Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults

Background

Imatinib mesylate (Gleevec^®) is a small molecule tyrosine kinase inhibitor approved for use in the management of chronic myeloid leukemia in adults and children and in gastrointestinal stromal tumors in adults. Population pharmacokinetic (PPK) studies evaluating the effect of population covariates on the pharmacokinetics of imatinib and its active metabolite have been developed in adults with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, this still remains to be described in children.

Purpose

The objectives of the analysis were to develop a PPK model of imatinib and its active metabolite, CGP74588, to describe exposure in children and young adults and to identify covariates that are predictors of variability in disposition.

Methods

Plasma concentrations from 26 subjects with Philadelphia (Ph+) leukemia (Phase I study) and 15 subjects with refractory solid tumors (Phase II study), who received oral imatinib at doses ranging from 260 to 570 mg/m², were available for the PPK analysis in NONMEM. Blood samples were drawn prior to dosing and over 24–48 h on days 1 and 8 of the studies. Covariates studied included weight, age, albumin, alanine aminotransferase and the study population.

Results

The pharmacokinetics of imatinib and CGP 74588 were well described by one and two compartment models, respectively. Total body weight was the only covariate found to significantly affect Cl/F and V/F. The final imatinib-CGP 74588 model is summarized as follows: CL/F _imatinib (L/h) = 10.8 × (WT/70)^0.75, V/F _imatinib (L) = 284 × (WT/70) and D1_{duration of zero order absorption,imatinib} (h) = 1.67 and CL/F _CGP 74588 (L/h) = 9.65 × (WT/70)^0.75, V1/F _CGP 74588 (L) = 11.6 × (WT/70), Q _CGP 74588 (L/h) = 2.9 × (WT/70)^0.75 and V2/F _CGP 74588 (L) = 256*(WT/70). Model evaluation indicated that the final model was robust and satisfactory.

Conclusions

Current imatinib dosing guidelines in pediatrics is based on the achievement of exposures consistent with doses known to be safe and efficacious in adults. Dose adjustments in children are guided empirically by the observance of drug-related toxicities. While, the pharmacokinetics of imatinib and its active metabolite, CGP 74588 in children are consistent with prior knowledge in adults, the model will form the basis to support the design of future trials, particularly with a view to managing toxicities and exploring dosing in this population.     

Cricotracheal separation: a review and a case with bilateral recovery of recurrent laryngeal nerve function

Cricotracheal separation (CTS) is an uncommon injury, with a high index of suspicion required to establish the diagnosis. Computerized tomography (CT) plays a role in diagnosis but cannot necessarily be relied upon. Bilateral recurrent laryngeal nerve (RLN) palsies are usually associated with this type of injury. We recently treated a patient with CTS in whom one RLN was intact from the time of the injury and the other nerve recovered within three months. Computed tomography was inconclusive. Early open repair of the injury and frequent follow-up examinations led to successful decannulation after six weeks and excellent short-term voice and airway outcomes. A detailed discussion of this unusual case is followed by a review of the current literature on CTS, with particular emphasis on significant management dilemmas and controversies. Clinical suspicion remains more sensitive than investigations in diagnosing CTS. Permanent bilateral RLN palsies are not inevitable following these injuries.     

Fractal analysis of eye movements during reading.

We present a new method for the analysis of reading eye movements based on the methods of nonlinear dynamics. In this preliminary study, the eye movements of normal and abnormal readers were analyzed for evidence of chaotic, nonlinear dynamical behavior. Both power spectral density analysis and fractal dimension determination showed evidence of nonlinearity as manifest in chaotic behavior. The computed fractal dimension of the system's presumed attractor seemed directly related to qualitative assessment of reading ability. Representative subjects did not differ in a similar analysis of pursuit movements. Although fractal analysis did not distinguish unconditionally between normal and abnormal reading in this preliminary study, it nevertheless offers a promising hitherto unused approach to the analysis of eye movements and the modeling of oculomotor behavior.     

LYMPHOCYTIC HYPOPHYSITIS: SPONTANEOUS RESOLUTION ON MRI WITH PROGRESSION OF ENDOCRINE DEFECT

Lymphocytic hypophysitis is an uncommon condition that typically occurs during the last trimester of pregnancy or in the postpartum period. Presentation is of an anterior pituitary mass with varying degrees of pituitary dysfunction. We present a case in which there was dramatic resolution of the pituitary lesion on sequential MRI scanning. Despite this apparent resolution, however, the patient continues to have significant pituitary dysfunction.     

EFFECT OF VARIOUS AGENTS ON THE BLOOD FLOW THROUGH THE CORONARY ARTERIES AND VEINS

The results obtained show that adrenalin, transfusion with salt solution, and the inhalation of tobacco smoke caused an increased circulation in the coronary vessels. Amyl nitrite and nitroglycerin produce the opposite effect. Digitalis, strophanthus, caffeine, and theobromine give no change in the velocity of circulation. We can conclude from the results that the blood pressure is the main element which influences coronary circulation, while the other factors play only a minor part in its variations.