A qualitative interview study with parents to identify barriers and drivers to childhood vaccination and inform public health interventions.

Vaccination coverage in the Federation of Bosnia and Herzegovina, in Bosnia and Herzegovina, has been declining since 2014. This qualitative study aimed to identify barriers and drivers to childhood vaccination for parents. The COM-B (capability-opportunity-motivation-behavior) model was the underpinning theoretical framework. Face-to-face interviews with 22 parents of fully (n = 6), delayed/partially vaccinated (n = 9) and unvaccinated (n = 7) children were conducted. Interviews explored individual factors (capability-knowledge and skills; motivation-attitudes, confidence and trust) and context factors (physical opportunity-information, access, health systems; and social opportunity - social support, norms). Data were analyzed in NVivo using content analysis exploring differences in COM factors by vaccination status and location. Parents of fully vaccinated children typically reported individual and context drivers to vaccination. They accepted vaccination, trusted health workers, and were content with services. Parents of delayed/partially vaccinated children fell into two subgroups: (1) Those who accepted vaccination and attributed delays to their organizational skills or frustration with appointment times. (2) Those fitting the profile of "vaccine hesitant" - generally valuing vaccination and health worker advice, yet with concerns often triggered by media/social media. Parents of unvaccinated children mentioned individual and context barriers to vaccination, notably significant concerns about safety, some distrust of health workers and resentment of mandatory vaccination. Urban/rural differences included urban parents being more likely to report experiences with vaccine shortages and very few had received information leaflets. The study identified complex and inter-related barriers and drivers to parents' childhood vaccination behaviors. These insights have informed the development of tailored interventions to improve coverage.

Interaction between Omeprazole and Gliclazide in Relation to CYP2C19 Phenotype.

The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4-1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and 2.6- and 3.8-fold in NM/RM/UM group, after simulated 20-day dosing with 40 mg omeprazole once and twice daily, respectively. The predicted results were corroborated by findings in patients with T2D which demonstrated 3.3-fold higher odds of severe gliclazide-induced hypoglycemia in NM/RM/UM patients concomitantly treated with omeprazole. Our results indicate that omeprazole may increase exposure to gliclazide and thus increase the risk of gliclazide-associated hypoglycemia in the majority of patients.

SCHOOL CHILDREN EXPOSURE TO LOW INDOOR AIR QUALITY IN CLASSROOMS DURING COVID-19 PANDEMIC: RESULTS OF A PILOT STUDY.

BACKGROUND: Indoor air quality (IAQ) in classrooms affects children's health and academic perfor-mance. The aim of this pilot study was to determine IAQ in elementary schools different in their inter-nal and external characteristics, in settings of COVID-19 epidemics. METHODS: IAQ parameters: fine particulate matter (PM2,5) mass concentration, CO2 concentration, tempera-ture and relative humidity were measured in parallel in four elementary schools/classrooms during October (non-heating season) and four months (including holiday in January) of heating season. IAQ parameters were measured in settings of anti-epidemic restrictions (≤13 students in classroom, frequent ventilation). RESULTS: During October, except in one school, PM2,5 concentrations were below the upper recommended value (25 µg/m³), but started rising in all schools in the heating season. The highest concentrations of PM2,5 were registered in two schools with closed or shortly opened windows. CO2 concentrations were mostly in the recommended range (up to 1000ppm) except in the school with constantly closed windows and in three schools in February when concentrations were higher. Except in one, the same school, and in January, both temperature and relative humidity were out of the recommended range (24,0-27,0°C in non-heating; 20,0-24,0°C in heating season; and 45-55%), with temperature mainly above and relative humidity mainly below it in three schools. The largest deviation in temperature and relative humidity were registered in urban schools. Registered differ-ences may be explained by different internal and external characteristics. CONCLUSION: Despite anti-epidemic restrictions, most of the measured IAQ parameters were out of the recom-mended values in heating season. In addition, further deterioration of IAQ could be expected if all students had been presented in the classroom. Finally, to assure a healthy school environment in heating season, further optimisation of both indoor and outdoor conditions is needed in both pandemic and non-pandemic settings.

