ABSTRACT
This study investigated the feasibility of predicting the neutropenia-related effects of a therapy that combines the investigational drug BI 2536 (inhibitor of Polo-like kinase 1) and pemetrexed, an approved anticancer drug. Predictions were arrived at using the pharmacokinetic/pharmacodynamic (PK/PD) parameters of each of the drugs obtained from monotherapy studies and assuming that the neutropenic effect is additive when the drugs are administered as a combination therapy. Subsequently, a PK/PD model was developed to determine whether this assumption of additive effect was reasonable in relation to these two drugs. All analyses and simulations were performed using the population approach in NONMEM, version VI.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Computer Simulation , Lung Neoplasms/drug therapy , Models, Biological , Neutropenia/chemically induced , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Clinical Trials, Phase I as Topic , Feasibility Studies , Glutamates/administration & dosage , Guanine/administration & dosage , Guanine/analogs & derivatives , Humans , Pemetrexed , Protein Kinase Inhibitors/administration & dosage , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Pteridines/administration & dosage , Treatment Outcome , Polo-Like Kinase 1ABSTRACT
The influence of different lengths of the pre-stimulation resting period on the magnitude of a hemodynamic response evoked by motor stimulation was examined in 10 subjects by means of near-infrared spectroscopy (NIRS). A motor stimulus was used which has been previously established as a model for functional activation studies with NIRS. Subjects performed a 20 s finger opposition task in the hand contralateral to NIRS probe localization over left sensorimotor area (C3', according to the 10-20 system). The duration of the pre-stimulation resting period was varied from 10s to 50s and response magnitude was assessed for each of the interstimulus intervals (10 s, 20 s, 30 s, 40 s and 50 s). Data analysis showed that response magnitude in oxygenated and deoxygenated haemoglobin concentration changed with different interstimulation intervals. Interestingly the greatest NIRS response was obtained with resting period 30 s prior to stimulation; shorter and longer resting periods resulted in smaller responses. The time course and the dependence of response magnitude on interstimulus interval differed between [oxy-Hb] and [deoxy-Hb] changes. For [oxy-Hb] the previously described fast initial increase ('overshoot') and the post-stimulation undershoot was more clearly seen with long prestimulation resting periods. Cytochromeoxidase oxygenation changes did not change significantly with different interstimulus intervals. We conclude that comparisons between different functional activation studies with techniques relying on stimulus evoked changes in cerebral hemodynamics must take into account not only the quality of the experimental paradigm and the length of the stimulation period, but also that the resting period between repetitive stimulations is important for response amplitude and its time course.
Subject(s)
Brain/metabolism , Hemodynamics/physiology , Motor Activity/physiology , Oxygen/blood , Oxygen/metabolism , Cerebrovascular Circulation/physiology , Evaluation Studies as Topic , Hemoglobins/metabolism , Humans , Motor Cortex/blood supply , Motor Cortex/metabolism , Oximetry , Oxyhemoglobins/metabolism , Psychomotor Performance/physiology , Spectroscopy, Near-Infrared , Time FactorsABSTRACT
We studied cerebral hemodynamic response to a sequential motor task in 56 subjects to investigate the time course and distribution of blood oxygenation changes as monitored by near-infrared spectroscopy (NIRS). To address whether response is modulated by different performance velocities, a group of subjects (n = 12) was examined while performing the motor task at 1, 2, and 3 Hz. The results demonstrate that 1) the NIRS response reflects localized changes in cerebral hemodynamics, 2) the response, consisting of an increase in oxygenated hemoglobin concentration [oxy-Hb] and a decrease in deoxygenated hemoglobin concentration ([deoxy-Hb]), is lateralized and increases in amplitude with higher performance rates, and 3) changes in [oxy-Hb] and [deoxy-Hb] differ in time course. Changes in [oxy-Hb] are biphasic, with a fast initial increase and a pronounced poststimulus undershoot. The stimulus-associated decrease in [deoxy-Hb] is monophasic, and response latency is greater. We conclude that NIRS is able to detect even small changes in cerebral hemodynamic response to functional stimulation.
