Clinical pharmacokinetics of antipsychotics in pediatric populations: a scoping review focusing on dosing regimen.

Introduction: Achieving optimal clinical responses and minimizing side effects through precision dosing of antipsychotics in children and adolescents with psychiatric disorders remains a challenge. Identifying patient characteristics (covariates) that affect pharmacokinetics can inform more effective dosing strategies and ultimately improve patient outcomes. This review aims to provide greater insight into the impact of covariates on the clinical pharmacokinetics of antipsychotics in pediatric populations.

Cost-utility analysis of tapering strategies of biologicals in rheumatoid arthritis patients in the Netherlands.

Objectives: Current guidelines recommend tapering biological disease-modifying antirheumatoid drugs (bDMARDs) in rheumatoid arthritis (RA) if the disease is under control. However, guidelines on tapering are lacking. Assessing cost-effectiveness of different tapering strategies might provide broader input for creating guidelines on how to taper bDMARDs in patients with RA.

Delayed Lithium Reintoxication in a Case of Severe Multidrug Intoxication: A Case Study.

The authors present a case of severe multidrug intoxication following massive ingestion of lithium, nortriptyline, aripiprazole, lorazepam, and temazepam. After initial treatment, serum lithium levels decreased significantly. However, 28 hours post ingestion, recurrent elevated lithium levels were observed, and serum lithium level increased 0.

Renal function after withdrawal of lithium.

Objectives: Patients on chronic lithium therapy sometimes develop chronic kidney disease. For clinical decision-making, it is important to know whether discontinuation of lithium can lead to improvement of renal function. We studied the trajectory of renal function in a population previously on chronic lithium therapy.

The added value of H antagonists in premedication regimens during paclitaxel treatment.

Background: Ranitidine, a histamine 2 blocker, is the standard of care to prevent hypersensitivity reactions (HSRs) caused by paclitaxel infusion. However, the added value of ranitidine in this premedication regimen is controversial. Therefore, we compared the incidence of HSRs during paclitaxel treatment between a standard regimen including ranitidine and a regimen without ranitidine.

Adequacy of a hospital-wide standard dose of 7mg/kg bodyweight gentamicin sufficient to achieve an adequate prophylactic maximum serum concentration (C) in burn patients undergoing surgical burn wound treatment.

Introduction: Pharmacokinetics of drugs can be significantly altered in burn patients. The aim of our study was to validate if the current hospital-wide standard dosage of 7mg/kg total bodyweight gentamicin is sufficient to achieve an adequate prophylactic C (C≥20mg/L).

Materials And Methods: A prospective observational cohort pharmacokinetic study was conducted in burn patients undergoing surgical burn wound treatment.

[Lithium: only acceptable with careful monitoring].

In the Netherlands, lithium is the mood stabilizer of choice for patients with bipolar disorder. Long-term treatment with lithium can only be implemented safely with frequent and appropriate monitoring of serum lithium concentrations. Here we use 3 cases to illustrate that severe complications can arise when careful monitoring is not performed: a 47-year-old woman with symptoms of a lithium intoxication with therapeutic plasma levels; a 73-year-old woman with chronic lithium intoxication; and a 56-year-old woman with end-stage renal failure after many years of probable toxic lithium levels.

Effects of cyclosporine a on single-dose pharmacokinetics of intravenous itraconazole in patients with hematologic malignancies.

An open-label, clinical pilot study was performed to study the effect of cyclosporine A (CsA) on single-dose pharmacokinetics of itraconazole in patients with a hematologic malignancy. Patients (n = 10), admitted for allogeneic stem cell transplantation, received a single dose of 200 mg itraconazole in a 1-hour intravenous infusion during their treatment period before initiation of CsA. This was repeated during the period that CsA was administered and a steady-state concentration of CsA was achieved (trough whole blood level 200-400 ng/mL).

Pharmacogenomics of drug-metabolizing enzymes and drug transporters in chemotherapy.

