Summary.-BDF' mice were inoculated with 106 leukaemic cells and, together with control mice, were given a single oral dose of cyclophosphamide-14C of 100 mg/kg body weight. In the leukaemic mice we observed an increased'4C concentration in the plasma, bone marrow, liver, lungs, spleen, kidney and particularly fat where the level was 2-4 times higher than in control mice. Conversely, during the same period, significantly less 14C was detected in the stomach and small intestine of the leukaemic mice. These results were obtained 6 days after tumour transplantation (median survival time 7*7 days) whereas no differences were observed when the studies were carried out 4 days after tumour transplantation. These findings indicate an increase in the gastrointestinal absorption and in the tissue storage of cyclophosphamide in L-1210 leukaemic mice at an advanced stage of the disease.
Summary.-A reduced response of a tumour to chemotherapy may be due to the host's drug metabolism. To test this hypothesis, we measured the metabolism of a model drug, para-aminosalicylate (PAS). Volunteers and cancer patients ingested a single oral dose (2 g) of PAS and we measured the plasma disappearance curve of the drug and its metabolite. In 7 patients suffering from lymphosarcoma, acute or chronic leukaemia and resistant to cancer chemotherapy, we observed low plasma PAS concentrations, an increase in PAS acetylation and an increased number (and a higher frequency) of abnormal liver-function tests. In 14 patients with malignant blood disease, yet responding well to chemotherapy, the metabolism of PAS is similar to that of healthy controls of the same age and sex. The plasma half-life of PAS is similar in sensitive and resistant patients, but slightly longer than in volunteers. Finally, in urine collected 120 min after drug administration, we observed the same results as in plasma. In conclusion, cancer patients resistant to chemotherapy do not metabolize the model drug PAS as volunteers or sensitive patients do, and this might be relevant to the terminal stage of the disease.
Pimavanserin is a selective serotonin‐modulating agent with inverse agonist/antagonist activity at the 5‐HT2A receptor. Safety and efficacy of pimavanserin 34 mg once daily was studied in adults with hallucinations and delusions associated with Parkinson's disease psychosis and other neuropsychiatric conditions. This analysis used model‐based simulations of pimavanserin steady‐state exposures to identify a dose that generated pediatric exposures comparable with adult exposures achieved with 34 mg pimavanserin.A population pharmacokinetics model was developed using pooled plasma drug concentration (i.e., actual) data from 13 clinical studies, including a phase 1 study of adolescent pediatric patients (13‐17 years) with various psychiatric conditions. Stochastic simulations were performed to predict exposures in a virtual (i.e., simulated) group of pediatric patients (5‐17 years). Steady‐state measures of area under the plasma concentration‐time curve (AUC) and maximum drug concentration (Cmax) were simulated for relevant age and weight stratifications and compared with simulated exposures in adults (18‐49 years).Simulated mean AUC ranged 47.41‐54.73 ng·d/mL and mean Cmax ranged 41.13‐50.07 ng/mL in adults receiving pimavanserin 34 mg. Simulated mean (SD) Cmax with 34 mg pimavanserin was similar in patients aged 10–17 years (56.54 [24.58] ng/mL) and adults. Pimavanserin 20 mg yielded a mean (SD) Cmax most like the 34‐mg adult Cmax in patients aged 5–9 years (45.30 [21.31] ng/mL) and in the 14–25 kg pediatric patient weight group (49.18 [22.91] ng/mL).Pimavanserin 20 and 34 mg in pediatric patients aged 5–9 and 10–17 years, respectively, yielded exposures similar to daily pimavanserin 34 mg in adults aged 18–49 years.This article is protected by copyright. All rights reserved
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