Tailoring Immunization Programmes: using patient file data to explore vaccination uptake and associated factors.

Vaccination uptake in the Federation of Bosnia and Herzegovina (FBiH), in Bosnia and Herzegovina, is suboptimal. This study aimed to (1) assess vaccination coverage, timeliness and drop-out for children born in 2015 and 2016 and compare these with official administrative coverage estimates, (2) identify associations between characteristics of children/caregivers and vaccination uptake. This was a cross-sectional study based on patient files for children 12-23 months (n = 1800) and 24-35 months (n = 1800). Methods were adapted from the World Health Organization cluster survey methodology. A two-stage stratified sampling procedure was conducted in urban and rural strata. A structured paper-based form was completed by a pediatrician/nurse from randomly selected primary care centers and patient files. Estimates were based on weighted analysis with a 95% confidence interval to account for the survey sampling design. Vaccination coverage was consistent with administrative coverage levels for BCG, DTP and MMR, and lower for HepB; all considerably lower than regional targets. Children in urban areas had lower vaccination uptake. An assumption that anti-vaccination sentiment prevails among caregivers was not confirmed; only 2% of children were not vaccinated at all, instead challenges related to delays and drop-out. An assumption of caregiver concerns for the MMR vaccine was confirmed with low uptake and delays. The FBiH has experienced vaccination schedule changes due to supply issues; findings confirmed that sustainability in supply and schedule is high priority. These data are new and provide important information for developing strategies to increase uptake.

Identifying barriers and drivers to vaccination: A qualitative interview study with health workers in the Federation of Bosnia and Herzegovina.

BACKGROUND: Vaccination coverage in Bosnia and Herzegovina has been declining over recent years. A World Health Organization Tailoring Immunization Programmes (TIP) project is underway to gain insights into the underlying reasons for this, to develop tailored interventions. As part of TIP, this study aimed to investigate the views of health workers on their barriers and drivers to positive childhood vaccination practices. METHODS: Face-to-face qualitative interviews explored 38 health workers' views on vaccination coverage, their vaccination attitudes, and system, programme and institutional influences on their vaccination practices. The data were analysed using content analysis and organised by the COM (Capability, Opportunity and Motivation) factors. FINDINGS: Very few differences in barriers and drivers were evident between high and low coverage primary care centres or across different professional roles. Capability: Drivers included awareness of the risks of low vaccination coverage, regular use of the Rulebook and Order, knowledge of how to advise parents on mild side effects and recognition of the importance of good communication with parents. Key barriers were the use of false contraindications to postpone vacination and poor skills in tailoring communication with parents. Opportunity: Drivers were sufficient time for adminstering vaccination and good availability of vaccines. Several barriers were evident: lack of implementation of mandatory vaccination, no uniform recall and reminder system or system for detecting under-vaccinated children, staff shortages and lack of time to discuss vaccination with parents. MOTIVATION: Drivers were a belief in the value, safety and effectiveness of vaccination and seeing that they have an important role to play. Barriers were a tendency to blame external factors e.g. anti-vax movement and a fear of being blamed for adverse events. CONCLUSIONS: The study identified complex and inter-related barriers and drivers to health worker positive vaccination practices. These insights will now inform a process to identify and prioritize interventions.

Neuroenhancing Substances Use, Exam Anxiety and Academic Performance in Bosnian-Herzegovinian First-Year University Students.

