cell Lung Cancer

Purpose: Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1 antibody with demonstrated efficacy, including durable responses and prolonged survival, in patients with previously treated, advanced non–small cell lung cancer (NSCLC). Exposure–response (E–R) analyses for efficacy and safety were conducted to inform the benefit–risk assessment of nivolumab in this patient population. Experimental Design: The analyses used clinical trial data from patients with squamous (n = 293) or nonsquamous (n = 354) NSCLC from four clinical trials who received nivolumab doses of 1 to 10 mg/kg every 2 weeks. E–R efficacy analyses were performed by investigating the relationship between time-averaged nivolumab concentration after the first dose (Cavg1) and the probability of overall survival by histology. E–R safety analyses examined relationships between nivolumab Cavg1 and hazards of adverse events leading to discontinuation or death (AEs-DC/D). Results: Nivolumab exposure was not associated with overall survival [the 95% confidence interval (CI) of effect included 1] in patients with squamous (HR, 0.802; 95% CI, 0.555–1.16) or nonsquamous NSCLC (HR, 0.94; 95% CI, 0.683–1.29). Similarly, nivolumab exposure was not associated with AEs-DC/D in the overall population (HR, 0.917; 95% CI, 0.644–1.31). The risk of AEs-DC/D was similar among patients with squamous or nonsquamous histology. Conclusions: Nivolumab monotherapy demonstrated a wide therapeutic margin, as evidenced by relatively flat E–R relationships over the range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W), supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with NSCLC. Clin Cancer Res; 23(18); 5394–405. ©2017 AACR.

Food Increased the Bioavailability of BMS‐690514, an Orally Active EGFR/HER2/VEGF Receptor Kinase Inhibitor, in Healthy Subjects

We studied the effect of food on pharmacokinetics, safety, and tolerability of BMS‐690514. Two open‐label, randomized, single‐dose, 2‐treatment, 2‐period crossover studies were performed in healthy subjects. In study 1 (N = 26), a single oral dose of BMS‐690514, 200 mg, was administered while fasting or after a high‐fat meal, and in study 2 (N = 17), a single oral dose of BMS‐690514, 200 mg, was administered while fasting or after a light meal. Compared with fasting, the adjusted geometric mean maximum observed plasma concentration (Cmax), area under the plasma concentration‐time curve from time zero to time of last quantifiable concentration (AUC0‐T), area under the plasma concentration‐time curve from time zero extrapolated to infinite time (AUCINF) of BMS‐690514 increased by 55%, 33%, and 34%, respectively, following a high‐fat meal (951 kcal, 52% fat) and by 41%, 20%, and 20%, respectively, following a light meal (336 kcal, 75% carbohydrate). BMS‐690514 was well tolerated in both studies. Most frequently occurring adverse events were diarrhea and acne in study 1 and rash, dry skin, and diarrhea in study 2. Systemic exposure of highly soluble BMS‐690514 was increased when given along with a meal, probably through inhibition of intestinal first‐pass metabolism and/or efflux transporters by food. These studies also demonstrated a tolerable safety profile of BMS‐690514 in the absence and presence of food.

Abstract A101: BMS‐754807, an oral dual IGF‐1R/IR inhibitor: First‐in‐human single‐dose study of safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy subjects

Background: Type 1 insulin‐like growth factor receptor (IGF‐1R) signaling drives survival and proliferation in a broad range of human tumors. Insulin receptor (IR) signaling can drive tumor growth and may act as an escape mechanism for IGF‐1R inhibition. BMS‐754807 is a potent and selective reversible inhibitor of IGF‐1R/IR family kinases (IGF‐1R, IR; Ki Methods:CA191001 was a placebo‐controlled, ascending single‐dose study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of BMS‐754807 in healthy subjects. Eight subjects per dose panel were randomized in a 3:1 ratio to receive a single oral dose of BMS‐754807 (2, 10, 20, 30, or 60 mg) or placebo after a 10 h fast. A 75 g glucose challenge was administered 2 h post‐dose at the 10 and 30 mg doses; a second 30 mg panel was dosed without a glucose challenge. The 60 mg panel received a second dose of BMS‐754807 or placebo with a high‐fat meal after at least a 7 day washout. Results: Forty‐eight male subjects received BMS‐754807 (n = 36) or placebo (n = 12). Adverse events (AEs) occurred in 26 subjects, all were mild or moderate. The most frequent AE was hypoglycemia, which occurred in 10 drug‐treated subjects and 1 placebo‐treated subject. Most hypoglycemia AEs occurred in subjects who received a glucose challenge and occurred in these subjects with a higher frequency after the 30 mg dose than after the 10 mg dose. There was no other apparent relationship of AEs, vital signs, or clinical lab abnormalities with dose. BMS‐754807 exposure was proportional to dose; mean half‐life was 9 – 13 h and median Tmax was 1 – 2 h. AUC was similar when administered in the fasted and fed states, however, Cmax was lower and delayed in the fed state. All subjects receiving at least a 10 mg dose exceeded the minimal efficacious exposure predicted from mouse IGF‐1R dependent xenograft tumors (RH41, IGF‐Sal). Dose‐related increases of insulin, C‐peptide and glucose occurred in the fasted state. In dose panels without glucose challenge plasma glucose levels returned to baseline within 4 h post‐dose. In subjects receiving a glucose challenge 2 h post‐dose a second increase of glucose and a marked increase of insulin and C‐peptide was observed, possibly explaining the observed hypoglycemia AEs in these subjects. There was no prolonged elevation of glucose after the glucose challenge. Conclusion: Current data suggest doses of BMS‐754807 in humans that produce exposure predicted to be efficacious are safe and tolerable. Pharmacodynamic effects on insulin and glucose support pharmacologic activity. Dual inhibition of IGF‐1R and IR is feasible and may provide differential activity from IGF‐1R‐specific monoclonal antibodies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A101.