Semi-physiological Enriched Population Pharmacokinetic Modelling to Predict the Effects of Pregnancy on the Pharmacokinetics of Cytotoxic Drugs.

BACKGROUND AND OBJECTIVE: As a result of changes in physiology during pregnancy, the pharmacokinetics (PK) of drugs can be altered. It is unclear whether under- or overexposure occurs in pregnant cancer patients and thus also whether adjustments in dosing regimens are required. Given the severity of the malignant disease and the potentially high impact on both the mother and child, there is a high unmet medical need for adequate and tolerable treatment of this patient population. We aimed to develop and evaluate a semi-physiological enriched model that incorporates physiological changes during pregnancy into available population PK models developed from non-pregnant patient data. METHODS: Gestational changes in plasma protein levels, renal function, hepatic function, plasma volume, extracellular water and total body water were implemented in existing empirical PK models for docetaxel, paclitaxel, epirubicin and doxorubicin. These models were used to predict PK profiles for pregnant patients, which were compared with observed data obtained from pregnant patients. RESULTS: The observed PK profiles were well described by the model. For docetaxel, paclitaxel and doxorubicin, an overprediction of the lower concentrations was observed, most likely as a result of a lack of data on the gestational changes in metabolizing enzymes. For paclitaxel, epirubicin and doxorubicin, the semi-physiological enriched model performed better in predicting PK in pregnant patients compared with a model that was not adjusted for pregnancy-induced changes. CONCLUSION: By incorporating gestational changes into existing population pharmacokinetic models, it is possible to adequately predict plasma concentrations of drugs in pregnant patients which may inform dose adjustments in this population.

Visceral obesity and muscle mass determined by CT scan and surgical outcome in patients with advanced ovarian cancer. A retrospective cohort study.

OBJECTIVE: Visceral obesity (VO) is a risk factor for developing postoperative complications in patients undergoing abdominal oncological surgery. However, in ovarian cancer patients this influence of body composition on postoperative morbidity is not well established. The aim of this study is to assess the association between body composition and complications in patients with advanced ovarian cancer undergoing cytoreductive surgery. METHODS: Patients with FIGO stage 3 or 4 ovarian cancer between 2006 and 2017 were included. Visceral fat area, total skeletal mass and total fat area were measured on a single slice on the level of L3-L4 of the preoperative CT-scan. VO was defined as visceral fat ≥100cm2. The perioperative data were extracted retrospectively. A multivariate logistic regression analysis was performed to test the predictive value of multiple variables such as body composition, albumin levels and preoperative morbidity. RESULTS: 298 consecutive patients out of nine referring hospitals were included. VO patients were more likely to be hypertensive (38% vs 17% p < 0.001), and to have an ASA 3 score (21% vs 10% P = 0.012). Complications occurred more often in VO patients (43% vs 21% P < 0.001). Thrombotic events were found in 4.9% of VO patients versus 0.6% of the non-visceral obese patients (p = 0.019). VO(OR: 4.37, p < 0.001), hypertension (OR:1.9, p = 0.046) and duration of surgery (OR: 1.004, p = 0.017) were predictors of post-surgical complications. Muscle mass is not a predictor of complications. CONCLUSION: Visceral obesity is associated with a higher occurrence of complications in patients with advanced ovarian cancer undergoing cytoreductive surgery.