OBJECTIVE: The aim of this study was to assess the relationship between the use of neuroenhancing substances, exam anxiety and academic performance among first-year Bosnian-Herzegovinian (BH) university students. METHODS: In a cross-sectional study, an ad hoc questionnaire was delivered to a sample of BH first-year university students. The following data were collected: socio-demographic features, consumption of neuroenchancing substances, the Westside Test Anxiety Scale (WTAS) and academic performance. RESULTS: A total of 214 students were included. Consumption of lifestyle substances, coffee, energy drinks, nicotine, alcohol, and marijuana, for the purpose of neuroenhancement increased during the week before the exams. OTC cognitive enhancer use was reported by 31.0%, and of benzodiazepines by 1.5% of students. No psycostimulants were used. A high to extremely high exam WTAS score was reported in 38.3% students. The exam WTAS score was positively correlated with consumption of coffee (rho=0.31; P<0.001), energy drinks (rho=0.18; P=0.009), and nicotine (rho=0.22; P=0.001), and negatively correlated with last exam grade (rho=-0.33; P<0.001). The exam WTAS score was a significant independent predictor (OR=0.55; 95% CI 0.31 to 0.97, P=0.039) for self-assessed academic performance. Self-assessed academic performance was positively correlated with last exam grade (rho=0.15; P=0.043). CONCLUSIONS: Although first-year BH university students do not seem to use either prescription or illicit psycostimulants, the consumption of nicotine, alcohol, and marijuana is worrying. However, the consumption of these neuroenhancing substances seems not to be related to better self-assessed academic performance. Finally, exam anxiety seems to be a significant problem among BH first-year university students.

Amikacin Pharmacokinetics To Optimize Dosing in Neonates with Perinatal Asphyxia Treated with Hypothermia.

Aminoglycoside pharmacokinetics (PK) is expected to change in neonates with perinatal asphyxia treated with therapeutic hypothermia (PATH). Several amikacin dosing guidelines have been proposed for treating neonates with (suspected) septicemia; however, none provide adjustments for cases of PATH. Therefore, we aimed to quantify the differences in amikacin PK between neonates with and without PATH to propose suitable dosing recommendations. Based on amikacin therapeutic drug monitoring data collected retrospectively from neonates with PATH, combined with a published data set, we assessed the impact of PATH on amikacin PK by using population modeling. Monte Carlo and stochastic simulations were performed to establish amikacin exposures in neonates with PATH after dosing according to the current guidelines and according to proposed model-derived dosing guidelines. Amikacin clearance was decreased 40.6% in neonates with PATH, with no changes in volume of distribution. Simulations showed that increasing the dosing interval by 12 h results in a decrease in the percentage of neonates reaching toxic trough levels (>5 mg/liter), from 40 to 76% to 14 to 25%, while still reaching efficacy targets compared to the results of current dosing regimens. Based on this study, a 12-h increase in the amikacin dosing interval in neonates with PATH is proposed to correct for the reduced clearance, yielding safe and effective exposures. As amikacin is renally excreted, further studies into other renally excreted drugs may be required, as their clearance may also be impaired.

Body weight, gender and pregnancy affect enantiomer-specific ketorolac pharmacokinetics.

AIMS: Although ketorolac analgesia is linked only to the S-enantiomer, there is limited information on the stereo-selective pharmacokinetics of this agent. We studied the stereo-selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4-5 months postpartum, and males and nonpregnant females. METHODS: Nonlinear mixed-effect modelling was used to evaluate the stereo-selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery (n = 41), 4-5 months postpartum (n = 8, paired), and in male (n = 12) and nonpregnant female (n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h. RESULTS: For both the R- and S-enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36% [95% confidence interval (CI) 15%, 58%] higher in male than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers. CONCLUSIONS: Besides the anticipated impact of body weight on clearance, R- and S-ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight.

Enantiomer-specific ketorolac pharmacokinetics in young women, including pregnancy and postpartum period.