There is wide variability in the response of individuals to standard doses of drug therapy. This is an important problem in clinical practice, where it can lead to therapeutic failures or adverse drug events. Polymorphisms in genes coding for metabolizing enzymes and drug transporters can affect drug efficacy and toxicity.

Rapid detection of the DPYD IVS14+1G>A mutation for screening patients to prevent fluorouracil-related toxicity.

Background: Deficiency of dihydropyrimidine dehydrogenase (DPD) has been linked to severe or lethal fluorouracil (FU)-related toxicity. The most prominent mutation in the DPYD gene is the IVS14+1G>A mutation, which causes skipping of exon 14 in the messenger RNA (mRNA) and results in DPD enzyme deficiency. Several methods have been described to detect this mutation, but all are labor intensive and low throughput.

Antiviral activity of HIV type 1 protease inhibitors nelfinavir and indinavir in vivo is not influenced by P-glycoprotein activity on CD4+ T cells.

P-glycoprotein (P-gp) can compromise the antiretroviral effect of a protease inhibitor (PI)-containing regimen for HIV-1, but can also reduce HIV-1 replication. We studied the net effect of P-gp on the intracellular HIV-1 RNA and DNA load in vivo. CD4(+) T cells were isolated from 27 HIV-1 patients (13 without and 14 with a PI-containing regimen) and subsequently sorted in CD45RO(-) (naive) and CD45RO(+) (memory) subsets with either high (P-gp(high)) or low (P-gp(low)) P-gp activity.

Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel.

Purpose: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability.

Metabolism of trabectedin (ET-743, Yondelis) in patients with advanced cancer.

Purpose: Trabectedin (ET-743, Yondelis) is a novel anti-cancer drug currently undergoing phase II-III evaluation, that has shown remarkable activity in pre-treated patients with soft tissue sarcoma. Despite extensive pharmacokinetic studies, the human disposition and metabolism of trabectedin remain largely unknown. We aimed to determine the metabolic profile of trabectedin and to identify its metabolites in humans.

Effect of age on functional P-glycoprotein in the blood-brain barrier measured by use of (R)-[(11)C]verapamil and positron emission tomography.

Introduction: P-glycoprotein (P-gp) is an efflux transporter responsible for the transport of various drugs across the blood-brain barrier (BBB). Loss of P-gp function with age may be one factor in the development and progression of neurodegenerative diseases. The aim of this study was to assess the effect of aging on BBB P-gp function.

Screening for polymorphisms in the PXR gene in a Dutch population.

Objective: Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of over 50% of all drugs currently in use. However, CYP3A4 expression shows a large inter-individual variation that cannot only be explained by genetic polymorphisms identified in this gene. The pregnane X receptor (PXR) has been identified as a transcriptional regulator of CYP3A4.

Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer.

There is wide variability in the response of individuals to standard doses of drug therapy. This is an important problem in clinical practice, where it can lead to therapeutic failures or adverse drug reactions. Polymorphisms in genes coding for metabolising enzymes and drug transporters can affect drug efficacy and toxicity.

Validation of in vitro cell models used in drug metabolism and transport studies; genotyping of cytochrome P450, phase II enzymes and drug transporter polymorphisms in the human hepatoma (HepG2), ovarian carcinoma (IGROV-1) and colon carcinoma (CaCo-2, LS180) cell lines.

Human cell lines are often used for in vitro biotransformation and transport studies of drugs. In vivo, genetic polymorphisms have been identified in drug-metabolizing enzymes and ABC-drug transporters leading to altered enzyme activity, or a change in the inducibility of these enzymes. These genetic polymorphisms could also influence the outcome of studies using human cell lines.

Detection of single nucleotide polymorphisms in the ABCG2 gene in a Dutch population.

Background: ABCG2 is a drug transporter involved in the protection of tissues by actively transporting toxic substances and xenobiotics out of cells. Cancer cells overexpressing the ABCG2 gene show multidrug resistance to mitoxantrone-, methotrexate-, doxorubicin-, and camptothecin-based anticancer drugs, such as topotecan and SN-38. Large interindividual differences have been shown in oral availability and clearance of drugs that are substrates for ABCG2.