Eculizumab is the first drug approved for the treatment of complement-mediated diseases, and current dosage schedules result in large interindividual drug concentrations. This review provides insight into the pharmacokinetic and pharmacodynamic properties of eculizumab, both for reported on-label (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis) and off-label (hematopoietic stem cell transplantation-associated thrombotic microangiopathy) indications. Furthermore, we discuss the potential of therapeutic drug monitoring to individualize treatment and reduce costs.

Efavirenz is recommended as a preferred first-line drug for women of childbearing potential living with human immunodeficiency virus. Efavirenz is known for its central nervous system side effects, which are partly mediated by serotonergic actions. The neurotransmitter serotonin exerts neurotrophic effects during neurodevelopment and antenatal exposure to serotonergic agents has been linked to developmental delay. Although the teratogenic risks of efavirenz appear to be minimal, data on long-term developmental effects remain scarce. Here, we aimed to investigate the short- and long-term behavioral and neurodevelopmental effects of perinatal efavirenz exposure. We treated pregnant rats from gestation day 1 until postnatal day 7 with efavirenz (100 mg/kg) or vehicle. We measured behavioral outcomes in male offspring during the first 3 postnatal weeks, adolescence and adulthood, and conducted brain immunohistochemistry analyses after sacrifice. Perinatal efavirenz exposure resulted in reduced body weight and delayed reflex and motor development. During adulthood, we observed a decrease in the total number of cells and mature neurons in the motor cortex, as well as an increase in the number of Caspase-3-positive cells and serotonergic fibers. Together, our data show a developmental delay and persistent changes in the brain motor cortex of rats exposed to efavirenz perinatally. Because over 1 million children born annually are exposed to antiretroviral therapy, our findings underline the need for clinical studies on long-term neurodevelopmental outcomes of perinatal exposure to efavirenz.

Pemetrexed is used for the treatment for non-small cell lung cancer and mesothelioma. Patients with renal impairment are withheld treatment with this drug as it is unknown what dose is well tolerated in this population.

Crizotinib is an effective drug for patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), but upon treatment, the tumors inevitably become crizotinib resistant in time. The resistance mechanisms are only partly understood. In this study, we aim to identify gene mutations associated with resistance in ALKpositive advanced non-squamous NSCLC treated with crizotinib. Four ALK positive patients with progressive disease following crizotinib treatment were identified with paired pre- and post-crizotinib tumor tissue from our previously published cohort. Somatic variants in these samples were detected by whole exome sequencing. In one of the four patients, an ALK-resistance associated mutation was identified. In the other three patients, no ALK-resistance associated mutations were present. In these patients we identified 89 relevant somatic mutations in 74 genes that were specific to the resistant tumors. These genes were enriched in 15 pathways. Four pathways, were related to epithelial-mesenchymal transition (EMT): proteoglycans in cancer, HIF-1 signaling, FoxO signaling pathway, and ECM-receptor interaction. Analysis of other EMT-related pathways revealed three additional genes with mutations specific to the crizotinib-resistant tumor samples. The enrichment of mutations in genes associated with EMT-related pathways indicates that loss of epithelial differentiation may represent a relevant resistance mechanism for crizotinib.

KRAS-driven non-small cell lung cancer (NSCLC) patients have no effective targeted treatment. In this study, we aimed to investigate targeting epidermal growth factor receptor (EGFR) as a therapeutic approach in KRAS-driven lung cancer cells. We show that ablation of EGFR significantly suppressed tumor growth in KRAS-dependent cells and induced significantly higher expression of CX chemokine receptor 7 (CXCR7) and activation of MAPK (ERK1/2). Conversely, rescue of EGFR led to CXCR7 downregulation in EGFR-/- cells. Dual EGFR and CXCR7 inhibition led to substantial reduction of MAPK (pERK) and synergistic inhibition of cell growth. Analysis of two additional EGFR knockout NSCLC cell lines using CRISPR/Cas9 revealed genotype dependency of CXCR7 expression. In addition, treatment of different cells with gefitinib increased CXCR7 expression in EGFRwt but decreased it in EGFRmut cells. CXCR7 protein expression was detected in all NSCLC patient samples, with higher levels in adenocarcinoma as compared to squamous cell lung carcinoma and healthy control cases. In conclusion, EGFR and CXCR7 have a crucial interaction in NSCLC, and dual inhibition may be a potential therapeutic option for NSCLC patients.