Racemic ketorolac clearance (CL) is significantly higher at delivery, but S-ketorolac disposition determines the analgesic effects. The aim of this study was to investigate the effect of pregnancy and postpartum period on enantiomer-specific (S and R) intravenous (IV) ketorolac pharmacokinetics (PKs). Data in women shortly following cesarean delivery (n=39) were pooled with data in a subgroup of these women that was reevaluated in the later postpartum period (postpartum group, n=8/39) and with eight healthy female volunteers. All women received single IV bolus of 30 mg ketorolac tromethamine. Five plasma samples were collected at 1, 2, 4, 6, and 8 hours and plasma concentrations were determined using high performance liquid chromatography. Enantiomer-specific PKs were calculated using PKSolver. Unpaired analysis showed that distribution volume at steady state (Vss, L/kg) for S- and R-ketorolac was significantly higher in women shortly following cesarean delivery (n=31) compared to postpartum group (n=8) or to healthy female volunteers (n=8). CL, CL to body weight, and CL to body surface area (CL/BSA) for S- and R-ketorolac were also significantly higher in women following delivery. In addition, S/R-ketorolac CL/BSA ratio was significantly higher at delivery. Paired PK analysis in eight women shortly following delivery and in postpartum group showed the same pattern. Finally, the simultaneous increase in CL and Vss resulted in similar estimates for elimination half-life in both unpaired and paired analysis. In conclusion, pregnancy affects S-, R-, and S/R-ketorolac disposition. This is of clinical relevance since S-ketorolac (analgesia) CL is even more increased compared to R-ketorolac CL, and S/R-ketorolac CL ratio is higher following delivery compared to postpartum period or to healthy female volunteers.

The amikacin research program: a stepwise approach to validate dosing regimens in neonates.

INTRODUCTION: For safe and effective use of antibacterial agents in neonates, specific knowledge on the pharmacokinetics (PK) and its covariates is needed. This necessitates a stepwise approach, including prospective validation. Areas covered: We describe our approach throughout almost two decades to improve amikacin exposure in neonates. A dosing regimen has been developed and validated using pharmacometrics, considering current weight, postnatal age, perinatal asphyxia, and ibuprofen use. This regimen has been developed based on clinical and therapeutic drug monitoring (TDM) data collected during routine care, and subsequently underwent prospective validation. A similar approach has been scheduled to quantify the impact of hypothermia. Besides plasma observations, datasets on deep compartment PK were also collected. Finally, the available literature on developmental toxicology (hearing, renal) of amikacin is summarized. Expert opinion: The amikacin model reflects a semi-physiological function for glomerular filtration. Consequently, this model can be used to develop dosing regimens for other aminoglycosides or to validate physiology-based pharmacokinetic models. Future studies should explore safety with incorporation of covariates like pharmacogenetics, biomarkers, and long-term outcomes. This includes a search for mechanisms of developmental toxicity. Following knowledge generation and grading the level of evidence in support of data, dissemination and implementation initiatives are needed.

Metformin use associated with protective effects for ocular complications in patients with type 2 diabetes - observational study.

OBJECTIVE: The aim was to study the association of the use of an oral antihyperglycemic agent metformin with the presence of ocular complications in patients with type 2 diabetes (T2D). METHODS: Medical records were reviewed for 234 patients with diagnosed T2D. 81.2% (n=190) patients were using metformin and 18.8% (n=44) using other oral antihyperglycemic agents. Plasma glucose concentration, glycated haemoglobin, and the presence of ocular complications in patients treated with metformin were compared to those in patients treated with other oral antihyperglycemic agents. RESULTS: Ocular complications occurred in 65 patients (27.8%). Patients treated with metformin had fewer ocular complications compared to patients treated with other oral antihyperglycemic agents (χ2=19.985; p<0.0001). After adjustment for gender, age, duration of T2D, serum concentration of cholesterol, smoking, body mass index and presence of other diseases, treatment with metformin decreased the odds of both glaucoma (OR=0.14, 95% CI: 0.03-0.57, p=0.006) and diabetic retinopathy (OR=0.33, 95% CI: 0.14-0.82, p=0.017) compared with other oral antihyperglycemic agents. CONCLUSION: Our results suggest that metformin may have a protective effect on ocular complications, especially glaucoma, in patients with T2D. The effects of metformin either regarding prevention of ocular complications or ocular complications already developed in patients with T2D, should be further investigated.

Paracetamol pharmacokinetics and metabolism in young women.

