A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function

Purpose Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function. Methods Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.73 m(2)), B (moderate renal impairment: CrCL 30 to <50 mL/min/1.73 m(2)) and C (severe impairment: CrCL < 30 mL/min/1.73 m(2)) received cabazitaxel 25 mg/m(2) (A, B) or 20 mg/m(2) (C, could be escalated to 25 mg/m(2)), once every 3 weeks. Pharmacokinetic parameters and cabazitaxel unbound fraction (F-U) were assessed using linear regression and mixed models. Geometric mean (GM) and GM ratios (GMRs) were determined using mean CrCL intervals (moderate and severe renal impairment: 40 and 15 mL/min/1.73 m(2)) versus a control (90 mL/min/1.73 m(2)). Results Overall, 25 patients received cabazitaxel (median cycles: 3 [range 1-20]; Cohort A: 5 [2-13]; Cohort B: 3 [1-15]; and Cohort C: 5 [1-20]), of which 24 were eligible for pharmacokinetic analysis (eight in each cohort). For moderate and severe renal impairment versus normal renal function, GMR estimates were: clearance normalized to body surface area (CL/BSA) 0.95 (90% CI 0.80-1.13) and 0.89 (0.61-1.32); area under the curve normalized to dose (AUC/dose) 1.06 (0.88-1.27) and 1.14 (0.76-1.71); and FU 0.99 (0.94-1.04) and 0.97 (0.87-1.09), respectively. Estimated slopes of linear regression of log parameters versus log CrCL (renal impairment) were: CL/BSA 0.06 (-0.15 to 0.28); AUC/dose -0.07 (-0.30 to 0.16); and FU 0.02 (-0.05 to 0.08). Cabazitaxel safety profile was consistent with previous reports. Conclusions Renal impairment had no clinically meaningful effect on cabazitaxel pharmacokinetics

Urinary Neopterin and Phenylalanine Loading Test as Tools for the Biochemical Diagnosis of Segawa Disease

Background. The diagnosis of autosomal dominant GTP-cyclohydrolase deficiency relies on the examination of the GCH1 gene and/or pterins and neurotransmitters in CSF. The aim of the study was to assess the diagnostic value, if any, of pterins in urine and blood phenylalanine (Phe) and tyrosine (Tyr) under oral Phe loading test. Methods. We report on two new pedigrees with four symptomatic and four asymptomatic carriers whose pattern of urinary pterins and blood Phe/Tyr ratio under oral Phe loading pointed to GTP-cyclohydrolase deficiency. The study was then extended to 3 further patients and 90 controls. The diagnostic specificity and sensitivity of these metabolic markers were analysed by backwards logistic analysis. Results. Two genetic alterations segregated alternatively in Family 1 (c.631-632 del AT and c.671A > G), while exon 1 deletion was transmitted along three generations in Family 2. Neopterin and biopterin concentrations in urine clustered differently in controls under and over the age of 15. Therefore patients and controls were sub grouped according to this age. Neopterin was significantly reduced in GCH1 mutated subjects younger than 15, and both neopterin and biopterin in those older than 15. Moreover, the Phe/Tyr ratios at the second and third hour were both significantly higher in patients than in controls. Backwards logistic regression demonstrated the high diagnostic sensitivity and specificity of combined values of neopterin concentration and Phe/Tyr ratio at the second hour. Conclusions. Pterins in urine and Phe loading test are non-invasive and reliable tools for the biochemical diagnosis of GTP-cyclohydrolase deficiency