Pharmacokinetics of Vandetanib in Subjects with Renal or Hepatic Impairment

• Published in: Clinical pharmacokinetics 2010-09, Vol.49 (9), p.607-618
• Main Authors: Weil, Angelika, Martin, Paul, Smith, Robert, Oliver, Stuart, Langmuir, Peter, Read, Jessica, Molz, Karl-Heinz
• Format: Article
• Language: English
• Subjects: Adult; Aged; Angiogenesis Inhibitors - pharmacokinetics; Area Under Curve; Biological and medical sciences; Complications and side effects; Dosage and administration; Drug therapy; Female; Gastroenterology. Liver. Pancreas. Abdomen; General pharmacology; Humans; Internal Medicine; Kidney Diseases - metabolism; Liver Diseases - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lung cancer; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Original Research Article; Other diseases. Semiology; Patient outcomes; Pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Piperidines - pharmacokinetics; Quinazolines - pharmacokinetics; Renal failure; Vandetanib
• ISSN: 0312-5963; 1179-1926
• DOI: 10.2165/11534330-000000000-00000

Background and Objective Vandetanib, an oncology drug being evaluated in phase III clinical trials, undergoes significant renal and hepatic excretion. The objective of these two studies was to investigate the single-dose pharmacokinetics of vandetanib in subjects with renal or hepatic impairment in comparison with healthy subjects. Subjects and Methods Two open-label, parallel-group studies were conducted at a single centre in Germany. Subjects aged 18-75 years with a body mass index of 18–32 kg/m2 were eligible. The renal impairment study recruited subjects with normal renal function and mild, moderate and severe renal impairment according to creatinine clearance calculated from a 24-hour urine collection pre-dose. The hepatic impairment study recruited subjects with normal hepatic function and mild, moderate and severe hepatic impairment according to the Child-Pugh classification. All subjects received a single 800mg oral vandetanib dose. Blood samples for measurement of vandetanib, N -desmethylvandetanib and vandetanib N -oxide were collected before and at various timepoints after vandetanib administration for up to 63 days. Pharmacokinetic parameters were determined using noncompartmental methods. Results Thirty-two subjects were recruited for the renal impairment study (ten with normal renal function and six, ten and six with mild, moderate and severe impairment, respectively). Thirty subjects were recruited for the hepatic impairment study (eight with normal hepatic function and eight, eight and six with mild, moderate and severe impairment, respectively). The area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) values of free vandetanib increased by approximately 46%, 62% and 79% in subjects with mild, moderate and severe renal impairment, respectively. These increases were statistically significant, with the increase in the severe renal impairment group having the possibility of being double the value observed in subjects with normal renal function (geometric least squares [GLS] mean ratio [renal impairment: normal renal function] of 1.79; 90% CI 1.39, 2.31). Peak plasma concentrations of free vandetanib increased slightly by approximately 7%, 9% and 11% in subjects with mild, moderate and severe renal impairment, respectively. Total plasma clearance of free vandetanib decreased with all degrees of renal dysfunction. Hepatic impairment did not have a statistically significant effect on the AUC ∞ of total vandetanib. Pe