BACKGROUND: There is relevant between individual variability in paracetamol clearance in young women. In this pooled study, we focused on the population pharmacokinetic profile of intravenous paracetamol metabolism and its covariates in young women. METHODS: Population PK parameters using non-linear mixed effect modelling were estimated in a pooled dataset of plasma and urine PK studies in 69 young women [47 at delivery, 8/47 again 10-15 weeks after delivery (early postpartum), and 7/8 again 1 year after delivery (late postpartum), 22 healthy female volunteers with or without oral contraceptives]. RESULTS: Population PK parameters were estimated based on 815 plasma samples and 101 urine collections. Compared to healthy female volunteers (reference group) not on oral contraceptives, being at delivery was the most significant covariate for clearance to paracetamol glucuronide (Factor = 2.03), while women in early postpartum had decreased paracetamol glucuronidation clearance (Factor = 0.55). Women on contraceptives showed increased paracetamol glucuronidation clearance (Factor = 1.46). The oestradiol level did not further affect this model. Being at delivery did not prove significant for clearance to paracetamol sulphate, but was higher in pregnant women who delivered preterm (<37 weeks, Factor = 1.34) compared to term delivery and non-pregnant women. Finally, clearance of unchanged paracetamol was dependent on urine flow rate. CONCLUSIONS: Compared to healthy female volunteers not on oral contraceptives, urine paracetamol glucuronidation elimination in young women is affected by pregnancy (higher), early postpartum (lower) or exposure to oral contraceptives (higher), resulting in at least a two fold variability in paracetamol clearance in young women.

Developmental pharmacokinetics of propylene glycol in preterm and term neonates.

AIM: Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg PG/200 mg phenobarbital) in preterm and term neonates. METHODS: A population pharmacokinetic analysis was performed based on 372 PG plasma concentrations from 62 (pre)term neonates (birth weight (bBW) 630-3980 g, postnatal age (PNA) 1-30 days) using NONMEM 6.2. The model was subsequently used to simulate PG exposure upon administration of paracetamol or phenobarbital in neonates (gestational age 24-40 weeks). RESULTS: In a one compartment model, birth weight and PNA were both identified as covariates for PG clearance using an allometric function (CL(i) = 0.0849 × {(bBW/2720)(1.69) × (PNA/3)(0.201)}). Volume of distribution scaled allometrically with current bodyweight (V(i) = 0.967 × {(BW/2720)(1.45)}) and was estimated 1.77 times higher when co-administered with phenobarbital compared with paracetamol. By introducing these covariates a large part of the interindividual variability on clearance (65%) as well as on volume of distribution (53%) was explained. The final model shows that for commonly used dosing regimens, the population mean PG peak and trough concentrations range between 33-144 and 28-218 mg l(-1) (peak) and 19-109 and 6-112 mg l(-1) (trough) for paracetamol and phenobarbital formulations, respectively, depending on birth weight and age of the neonates. CONCLUSION: A pharmacokinetic model was developed for PG co-administered with paracetamol or phenobarbital in neonates. As such, large variability in PG exposure may be expected in neonates which is dependent on birth weight and PNA.

Pharmacokinetics of paracetamol and its metabolites in women at delivery and post-partum.

AIM: A recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non-pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post-partum in which the different pathways were considered. METHODS: Population PK parameters using non-linear mixed effect modelling were estimated in a two-period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10-15 weeks post-partum. RESULTS: Population PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post-partum. Total clearance was higher in women at delivery compared with 12th post-partum week (21.1 vs. 11.7 l h⁻¹) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h⁻¹), to oxidative metabolites (4.95 vs. 2.77 l h⁻¹) and of unchanged paracetamol (1.15 vs. 0.75 l h⁻¹). In contrast, there was no difference in clearance to paracetamol sulphate. CONCLUSION: The increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group.

The impact of pregnancy on urinary ketorolac metabolites after single intravenous bolus.

