Volume of Distribution for Dosing Interval Normalized by Body Mass Index

In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, treatment with glucocorticoid and mineralocorticoid substitution is not always satisfactory. Suboptimal control is often observed in pubertal patients, despite adequate replacement doses and adherence to treatment. We investigated whether the pubertal process is associated with alterations in cortisol pharmacokinetics resulting in a loss of control of the hypothalamic-pituitary-adrenal axis. We determined the pharmacokinetics of hydrocortisone administered iv as a bolus. A dose of 15 mg/m2 body surface area was given to 14 prepubertal (median age, 9.4 yr; range, 6.1–10.8 yr), 20 pubertal (median, 13.5 yr; range, 10.6–16.8 yr), and 6 postpubertal (median, 18.2 yr; range, 17.2–20.3 yr) patients with salt-wasting CAH. All patients were on standard replacement therapy with hydrocortisone and 9α-fludrocortisone. Serum total cortisol concentrations were measured at 10-min intervals for 6 h following iv hydrocortisone bolus and analyzed using a solid-phase RIA. The serum total cortisol clearance curve was monoexponential. Mean clearance was significantly higher in the pubertal group (mean, 427.0 mL/min; sd, 133.4) compared with the prepubertal (mean, 248.7 mL/min; sd, 100.6) and postpubertal (mean, 292.4 mL/min; sd, 106.3) (one-way ANOVA, F = 9.8, P < 0.001) groups. This effect persisted after adjustment for body mass index. The mean volume of distribution was also significantly higher in the pubertal (mean, 49.5 L; sd, 12.2) than the prepubertal (mean, 27.1 L; sd, 8.4) patients but not in the postpubertal (mean, 40.8 L; sd, 16) (ANOVA, F = 15.2, P < 0.001) patients. The significance remained after correction for body mass index. There was no significant difference in mean half-life of total cortisol in prepubertal (mean, 80.2 min; sd, 19.4), pubertal (mean, 84.4 min; sd, 24.9), and postpubertal (mean, 96.7 min; sd, 9.9) patients. Similar differences between groups were observed when the pharmacokinetic parameters of free cortisol were examined. In addition, the half-life of free cortisol was significantly shorter in females compared with males (P = 0.04). These data suggest that puberty is associated with alterations in cortisol pharmacokinetics resulting in increased clearance and volume of distribution with no change in half-life. These alterations probably reflect changes in the endocrine milieu at puberty and may have implications for therapy of CAH and other conditions requiring cortisol substitution in the adolescent years.

Download Full-text

Differential Benefit of Adjuvant Docetaxel-Based Chemotherapy in Patients With Early Breast Cancer According to Baseline Body Mass Index

Journal of Clinical Oncology ◽

10.1200/jco.19.01771 ◽

2020 ◽

Vol 38 (25) ◽

pp. 2883-2891 ◽

Cited By ~ 1

Author(s):

Christine Desmedt ◽

Marco Fornili ◽

Florian Clatot ◽

Romano Demicheli ◽

Davide De Bortoli ◽

...

Keyword(s):

Breast Cancer ◽

Body Mass Index ◽

Body Mass ◽

Disease Free Survival ◽

Dose Intensity ◽

Clinical Trial Data ◽

Volume Of Distribution ◽

Baseline Body Mass Index ◽

Docetaxel Group ◽

Er Status

PURPOSE Lipophilic drugs, such as taxanes, have a high affinity for adipose tissue and a resulting higher volume of distribution. Here, we reanalyzed clinical trial data to investigate whether the efficacy of docetaxel-based chemotherapy differs from non-docetaxel–based chemotherapy in patients with breast cancer according to their baseline body mass index (BMI). PATIENTS AND METHODS We retrospectively analyzed data from all of the patients in the adjuvant BIG 2-98 trial (ClinicalTrials.gov identifier: NCT00174655 ; N = 2,887) comparing non-docetaxel– to docetaxel-containing chemotherapy. BMI (kg/m2) was categorized as follows: 18.5 to < 25, lean; 25 to < 30, overweight; and ≥ 30, obese. Disease-free survival (DFS) was the primary endpoint, and overall survival (OS) was the secondary endpoint. A second-order interaction was assessed among treatment, BMI, and estrogen receptor (ER) status. RESULTS There was no difference in DFS or OS according to BMI in the non-docetaxel group, while reduced DFS and OS were observed with increasing BMI category in the docetaxel group. Adjusted hazard ratios for DFS and OS were, respectively, 1.12 (95% CI, 0.98 to 1.50; P = .21) and 1.27 (95% CI, 1.01 to 1.60; P = .04) for overweight versus lean groups and were 1.32 (95% CI, 1.08 to 1.62; P = .007) and 1.63 (95% CI, 1.27 to 2.09; P < .001), respectively, for obese versus lean groups. Similar results were obtained when considering ER-negative and ER-positive tumors separately and when considering only patients who received a relative dose intensity ≥ 85% for docetaxel. A joint modifying role of BMI and ER status on treatment effect was evident for DFS (adjusted P = .06) and OS (adjusted P = .04). CONCLUSION This retrospective analysis of a large adjuvant trial highlights a differential response to docetaxel according to BMI, which calls for a body composition–based re-evaluation of the risk-benefit ratio of the use of taxanes in breast cancer. These results now must be confirmed in additional series.

Download Full-text