Semiphysiological versus Empirical Modelling of the Population Pharmacokinetics of Free and Total Cefazolin during Pregnancy

This work describes a first population pharmacokinetic (PK) model for free and total cefazolin during pregnancy, which can be used for dose regimen optimization. Secondly, analysis of PK studies in pregnant patients is challenging due to study design limitations. We therefore developed a semiphysiological modeling approach, which leveraged gestation-induced changes in creatinine clearance (CrCL) into a population PK model. This model was then compared to the conventional empirical covariate model. First, a base two-compartmental PK model with a linear protein binding was developed. The empirical covariate model for gestational changes consisted of a linear relationship between CL and gestational age. The semiphysiological model was based on the base population PK model and a separately developed mixed-effect model for gestation-induced change in CrCL. Estimates for baseline clearance (CL) were 0.119 L/min (RSE 58%) and 0.142 L/min (RSE 44%) for the empirical and semiphysiological models, respectively. Both models described the available PK data comparably well. However, as the semiphysiological model was based on prior knowledge of gestation-induced changes in renal function, this model may have improved predictive performance. This work demonstrates how a hybrid semiphysiological population PK approach may be of relevance in order to derive more informative inferences

Weight, pregnancy and oral contraceptives affect intravenous paracetamol clearance in young women

CONCLUSIONS: Weight, pregnancy and OC result in higher clearance of IV paracetamol in young women. Besides compound specific relevance, these findings also unveil covariates of drug metabolism in young women

Gastric cancer during pregnancy: A report on 13 cases and review of the literature with focus on chemotherapy during pregnancy

Introduction: Gastric cancer during pregnancy is extremely rare and data on optimal treatment and possible chemotherapeutic regimens are scarce. The aim of this study is to describe the obstetric and maternal outcome of women with gastric cancer during pregnancy and review the literature on antenatal chemotherapy for gastric cancer. Material and methods: Treatment and outcome of patients registered in the International Network on Cancer, Infertility and Pregnancy database with gastric cancer diagnosed during pregnancy were analyzed. Results: In total, 13 women with gastric cancer during pregnancy were registered between 2002 and 2018. Median gestational age at diagnosis was 22 weeks (range 6-30 weeks). Twelve women were diagnosed with advanced disease and died within 2 years after pregnancy, most within 6 months. In total, 8 out of 10 live births ended in a preterm delivery because of preeclampsia, maternal deterioration, or therapy planning. Two out of 6 women who initiated chemotherapy during pregnancy delivered at term. Two neonates prenatally exposed to chemotherapy were growth restricted and 1 of them developed a systemic infection with brain abscess after preterm delivery for preeclampsia 2 weeks after chemotherapy. No malformations were reported. Conclusions: The prognosis of gastric cancer during pregnancy is poor, mainly due to advanced disease at diagnosis, emphasizing the need for early diagnosis. Antenatal chemotherapy can be considered to reach fetal maturity, taking possible complications such as growth restriction, preterm delivery, and hematopoietic suppression at birth into account

Immunomodulatory Effects of Streptococcus suis Capsule Type on Human Dendritic Cell Responses, Phagocytosis and Intracellular Survival

Streptococcus suis is a major porcine pathogen of significant commercial importance worldwide and an emerging zoonotic pathogen of humans. Given the important sentinel role of mucosal dendritic cells and their importance in induction of T cell responses we investigated the effect of different S. suis serotype strains and an isogenic capsule mutant of serotype 2 on the maturation, activation and expression of IL-10, IL-12p70 and TNF-α in human monocyte-derived dendritic cells. Additionally, we compared phagocytosis levels and bacterial survival after internalization. The capsule of serotype 2, the most common serotype associated with infection in humans and pigs, was highly anti-phagocytic and modulated the IL-10/IL-12 and IL-10/TNF-α cytokine production in favor of a more anti-inflammatory profile compared to other serotypes. This may have consequences for the induction of effective immunity to S. suis serotype 2 in humans. A shielding effect of the capsule on innate Toll-like receptor signaling was also demonstrated. Furthermore, we showed that 24 h after phagocytosis, significant numbers of viable intracellular S. suis were still present intracellularly. This may contribute to the dissemination of S. suis in the body

Women’s beliefs about medicines and adherence to pharmacotherapy in pregnancy: Opportunities for community pharmacists?