Compared to female volunteers or postpartum, ketorolac clearance is higher at delivery. To explore the alterations that explain this higher clearance, urinary ketorolac metabolites collected at delivery (n = 40) were compared to female volunteers (unpaired, n = 8) or postpartum (paired, n = 8) following intravenous administration of 30 mg ketorolac tromethamine. A mean 38 (SD 9) % of the ketorolac dose was retrieved in 8-h urine collections. This was based on mean portions of 56 (20), 10 (14) and 33 (12) % for free ketorolac, ketorolac-glucuronide and p-hydroxy-ketorolac, respectively. The mean ketorolac-glucuronide portion at delivery (5 %) was lower compared to female volunteers (21 %) or postpartum (21 %) (p = 0.003 and p = 0.002, respectively). Similarly, there was a difference in mean portion of free urinary ketorolac at delivery when compared to healthy female volunteers (60-45 %, p = 0.046). Using paired statistics, the mean portion of total urinary ketorolac was lower (62-73 %, p = 0.015) while the portion retrieved as p-hydroxy-ketorolac was significantly higher at delivery compared to postpartum (38-28 %, p = 0.031). The differences in urine metabolites suggest that the increased ketorolac clearance at delivery is in part explained by increased metabolic clearance to p-hydroxy-ketorolac, reflecting increased oxidation activity.

Urinary metabolites after intravenous propofol bolus in neonates.

In neonates, propofol mainly undergoes hydroxylation to quinol metabolites with only limited glucuronidation. The aim of this study is to search for covariates of neonatal propofol biotransformation based on 24 h urine collections. In neonates receiving an intravenous propofol bolus for short procedural sedation, urine was collected during 24 h. Urinary propofol metabolites [propofol glucuronide (PG), 1- and 4-quinol glucuronide (QG)] were determined using high-performance liquid chromatography after a dual-step solid phase extraction combined with ultraviolet and fluorescence detection. Propofol metabolites, their contribution to total metabolite elimination and propofol glucuronide/quinol glucuronide (PG/QG) ratio were determined. The impact of continuous [postmenstrual age (PMA), postnatal age (PNA), body weight, propofol dose, creatinaemia] and dichotomous variables [PNA ≤ 7 days (yes/no), PNA ≥ 10 days (yes/no), hyperbilirubinaemia (yes/no), cardiopathy (yes/no)] on PG/QG ratio and on patients with low (≤10 %) vs. high (>10 %) urinary PG recovery were examined. Thirty-two neonates were included. Median total propofol metabolite recovery was 40.95 (2.01-129.81) % with PG/QG ratio 0.44 (0.01-5.93). PNA (dichotomous 7 days as well as 10 days) was a significant covariate of PG/QG ratio. Late PNA more frequently resulted in high urinary PG fraction. Significance was more pronounced with PNA 10 days as cut-off point for early neonatal life compared to 7 days. Age 10 days is pivotal in early life propofol metabolism. This confirms earlier documented propofol clearance studies. This is the first report of the modified quantification assay used to determine urinary propofol metabolites in neonates.

Biochemical tolerance during low dose propylene glycol exposure in neonates: A formulation-controlled evaluation.

BACKGROUND AND PURPOSE OF THE STUDY: Propylene glycol (PG) is a frequently co-administered solvent in formulations administered to neonates, but reports on its (in)tolerance are limited. We aimed to report on renal, metabolic and hepatic tolerance before, during and following intravenous (iv) PG-paracetamol exposure and compared these data with similar datasets reported in literature on neonates exposed to PG without paracetamol or paracetamol without PG. METHODS: Renal (diuresis, creatinemia, sodium), metabolic (Base Excess, Anion Gap, lactate, bicarbonate) and hepatic (liver enzymes, bilirubinemia) indicators before, during and following iv paracetamol-PG exposure in neonates as included in the PARANEO (paracetamol in neonates) study (intra-individual trends, ANOVA) were collected and analysed. Comparison with observations collected in cases exposed to either iv phenobarbital-PG or iv paracetamol-mannitol (inter-individual comparison, Mann Whitney-U test) were made. RESULTS: PG exposure (median 34.1 mg/kg/24 h) did not affect postnatal renal, metabolic and hepatic adaptations in 60 cases exposed to paracetamol-PG. These indicators were similar when compared to 29 cases exposed to phenobarbital-PG or 172 cases exposed to paracetamol-mannitol. MAJOR CONCLUSION: Based on observations in 89 neonates, low dose PG exposure was tolerated well. Studies on PG pharmacokinetics and its covariates are needed to estimate the upper level of PG tolerance in neonates.