When protease inhibitor (PI)-based second-line ART fails, guidelines recommend drug resistance testing and individualized third-line treatment. However, PI-resistant viral strains are rare and drug resistance testing is costly. We investigated whether less costly PI-exposure testing can be used to select those patients who would benefit most from drug resistance testing.

EGFR mutation analysis in non-small-cell lung cancer (NSCLC) patients is currently standard-of-care. We determined the uptake of EGFR testing, test results and survival of EGFR-mutant NSCLC patients in the Netherlands, with the overall objective to characterize the landscape of clinically actionable EGFR mutations and determine the role and clinical relevance of uncommon and composite EGFR mutations. Non-squamous NSCLC patients diagnosed in 2013, 2015 and 2017 were identified in the Netherlands Cancer Registry (NCR) and matched to the Dutch Pathology Registry (PALGA). Overall, 10,254 patients were included. Between 2013-2017, the uptake of EGFR testing gradually increased from 72.7% to 80.9% (p < 0.001). Multi-gene testing via next-generation sequencing (increased from 7.8% to 78.7% (p < 0.001), but did not affect the number of detected EGFR mutations (n = 925; 11.7%; 95% confidence interval (CI), 11.0-12.4) nor the distribution of variants. For patients treated with first-line EGFR inhibitors (n = 651), exon 19 deletions were associated with longer OS than L858R (HR 1.58; 95% CI, 1.30-1.92; p < 0.001) or uncommon, actionable variants (HR 2.13; 95% CI, 1.60-2.84; p < 0.001). Interestingly, OS for patients with L858R was similar to those with uncommon, actionable variants (HR 1.31; 95% CI, 0.98-1.75; p = 0.069). Our analysis indicates that grouping exon 19 deletions and L858R into one class of 'common' EGFR mutations in a clinical trial may mask the true activity of an EGFR inhibitor towards specific mutations.

Neutropenia is a dose-related treatment-limiting and costly adverse event of pemetrexed. We postulate that individualized dosing reduces the incidence of neutropenia. The aims of this study were (i) to investigate the costs of pemetrexed-related neutropenia and (ii) to determine the pharmacoeconomic benefits of individualized dosing of pemetrexed in terms of budget impact, yearly cost savings, and reduction in severe neutropenia. Retrospective data on the treatment of grade 3 or higher neutropenia during pemetrexed-based chemotherapy were collected from three Dutch hospitals to determine the mean healthcare consumption during a neutropenic episode. Subsequently, Monte Carlo simulations were performed using a validated pharmacokinetic/pharmacodynamic model to predict the neutropenia incidence during four cycles for standard dosing of pemetrexed and individualized dosing. The mean costs per neutropenia and the expected neutropenia incidence were combined to calculate the budget impact and cost savings. We found that the average costs per pemetrexed-associated neutropenic episode to be €1,490 (US $1,674). The neutropenia incidence for the standard and individualized pemetrexed dosing strategies were 12.7% and 9.9%, respectively. This resulted in total expected neutropenia-related costs of ~ €3.0 million (US $3.372 million) and €2.4 million (US $2.697 million), respectively. Taking the number of patients eligible for pemetrexed treatment into account, individualized dosing could result in saving €686,000 (US $770,995) on a yearly basis in the Netherlands alone. Individualized dosing of pemetrexed can decrease the incidence of neutropenia and thus result in a significant decrease in neutropenia-related costs and decreased risk of hospitalization or even death while maintaining therapeutic exposure.

The risk for thromboembolisms in nonsmall cell lung cancer (NSCLC) patients is increased and often requires treatment or prophylaxis with direct oral anticoagulants (DOACs). Small-molecule inhibitors (SMIs) to treat NSCLC may cause relevant drug-drug interactions (DDIs) with DOACs. Guidance on how to combine these drugs is lacking, leaving patients at risk of clotting or bleeding. Here, we give practical recommendations to manage these DDIs.