Background During pregnancy women might weigh benefits of treatment against potential risks to the unborn child. However, non-adherence to necessary treatment can adversely affect both mother and child. To optimize pregnant women’s beliefs and medication adherence, community pharmacists are ideally positioned to play an important role in primary care. Objective This narrative review aimed to summarize the evidence on 1) pregnant women’s beliefs, 2) medication adherence in pregnancy, and 3) community pharmacists’ counselling during pregnancy. Method Three search strategies were used in Medline and Embase to find original studies evaluating women’s beliefs, medication adherence and community pharmacists’ counselling during pregnancy. All original descriptive and analytic epidemiological studies performed in Europe, North America and Australia, written in English and published from 2000 onwards were included. Results We included 14 studies reporting on women’s beliefs, 11 studies on medication adherence and 9 on community pharmacists’ counselling during pregnancy. Women are more reluctant to use medicines during pregnancy and tend to overestimate the teratogenic risk of medicines. Risk perception varies with type of medicine, level of health literacy, education level and occupation. Furthermore, low medication adherence during pregnancy is common. Finally, limited evidence showed current community pharmacists’ counselling is insufficient. Barriers hindering pharmacists are insufficient knowledge and limited access to reliable information. Conclusion Concerns about medication use and non-adherence are widespread among pregnant women. Community pharmacists’ counselling during pregnancy is insufficient. Further education, training and research are required to support community pharmacists in fulfilling all the opportunities they have when counselling pregnant women

Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice

<div><p>Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1) mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2%) and to 80% in the male offspring of L1 (control value 33%). These increases are similar to those observed in both lines of mice by radiation. <i>In utero</i> exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼70% of control and induced atrophic seminiferous tubules in ∼30% of the testes. When the <i>in utero</i> CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i) DNA damage is a common mechanism leading to induction of testicular cancer, ii) increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii) children exposed to radiation or DNA damaging chemotherapeutic agents <i>in utero</i> may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.</p></div

Pharmacokinetics of intravenous ketorolac following caesarean delivery

ABSTRACT Background: Drug disposition is altered by pregnancy and the peripartum period but data on intravenous ketorolac pharmacokinetics following caesarean delivery have not been previously reported. Methods: At the end of caesarean delivery, women received an intravenous bolus of ketorolac tromethamine 30 mg (immediate postpartum, Group IP). Plasma samples were collected at 1, 2, 4, 6 and 8 h. A similar pharmacokinetic study was repeated in a subgroup of these women 4-5 months after delivery (late postpartum, Group LP) and in a group of unrelated, healthy nonpregnant female volunteers (controls, Group C). A non-compartmental linear disposition model was applied to analyse individual ketorolac time-concentration profiles. Results at delivery were compared with controls using unpaired or paired statistics as appropriate. Covariates of pharmacokinetic estimates at delivery were examined. Results: Thirty-nine women were studied at caesarean delivery, of whom eight were re-evaluated 4-5 months later. In addition, eight volunteers were studied. Clearance in Group IP was higher compared to Groups LP and C (2.11 vs. 1.43 and 1.07 L/ hAEm 2 respectively, P &lt; 0.05). Volume of distribution was also increased in Group IP compared to Groups LP and C (0.24 vs. 0.16 and 0.17 L/kg respectively, P &lt; 0.05). No significant covariates of pharmacokinetic estimates, including gestational age, preterm vs. term, twin vs. singleton and maternal co-morbidity, were seen in Group IP. Conclusions: Ketorolac clearance and distribution volume are significantly increased following caesarean delivery. These data provide pharmacokinetic estimates on which to base studies on post caesarean analgesia

Weight, pregnancy and oral contraceptives affect intravenous paracetamol clearance in young women

OBJECTIVES: Because of the extensive variability in paracetamol clearance in young women, published data were pooled with newly collected observations in search of covariates of paracetamol pharmacokinetics (PK) within this specific population. SUBJECTS AND METHODS: PK estimates and clinical characteristics [pregnant, weight, exposure to oral contraceptives (OC)] in young women following IV loading dose (2 g paracetamol) were pooled, using a non-compartmental linear disposition model in individual time-concentration profiles. Data were reported by median and range. Rank correlation was used to link clearance (l/h) to weight, Mann Whitney U test to compare clearance (l/h.m-2) between subgroups (pregnant, OC exposure). Finally, a multiple regression model with clearance (l/h) in all women and all non-pregnant women was performed. RESULTS: Based on 73 paracetamol PK estimates, a 8-fold variability in clearance (range 7.1-62.2 l/h) was documented, in part explained by a correlation (r2=0.36) between clearance (l/h) and weight. Clearance (l/h and l/h.m-2) and distribution volume (l) at delivery (n=36) were higher compared to non-pregnant observations. In nonpregnant women, women on OC (n=20) had a higher paracetamol clearance (l/h.m-2) compared to women (n=17) not on OC (p = 0.023).Weight (p = 0.0043) and pregnancy (p = 0.02) were independent variables (r=0.56) of paracetamol clearance (l/h). In non-pregnant women, weight (p = 0.009) and OC exposure (p = 0.03) were independent variables (r=0.51). CONCLUSIONS: Weight, pregnancy and OC result in higher clearance of IV paracetamol in young women. Besides compound specific relevance, these findings also unveil covariates of drug metabolism in young women.</p