Purpose Safety data on clozapine use during pregnancy are limited. The aim of this study was to determine disproportionality in case safety reports on adverse pregnancy outcomes between clozapine and other antipsychotics (OAP) used during pregnancy. Methods We included all reports of suspected adverse drug reactions (ADRs) to antipsychotics registered in the World Health Organization global individual case safety report (ICSR) database (VigiBase) in children younger than 2 years and women aged 12‐45 years. A case/non‐case approach was used to evaluate the association between several pregnancy‐related ADRs and clozapine exposure during pregnancy, using 2×2 contingency tables to investigate disproportionality and Standard MedDRA Queries to select cases. Clozapine exposure was defined as all ICSR‐ADR combinations with clozapine as (one of) the suspected drug(s). Non‐exposure was defined as all ICSR‐ADR combinations with OAP as (one of) the suspected drug(s). Results We identified 42 236 unique ICSR‐ADR combinations related with clozapine exposure and 170 710 with OAP exposure. Of these, 494 and 4645 ICSR‐ADR combinations involved adverse pregnancy outcomes related with clozapine exposure and OAP exposure respectively. Overall, no signal of disproportionate reporting associating clozapine with the studied adverse pregnancy outcomes was found compared with OAP exposure. Conclusion Based on global pharmacovigilance data, we did not find any evidence that clozapine is less safe during pregnancy than OAP. Although this is not automatically equivalent to the relative safety of clozapine during pregnancy, these findings add to the convergence of proofs to allow final conclusions and decisions regarding the treatment of pregnant women with clozapine.

Therapeutic drug monitoring (TDM) of gentamicin in neonates is recommended for safe and effective dosing and is currently performed by plasma sampling, which is an invasive and painful procedure. In this study, feasibility of a non-invasive gentamicin TDM strategy using saliva was investigated.Methods: This was a multicentre, prospective, observational cohort study including 54 neonates. Any neonate treated with intravenous gentamicin was eligible for the study. Up to eight saliva samples were collected per patient at different time-points.Gentamicin levels in saliva were determined with liquid chromatography tandem mass-spectrometry (LC-MS/MS). A population pharmacokinetic (PK) model was developed using nonlinear mixed-effects modelling (NONMEM) to describe the relation between gentamicin concentrations in saliva and plasma. Monte Carlo simulations with a representative virtual cohort (n = 3000) were performed to evaluate the probability of target attainment with saliva versus plasma TDM.Results: Plasma PK was adequately described with an earlier published model. An additional saliva compartment describing the salivary gentamicin concentrations was appended to the model with first-order input (k 13 0.023 h À1 ) and first-order elimination (k 30 0.169 h À1 ). Inter-individual variability of k 30 was 38%. Postmenstrual age Amadou Samb and Matthijs Kruizinga contributed equally to this study.The authors confirm that the Principal Investigator for this paper is Timo R. de Haan and that he had direct clinical responsibility for patients.

Background: While positive blood cultures are the gold standard for late-onset sepsis (LOS) diagnosis in premature and very low birth weight (VLBW) newborns, these results can take days, and early markers of possible treatment efficacy are lacking. The objective of the present study was to investigate whether the response to vancomycin could be quantified using bacterial DNA loads (BDLs) determined by real-time quantitative polymerase chain reaction (RT-qPCR).Methods: VLBW and premature neonates with suspected LOS were included in a prospective observational study. Serial blood samples were collected to measure BDL and vancomycin concentrations. BDLs were measured with RT-qPCR, whereas vancomycin concentrations were measured by LC-MS/MS. Population pharmacokinetic–pharmacodynamic modeling was performed with NONMEM.Results: Twenty-eight patients with LOS treated with vancomycin were included. A one-compartment model with post-menstrual age (PMA) and weight as covariates was used to describe the time PK profile of vancomycin concentrations. In 16 of these patients, time profiles of BDL could be described with a pharmacodynamic turnover model. The relationship between vancomycin concentration and first-order BDL elimination was described with a linear-effect model. Slope S increased with increasing PMA. In 12 patients, no decrease in BDL over time was observed, which corresponded with clinical non-response.Discussion: BDLs determined through RT-qPCR were adequately described with the developed population PKPD model, and treatment response to vancomycin using BDL in LOS can be assessed as early as 8 h after treatment initiation.

Background and method Dutch obstetrics guideline suggest an initial maternal benzylpenicillin dose of 2,000,000 IU followed by 1,000,000 IU every 4 h for group-B-streptococci (GBS) prophylaxis. The objective of this study was to evaluate whether concentrations of benzylpenicillin reached concentrations above the minimal inhibitory concentrations (MIC) in umbilical cord blood (UCB) and neonatal plasma following the Dutch guideline. Results Forty-six neonates were included. A total of 46 UCB samples and 18 neonatal plasma samples were available for analysis. Nineteen neonates had mothers that received intrapartum benzylpenicillin. Benzylpenicillin in UCB corresponded to concentrations in plasma drawn directly postpartum (R2 = 0.88, p < 0.01). A log-linear regression suggested that benzylpenicillin concentrations in neonates remained above the MIC threshold 0.125 mg/L up to 13.0 h after the last intrapartum dose. Conclusions Dutch intrapartum benzylpenicillin doses result in neonatal concentrations above the MIC of GBS.