This phase I study evaluated the safety, tolerability, and pharmacokinetics of copanlisib, an intravenously administered pan-phosphatidylinositol 3-kinase inhibitor in patients with advanced solid tumors or non-Hodgkin's lymphoma. Copanlisib was well tolerated with a manageable safety profile, with anti-tumor activity in both advanced solid tumors and hematological malignancies.

AimsTo characterize alemtuzumab pharmacokinetics and its exposure-response relationship with white blood cell (WBC) count in patients with B-cell chronic lymphocytic leukaemia (CLL). MethodsNonlinear mixed effects models were used to characterize plasma concentration-time data and WBC count-time data from 67 patients. Logistic regression was used to relate summary measures of drug exposure to tumour response. ResultsAlemtuzumab pharmacokinetics were best characterized by a two-compartment model with nonlinear elimination where Vmax (mg h -1 ) was [1020 ¥ (WBC count/10 ¥ 10 9 l -1 ) 0.194 ], Km was 338 mg l -1 , V1 was 11.3 l, Q was 1.05 l h -1 and V2 was 41.5 l. Intersubject variability (ISV) in Vmax, Km, V1 and V2 was 32%, 145%, 84% and 179%, respectively. The reduction in WBC over time was modelled by a stimulatory loss indirect response model with values of 18.2 for Emax, 306 mg l -1 for EC50, 1.56 ¥ 10 9 cells l -1 h -1 for Kin and 0.029 per h for Kout. The probability of achieving a complete or partial response was Ն50% when the maximal trough concentration exceeded 13.2 mg ml -1 or when AUC0-t exceeded 484 mg h -1 ml -1 . ConclusionsAlemtuzumab displayed time-and concentration-dependent pharmacokinetics with large interpatient variability, both in pharmacokinetics and pharmacodynamics, which was probably reflective of differences in tumour burden among patients. A direct relationship between maximal trough concentrations and clinical outcomes was observed, with increasing alemtuzumab exposure resulting in a greater probability of positive tumour response.

Observed differences in pharmacokinetics were attributed to body weight, with no additional independent effect of age. Thus, no dose adjustment from the standard dose of gadobutrol in adults based on body weight (0.1 mmol/kg) is necessary in pediatric patients aged 2 to 17 years. Gadobutrol was safe and well tolerated in the pediatric population in this study.

Grapefruit juice seems to reduce rather than increase oral bioavailability of etoposide. Moreover, we did not observe a reduction in interpatient variability of bioavailability.

SummaryAs the systemic administration of etoposide is effective in the treatment of relapsed and metastatic brain tumours, a pilot trial was designed to study the feasibility of intraventricular administration of etoposide in such patients. 14 patients aged 2.1 to 33.2 years were treated with intraventricular etoposide simultaneously with either oral or intravenous chemotherapy with trofosfamide or carboplatin and etoposide. In 59 courses (1-12/patient) 0.5 mg etoposide was administered daily via an indwelling subcutaneous reservoir for 5 consecutive days every 2-5 weeks over a period of 0-11 months. During 15 courses in 5 patients serial CSF samples were obtained and etoposide levels were determined by reversed-phase HPLC. Side effects included transient headache and bacterial meningitis, each during 2 courses. Pharmacokinetic data analysis in the CSF (11 courses, 4 patients) revealed a terminal half-life of 7.4±1.2 hours and an AUC of 25.0 ± 9.5 µg h ml -1 (mean ± standard deviation). The volume of distribution at steady state and total clearance exhibited a large interindividual variability with mean values of 0.16 l and 0.46 ml min -1 respectively. Intraventricularly administered etoposide is well tolerated. CSF peak levels exceed more than 100-fold those achieved with intravenous infusions. Further studies should be focused on optimizing the dose and schedule and on determining the effectiveness of intraventricularly administered etoposide.