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1.
Br J Clin Pharmacol ; 85(1): 136-146, 2019 01.
Article in English | MEDLINE | ID: mdl-30261554

ABSTRACT

AIMS: Carboplatin dosage is calculated by using the estimated glomerular filtration rate (GFR) to achieve a target plasma area under the plasma concentration-time curve (AUC). The aims of the present study were to investigate factors that influence the pharmacokinetics of carboplatin in children with high-risk neuroblastoma, and whether target exposures for carboplatin were achieved using current treatment protocols. METHODS: Data on children receiving high-dose carboplatin, etoposide and melphalan for neuroblastoma were obtained from two study sites [European International Society for Paediatric Oncology (SIOP) Neuroblastoma study, Children's Hospital at Westmead; n = 51]. A population pharmacokinetic model was built for carboplatin to evaluate various dosing formulas. The pharmacokinetics of etoposide and melphalan was also investigated. The final model was used to simulate whether target carboplatin AUC (16.4 mg ml-1 ·min) would be achieved using the paediatric Newell formula, modified Calvert formula and weight-based dosing. RESULTS: Allometric weight was the only significant, independent covariate for the pharmacokinetic parameters of carboplatin, etoposide and melphalan. The paediatric Newell formula and modified Calvert formula were suitable for achieving the target AUC of carboplatin for children with a GFR <100 ml min-1 1.73 m-2 but not for those with a GFR ≥100 ml min-1 1.73 m-2 . A weight-based dosing regimen of 50 mg kg-1 achieved the target AUC more consistently than the other formulas, regardless of renal function. CONCLUSIONS: GFR did not appear to influence the pharmacokinetics of carboplatin after adjusting pharmacokinetic parameters for weight. This model-based approach validates the use of weight-based dosing as an appropriate alternative for carboplatin in children with either mild renal impairment or normal renal function.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Carboplatin/pharmacokinetics , Etoposide/pharmacokinetics , Kidney/physiopathology , Melphalan/pharmacokinetics , Neuroblastoma/drug therapy , Age Factors , Antineoplastic Agents/administration & dosage , Area Under Curve , Body Weight , Carboplatin/administration & dosage , Child , Child, Preschool , Dose-Response Relationship, Drug , Drug Dosage Calculations , Etoposide/administration & dosage , Female , Glomerular Filtration Rate/physiology , Humans , Infant , Male , Melphalan/administration & dosage , Models, Biological
2.
Diabetes Obes Metab ; 14(10): 963-5, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22564555

ABSTRACT

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open-label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15-40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250-2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3-5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.


Subject(s)
Acidosis, Lactic/chemically induced , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/administration & dosage , Lactic Acid/blood , Metformin/administration & dosage , Renal Insufficiency, Chronic/complications , Acidosis, Lactic/blood , Acidosis, Lactic/etiology , Aged , Aged, 80 and over , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Hypoglycemic Agents/adverse effects , Male , Metformin/adverse effects , Middle Aged , Renal Dialysis , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/therapy , Risk Factors
3.
Oncogene ; 25(41): 5664-72, 2006 Sep 14.
Article in English | MEDLINE | ID: mdl-16652155

ABSTRACT

The four members of the ErbB family of receptor tyrosine kinases are involved in development and tumorigenesis of the mammary gland. Whereas the epidermal growth factor receptor, ErbB2 and ErbB3 are positively associated with various cancers, clinical studies of ErbB4 in breast cancer are contradictory. Results from tissue culture analyses and some clinical studies suggested that ErbB4 is either a tumor suppressor or is a negative regulator of ErbB2-driven tumors. Neu-Cre-ErbB4(flox/null) mice in which ErbB4 was inactivated by Cre-lox-mediated recombination in the mammary gland developed MMTV-Neu-driven mammary tumors with a similar latency period to mice with one or two wild-type ErbB4 alleles. Moreover, there was no difference in the histologies of tumors that developed, nor in the propensity to form lung metastases. Taken together these results suggest that ErbB4 is not a potent, highly penetrant tumor suppressor, nor is it a factor in Neu-mediated tumorigenesis in this model.


Subject(s)
ErbB Receptors/physiology , Gene Deletion , Genes, erbB-2 , Mammary Neoplasms, Experimental/genetics , Animals , Base Sequence , Blotting, Western , DNA Primers , ErbB Receptors/genetics , Immunoprecipitation , Lung Neoplasms/secondary , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Transgenic , Polymerase Chain Reaction , Receptor, ErbB-4
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