Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a “European Pediatric Oncology Off-patents Medicines Consortium” trial

Figures

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  Fig. 1. Study design (sampling scheme for patients >3 years). Simplified overview of the main trial procedures, including pharmacokinetic and natriuretic peptides/troponin sampling times (termed A–E) as well as echocardiography schedules (termed 1.1–2.2). Sampling had to be done from two different chemotherapy blocks chosen by the investigator. Sampling schemes for patients <3 years were identical, with the exception that only 5 PK samples (3 + 2) were requested

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  Fig. 2. Plasma concentration time curves. Doxorubicin plasma concentration time curves estimated by the PopPK model of the first sampling period for four different patients are shown together with the corresponding doxorubicin plasma concentration half-lives. The open circles present the actual measured values. A and B were patients with soft tissue sarcoma and a scheduled infusion duration of 4 h. Patient A was 12.99 years old and patient B 0.66 years. The actual infusion time for patient B was 4.77 h. C and D were patients with ALL and a scheduled infusion duration of 1 h. Patient C was 12.89 years and patient D 2.09 years. The actual infusion time for D was 1.04 h

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  Fig. 3. Age dependency of doxorubicin clearance. Distribution of clearance (CL) (normalized to BSA) for the two investigated age groups (A: <3 years and B: 3 to <18 years). Data are summarized as box-and-whisker plots. In each plot, the central box represents values from the lower to upper quartile (25–75 percentiles) and the middle line the median. The end of the upper whisker corresponds to the largest observation smaller than the 75 % quantile + 2*IQR. Likewise, the end of the lower whisker corresponds to the smallest observation larger than the 25 % quantile − 2*IQR. Observations that are beyond the whiskers can be regarded as outliers

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  Fig. 4. Biomarker concentrations of NT-proBNP and cTnT before and after doxorubicin administration. NT-proBNP (a exemplary for the three natriuretic peptides) and cTnT (b exemplary for the two cardiac troponins) concentrations in plasma samples before (Samples A and C) and at different times after doxorubicin administration (samples B, D, E). Data are summarized as box-and-whisker plots as explained in Fig. 3