Malaria elimination requires interruption of the highly efficient transmission of Plasmodium parasites by mosquitoes. TB31F is a humanised monoclonal antibody that binds the gamete surface protein Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission. We aimed to evaluate the safety and efficacy of TB31F in malaria-naive participants.

Eculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient.

An influential covariate for pharmacokinetics is (body) size. Recently, the method of estimation of normal fat mass (NFM) has been advocated. Here, the relative contribution of fat mass, estimated as a fraction fat (Ffat), is used to explain differences in pharmacokinetic parameters. This concept is more and more applied. However, it remains unclear whether NFM can be reliably estimated in these typical studies.

Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin-related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P = .196) or volume of distribution (+7% change, P = .002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.

Pemetrexed is an antifolate drug approved for the treatment of non-small-cell lung cancer and mesothelioma. Assessing pemetrexed pharmacokinetics after administration of a microdose (100 μg) may facilitate drug-drug interaction and dose individualization studies with cytotoxic drugs, without causing harm to patients. Therefore, a highly sensitive bioanalytical assay is required. A reversed-phase ultra-high performance liquid chromatography method was developed to determine pemetrexed concentrations in human ethylenediaminetetraacetic acid-plasma after microdosing. [13 C5 ]-Pemetrexed was used as the internal standard. The sample preparation involved solid-phase extraction from plasma. Detection was performed using MS/MS in a total run time of 9.5 min. The assay was validated over the concentration range of 0.0250-25.0 μg/L pemetrexed. The average accuracies for the assay in plasma were 96.5 and 96.5%, and the within-day and between-day precision in coefficients of variations was <8.8%. Extraction recovery was 59 ± 1 and 55 ± 5% for pemetrexed and its internal standard. Processed plasma samples were stable for 2 days in a cooled autosampler at 10°C. The assay was successfully applied in a pharmacokinetic curve, which was obtained as a part of an ongoing clinical microdosing study.

Vancomycin is an important antibiotic for critically ill patients with Gram-positive bacterial infections. Critically ill patients typically have severely altered pathophysiology, which leads to inefficacy or toxicity. Model-informed precision dosing may aid in optimizing the dose, but prospectively validated tools are not available for this drug in these patients. We aimed to prospectively validate a population pharmacokinetic model for purpose model-informed precision dosing of vancomycin in critically ill patients.

The objectives of these two separate trials are: (1) to reduce health care workers (HCWs) absenteeism; and (2) to reduce hospital admission among the elderly during the COVID-19 pandemic through BCG vaccination.

Ibuprofen is the drug of choice for treatment of patent ductus arteriosus (PDA). There is accumulating evidence that current ibuprofen-dosing regimens for PDA treatment are inadequate. We aimed to propose an improved dosing regimen, based on all current knowledge.

Tafenoquine was recently approved as a prophylaxis and radical cure for Plasmodium vivax infection, but its Plasmodium falciparum transmission-blocking efficacy is unclear. We aimed to establish the efficacy and safety of three single low doses of tafenoquine in combination with dihydroartemisinin-piperaquine for reducing gametocyte density and transmission to mosquitoes.

Ravulizumab is a very expensive complement C5-inhibitor for the treatment of paroxysmal nocturnal haemoglobinuria, with a fixed-dosing interval of 8 weeks. For lifelong treatment, a cost-effective and patient-friendly dosing strategy is preferred. We therefore explored alternative ravulizumab dosing regimens in silico based on the thorough dose-finding studies of the manufacturer. Extending the interval to 10 weeks or individually extending the interval to a mean of 12.8 weeks based on pharmacokinetic monitoring resulted in noninferior efficacy in terms of lactate dehydrogenase normalization, with drug cost savings up to 37%. We here show the potential of individualized ravulizumab dosing to improve patient-friendliness at reduced costs.

Pyronaridine-artesunate is the most recently licensed artemisinin-based combination therapy. WHO has recommended that a single low dose of primaquine could be added to artemisinin-based combination therapies to reduce Plasmodium falciparum transmission in areas aiming for elimination of malaria or areas facing artemisinin resistance. We aimed to determine the efficacy of pyronaridine-artesunate and dihydroartemisinin-piperaquine with and without single low-dose primaquine for reducing gametocyte density and transmission to mosquitoes.