The pharmacokinetics of a high intravenous dose of paracetamol after caesarean delivery: the effect of gestational age.

CONTEXT: Pregnancy affects intravenous paracetamol pharmacokinetics, but there are no studies on covariates of intravenous paracetamol pharmacokinetics around delivery. OBJECTIVES: To document the impact of gestational age at delivery on pharmacokinetics of a high intravenous dose of paracetamol. DESIGN: Pharmacokinetic study in women shortly after caesarean delivery. This study is an alternative analysis of a previously published study, using the same cohort but with added participants. SETTING: Single, tertiary perinatal care centre. PATIENTS: Of 36 patients recruited, pharmacokinetics analysis was performed in 34. Shortly following caesarean delivery, women received a loading dose (2 g) of intravenous paracetamol and four (at 1, 2, 4 and 6 h) plasma samples were collected. Of these 36 women, 28 had already been reported, but without further discrimination between preterm and term delivery, or any other covariate. Individual pharmacokinetic profiles were calculated assuming a linear one-compartment model with instantaneous input, first-order output. Covariates of between individual variability (preterm vs. term, maternal disease vs. healthy, twin vs. singleton pregnancy) of individual pharmacokinetics within this cohort were explored (Mann-Whitney U-test). MAIN OUTCOME MEASURES: Individual paracetamol pharmacokinetics. RESULTS: Mean (SD) paracetamol clearance was 22.4 l h(-1) (9.3) or - when corrected for body surface area - 11.5 l h(-1) m(-2) (4.0). No significant effects of twin pregnancy (n = 8) or maternal co-morbidity (n = 3) were observed, but mean clearance after preterm delivery (n = 12, <37 weeks gestational age) was significantly higher [13.8 (5.7) vs. 10.2 l h(-1) m(-2) (1.9), P = 0.028] compared with term delivery (n = 22). Similarly, there was a difference in mean distribution volume [0.83 (0.25) vs. 0.69 l kg(-1) (0.1), P = 0.037], resulting in the absence of differences in median elimination half-life [112 (28) vs. 119 min (19)]. CONCLUSION: Women who underwent a preterm caesarean delivery had a higher paracetamol clearance compared with term delivery. These pharmacokinetic differences illustrate the relevance of performing pharmacokinetic studies at delivery. We encourage clinicians to perform similar studies for other drugs administered in this group. TRIAL REGISTRATION: EudraCT 2010-020164-37.

The impact of Caesarean delivery on paracetamol and ketorolac pharmacokinetics: a paired analysis.

Pharmacokinetics is a first, but essential step to improve population-tailored postoperative analgesia, also after Caesarean delivery. We therefore aimed to quantify the impact of caesarean delivery on the pharmacokinetics of intravenous (iv) paracetamol (2 g, single dose) and iv ketorolac tromethamine (30 mg, single dose) in 2 cohorts eachof 8 women at caesarean delivery and to compare these findings with postpartum to quantify intrapatient changes. We documented a higher median paracetamol clearance at delivery when compared to 10-15 weeks postpartum (11.7 to 6.4 L/h·m², P < 0.01), even after correction for weight-related changes. Similar conclusions were drawn for ketorolac: median clearance was higher at delivery with a subsequent decrease (2.03 to 1.43 L/h·m², P < 0.05) in postpartum (17-23 weeks). These differences likely reflect pregnancy- and caesarean-delivery-related changes in drug disposition. Moreover, postpartum paracetamol clearance was significantly lower when compared to estimates published in healthy young volunteers (6.4 versus 9.6 L/h·m²), while this was not the case for ketorolac (1.43 versus 1.48 L/h·m²). This suggests that postpartum is another specific status in young women that merits focused, compound-specific pharmacokinetic evaluation.