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Aims: This study explores the impact of paediatric patient related factors and choice of formulation on the dissolution characteristics of nifedipine and lorazepam, 2 drug substances regularly applied in very young patients and in compounded formulations., Methods: Dissolution experiments were designed to reflect clinical practice in a paediatric hospital, with respect to dosage forms, feeding regimens and methods of administration. Solubility studies addressed the influence of age and prandial state. Drug solubility and dissolution experiments were conducted in biorelevant media and adapted age-specific (neonate and infant) media. Dissolution studies were performed with the mini-paddle apparatus and the flow-through cell apparatus., Results: Dissolution of nifedipine formulations was not affected by age-related changes of the fasted state simulated gastrointestinal fluids, and by disintegration of the formulation before administration. However, a significant difference in nifedipine's dissolution rate from commercial tablets and compounded capsules was observed. The dissolution of lorazepam tablets was affected by fasted- vs fed-state media, but it was deemed less likely to be clinically relevant. The significant effect of fed-state media on nifedipine's solubility was considered to have possible clinical relevance since very young patients are almost continuously in a fed state., Conclusion: The in vitro results obtained from these studies reveal the potential of biorelevant solubility and dissolution studies reflecting clinical practice to predict drug performance in paediatric patients., (© 2019 The British Pharmacological Society.)

Aim: To study the effect of the CYP2D6*4 polymorphism on serum sodium concentration in users of antidepressants [selective serotonin reuptake inhibitors and tricyclic antidepressants (TCAs)]., Methods: In this population-based cohort study, all subjects in the Rotterdam Study were included who used an antidepressant at baseline and from whom a blood sample was available in which CYP2D6 genotype and serum sodium concentration could be determined (n= 76). Multivariate linear regression was used to study the association between CYP2D6*4 and serum sodium concentration., Results: CYP2D6 poor metabolizers (PMs) (*4/*4) had a significantly lower mean serum sodium concentration in comparison with CYP2D6 extensive metabolizers (EMs) (*1/*1) [difference -3.9 mmol l(-1); 95% confidence interval (CI) -0.86, -7.03; P= 0.013]. In CYP2D6*4 heterozygotes (*1/*4) serum sodium concentration was 1.7 mmol l(-1) (95% CI -3.48, 0.18) lower compared with CYP2D6 EMs, but this difference was not statistically significant (P= 0.077)., Conclusions: The serum sodium concentration in PMs was lower in users of an antidepressant, especially in TCA users. Therefore CYP2D6 PMs might be at increased risk of developing symptoms of hyponatraemia.

Aims: To investigate whether, in patients in whom drug-drug interaction (DDI) alerts on QTc prolongation were overridden, the physician had requested an electrocardiogram (ECG), and if these ECGs showed clinically relevant QTc prolongation., Methods: For all patients with overridden DDI alerts on QTc prolongation during 6 months, data on risk factors for QT prolongation, drug class and ECGs were collected from the medical record. Patients with ventricular pacemakers, patients treated on an outpatient basis, and patients using the low-risk combination of cotrimoxazole and tacrolimus were excluded. The magnitude of the effect on the QTc interval was calculated if ECGs before and after overriding were available. Changes of the QTc interval in these cases were compared with those of a control group using one QTc-prolonging drug., Results: In 33% of all patients with overridden QTc alerts an ECG was recorded within 1 month. ECGs were more often recorded in patients with more risk factors for QTc prolongation and with more QTc overrides. ECGs before and after the QTc override were available in 29% of patients. Thirty-one percent of patients in this group showed clinically relevant QTc prolongation with increased risk of torsades de pointes or ventricular arrhythmias. The average change in QTc interval was +31 ms for cases and -4 ms for controls., Conclusions: Overriding the high-level DDI alerts on QTc prolongation rarely resulted in the preferred approach to subsequently record an ECG. If ECGs were recorded before and after QTc overrides, clinically relevant QTc prolongation was found in one-third of cases. ECG recording after overriding QTc alerts should be encouraged to prevent adverse events.

What Is Already Known About This Subject: * Most antidepressants are metabolized by CYP2D6. The variant allele CYP2D6*4 is the main polymorphism resulting in reduced enzyme activity in Caucasians. * Reduced enzyme activity potentially leads to increased toxicity of antidepressants, but the relevance of genotyping for clinical practice is unclear. Most clinical studies suffer from small numbers of patients., What This Study Adds: * This large population-based cohort study in 1198 elderly Dutch patients examines the influence of the CYP2D6*4 polymorphism on intolerability of antidepressants. * The risk of switching to another antidepressant in tricyclic antidepressant users is higher in poor metabolizers (PMs), but not in SSRI users. PMs require a lower maintenance dose of antidepressants compared with extensive metabolizers (EMs). * Antidepressants were initiated in a relatively low dose, with gradual dose increments thereafter, reducing the risk of adverse drug reactions. Therefore, the question remains whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy., Aims: To study the effect of CYP2D6*4 on antidepressant dose, switching and discontinuation of therapy., Methods: The study consisted of all subjects in the Rotterdam Study, who received a first antidepressant prescription between April 1st 1991 and July 1st 2005 and for whom data on CYP2D6 genotype were available. Binary logistic regression was performed to study the association between CYP2D6*4 and switching to any other antidepressant or discontinuation of therapy within 45 days. The difference in mean antidepressant dose was compared between CYP2D6 genotypes using t-tests and repeated measurements analyses., Results: In users of tricyclic antidepressants (TCAs) the risk of switching to another antidepressant was significantly higher in poor metabolizers (PMs:*4/*4) compared with extensive metabolizers (EMs:*1/*1), with an adjusted OR of 5.77 (95% CI 1.59, 21.03; P = 0.01). In SSRI users there was no significant difference (OR 0.91; 95% CI 0.20, 4.15; P = 0.90). Heterozygous patients did not have an increased risk of switching in both TCA and SSRI users. The mean TCA dose was significantly lower in PMs than in EMs at the third and fourth prescription (difference 0.11 DDD, P = 0.03). In SSRI users the difference in mean dose between PMs and EMs was significant at the third prescription (0.17 DDD; P = 0.02)., Conclusions: The risk of switching to another antidepressant in TCA users is higher in PMs than in EMs. The maintenance doses of antidepressants were significantly lower in PMs. However, the question whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy, requires further study.

Some medical textbooks on drug interactions take note of the potential interaction between laxatives and coumarin anticoagulants, but epidemiological evidence that this interaction is of practical importance is lacking. We conducted a follow-up study in a large population-based cohort to investigate which laxatives are associated with overanticoagulation during therapy with coumarins. Of the 1124 patients in the cohort, 351 developed an International Normalized Ratio > or = 6.0. The only laxative with a moderate but significantly increased relative risk of overanticoagulation was lactulose (relative risk 3.4, 95% confidence interval 2.2, 5.3). In view of the widespread use of lactulose, especially among the elderly, awareness of this potential drug interaction is required.