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The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No: EGF109275
Title : An Open-Label, Single Sequence Study to Examine the Effects of Esomeprazole on the Pharmacokinetics of
Orally Administered Lapatinib in Subjects with Metastatic ErbB2 Positive Breast Cancer
Rationale: The in vitro solubility of lapatinib declines significantly at pH greater than four. As a result, it was
considered useful to determine if the elevated gastric pH could affect the rate or extent of oral absorption of lapatinib. This study was conducted to assess the potential effects of elevated gastric pH on lapatinib pharmacokinetics based on within-subject comparisons following chronic administration of lapatinib alone and in combination with esomeprazole.
Phase: I
Study Period: 10 March 2009 – 24 November 2009
Study Design: Multicenter, two-part, open-label, single sequence study.
Centres: 2 centers in South Korea, 1 center in Spain, and 1 center in the USA
Indication: Breast Cancer
This was an open-label, single sequence study comprised of two periods:
Period 1: fasted subjects received 1250 mg lapatinib once-daily in the morning, for seven consecutive days prior to pharmacokinetic (PK) sampling at the Period 1 visit. To provide scheduling flexibility or accommodate a single missed or vomited dose, the Period 1 Visit PK assessment could be conducted within a range of 7-14 days following the administration of the 1st dose of lapatinib. Period 2: fasted subjects received 1250 mg lapatinib once-daily in the morning, for seven consecutive days along with 40 mg esomeprazole at bedtime over the same period. Esomeprazole was given at bedtime (3 hours after dinner and 12 hours prior to lapatinib administration) in order to achieve maximum inhibition of gastric acid secretion. The Period 2 Visit PK assessments were conducted seven days after the Period 1 PK assessments, provided that at least four days of continuous dosing of both esomeprazole and lapatinib was achieved prior to Objectives: The primary objective of the study was to characterize the effect of elevated gastric pH produced by
repeat oral doses of esomeprazole on lapatinib pharmacokinetics following repeat dose oral lapatinib treatment in adult
cancer patients diagnosed with metastatic ErbB2 positive breast cancer.
Primary Outcome Variable: The area under the plasma concentration versus time curve (AUC[0-24]), minimum
observed plasma concentration (Cmin), maximum observed plasma concentration (Cmax), time of maximal plasma
concentration (tmax), and lag time (tlag) in the appearance of measurable plasma concentrations of lapatinib following
steady-state administration.
Secondary Outcome Variables: Safety and tolerability assessments including evaluation of adverse events (AEs)
and changes in laboratory values, and vital signs.
Statistical Methods:
Pharmacokinetics: The following pharmacokinetic (PK) parameters were determined from the plasma concentration-
time data using standard compartmental and/or noncompartmental methods with WinNonlin (version 5.2): Cmax, tmax, AUC(0-24), AUC(0-4), AUC(4-24), tlag, and Cmin. All of the derived parameters were listed. For each of these parameters summary statistics were calculated for each active treatment group. To assess the influence of esomeprazole on the pharmacokinetics of lapatinib, loge-transformed values of AUC(0-24), AUC(0-4), AUC(4-24), Cmax, and Cmin were separately analyzed with a mixed effects model. This analysis considered treatment as a fixed effect and subject as a random effect. Models were run with and without age as a covariate to determine its impact on the results. Age did not significantly impact the results. The results of CYP2C19 genotyping and H. pylori status were generated for each subject and added as a covariate in the model, if appropriate. The analysis was performed using the mixed linear models procedure within the SAS/STAT module of the SAS system. Point estimates and 90% confidence intervals (CIs) of the differences in least-square (LS) means of the test less the reference treatment were derived and then back-transformed for the ratio lapatinib+esomeprazole:lapatinib alone. The PK Population included subjects in the All Treated Population for whom a PK sample was obtained and analyzed.
Safety: Listings and descriptive summaries were used to report the safety data, including AEs, serious adverse events
(SAEs), clinical chemistry, hematology, vital signs, and electrocardiograms. The All Treated Population was the primary population for the reporting of safety data, and included all subjects who received at least one dose of study medication. Study Population: The study population was comprised of adult females (non-child bearing potential) aged 18 to 65
years with histologically confirmed metastatic breast cancer that overexpressed ErbB2 (3+ by IHC, FISH, or CISH
positive). Subjects in the study were required to have no clinically significant cardiac illness or disease, and no
predisposing condition that would interfere with the absorption, distribution, metabolism, or excretion of drugs.
Number of Subjects:
1. Sixteen subjects were planned to be enrolled into this study, however one subject withdrew due to an SAE of spinal cord compression; the event was not considered by the investigator to be related to study medication. Therefore the study site enrolled an additional subject for a total enrollment of 17 subjects. Pharmacokinetics (PK) Results: Dosing lapatinib in the morning when gastric pH was highest (for maximum
interaction potential) after administration of esomeprazole in the evening resulted in a geometric mean (90% CI) 26% (18-34%) decrease in lapatinib AUC(0-24) after correction for the effect of age. This decrease in bioavailability appeared to diminish with increasing age, and subjects with CYP2D6 poor metabolizer or H. pylori positive status were less sensitive to this effect.
Safety results: Adverse event (AE) data were collected and recorded starting after the subjects signed the informed
consent form and continued until the subjects discontinued study drug, or transitioned into a continuation (roll-over)
study. AEs reported in this trial were consistent with those observed in other trials of lapatinib monotherapy. One subject withdrew from the study due to an SAE of spinal cord compression; the event was not considered by the investigator to be related to study medication. No deaths occurred during the study. All Treated Subjects
Most Frequent AEs: on-therapy AEs occurring in >1 subject, n (%):
Serious Adverse Events, n (%) [n considered by the investigator to be
All Treated Subjects
related, possibly related, or probably related to study medication]:


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