Clinical Pharmacokinetics and Pharmacodynamics of Ganciclovir and Valganciclovir in Children with Cytomegalovirus Infection

Introduction: Among infants and immunocompromised children cytomegalovirus (CMV) is associated with significant morbidity and mortality. Areas covered: This review describes the clinical pharmacokinetics and pharmacodynamics of ganciclovir and valganciclovir for the treatment and prevention of CMV infection in children. Expert opinion: A 24-h ganciclovir area under the concentration versus time curve (AUC0 – 24) of 40 – 60 μg h/ml decreased the risk of CMV infection for adults undergoing CMV prophylaxis. For adults undergoing treatment for active CMV disease, a target AUC0 – 12 of 40 – 60 μg h/ml has been suggested. The applicability of these targets to children remains uncertain; however, with the most sophisticated dosing regimens developed to date only 21% of patients are predicted to reach these targets. Moving forward, identification of optimal pediatric ganciclovir and valganciclovir dosing regimens may involve the use of an externally validated pediatric population pharmacokinetic model for empirical dosing, an optimal sampling strategy for collecting a minimal number of blood samples for each patient and Bayesian updating of the dosing regimen based on an individual patient’s pharmacokinetic profile

A Phase I Trial of Bortezomib in Combination with Epirubicin, Carboplatin and Capecitabine (VECarboX) in Advanced Gastric and Gastro-oesophageal Junction Adenocarcinoma

Purpose: The protease inhibitor bortezomib attenuates the action of NF-κB and has shown preclinical activity alone and in combination with chemotherapy. Design A Phase I dose-escalation study was performed administering bortezomib (0.7, 1.0, 1.3 and 1.6 mg m−2 on days 1 and 8 from cycle 2 onwards) in combination with Epirubicin 50 mg m−2 intravenously on day 1, Carboplatin AUC 5 day 1 and Capecitabine 625 mg m−2 BD days 1–21 every 21 days (VECarboX regimen), in patients with advanced oesophagogastric adenocarcinoma. The primary objective was to define the maximum tolerated dose (MTD) of Bortezomib when combined with ECarboX. Results 18 patients received bortezomib 0.7 (n = 6), 1.0 (n = 3), 1.3 (n = 6) and 1.6 mg m−2 (n = 3) and a protocol amendment reducing the capecitabine dose to 500 mg m−2 BD was enacted due to myelotoxicity. Common treatment-related non-haematological adverse events of any grade were fatigue (83.3 %), anorexia (55.6 %), constipation (55.6 %) and nausea (55.6 %). Common Grade 3/4 haematological toxicities were neutropenia (77.8 %) and thrombocytopenia (44.4 %). Objective responses were achieved in 6 patients (33.3 %) and a further 5 patients (27.8 %) had stable disease for >8 weeks. Conclusions: The addition of Bortezomib to ECarboX is well tolerated and response rates are comparable with standard chemotherapy