Drug Levels Research Articles

Proactive therapeutic drug monitoring of biologic drugs in adult patients with inflammatory bowel disease, inflammatory arthritis, or psoriasis: a clinical practice guideline.

In adult patients with inflammatory bowel disease, inflammatory arthritis (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis), or psoriasis taking biologic drugs, does proactive therapeutic drug monitoring (TDM) improve outcomes as compared with standard care? Standard care for immune mediated inflammatory diseases includes prescribing biologic drugs at pre-determined doses. Dosing may be adjusted reactively, for example with increased disease activity. In proactive TDM, serum drug levels and anti-drug antibodies are measured irrespective of disease activity, and the drug dosing is adjusted to achieve target serum drug levels, usually within pre-specified therapeutic ranges. The role of proactive TDM in clinical practice remains unclear, with conflicting guideline recommendations and emerging evidence from randomised controlled trials. Linked systematic review and pairwise meta-analysis which identified 10 trials including 2383 participants. Inflammatory bowel disease, inflammatory arthritis, and psoriasis were grouped together as best current research evidence on proactive TDM did not suggest heterogeneity of effects on outcomes of interest. Proactive TDM of intravenous infliximab during maintenance treatment may increase the proportion of patients who experience sustained disease control or sustained remission without considerable additional harm. For adalimumab, it remains unclear if proactive TDM during maintenance treatment has an effect on sustained disease control or sustained remission. At induction (start) of treatment, proactive TDM of intravenous infliximab may have little or no effect on achieving remission. No eligible trial evidence was available for proactive TDM of adalimumab at induction (start) of treatment. No eligible trial evidence was available for proactive TDM of other biologic drugs in maintenance or at induction (start) of treatment. The guideline panel issued the following recommendations for patients with inflammatory bowel disease, inflammatory arthritis, or psoriasis:1. A weak recommendation in favour of proactive TDM for intravenous infliximab during maintenance treatment2. A weak recommendation against proactive TDM for adalimumab and other biologic drugs during maintenance treatment3. A weak recommendation against proactive TDM for intravenous infliximab, adalimumab, and other biologic drugs during induction (start) of treatment. When considering proactive TDM, clinicians and patients should engage in shared decision making to ensure patients make choices that reflect their values and preferences. The availability of laboratory assays to implement proactive TDM should also be considered. Further research is warranted and may alter recommendations in the future. An international panel including patient partners, clinicians, and methodologists produced these recommendations based on a linked systematic review and pairwise meta-analysis which identified 10 trials including 2383 participants. The panel followed standards for trustworthy guidelines and used the GRADE approach, explicitly considering the balance of benefits and harms and burdens of treatment from an individual patient perspective.

Chronic polypharmacy, monotherapy, and deprescribing: Understanding complex effects on the hepatic proteome of aging mice.

Polypharmacy (use of ≥5 concurrent medications) is highly prevalent among older adults to manage chronic diseases and is linked to adverse geriatric outcomes, including physical and cognitive functional impairments, falls, frailty, hospitalization, and mortality. Deprescribing (withdrawal) is a potential strategy to manage polypharmacy. The broad molecular changes by which polypharmacy causes harm and deprescribing may be beneficial are unknown and unfeasible to study rigorously in tissue from geriatric patients. Therefore, in a randomized controlled trial, we administered therapeutic doses of commonly used chronic medications (oxycodone, oxybutynin, citalopram, simvastatin, or metoprolol) as monotherapy or concurrently (polypharmacy) from middle-age (12 months) to old-age (26 months) to male C57BL/6J (B6) mice and deprescribed (gradually withdrew) treatments in a subset from age 21 months. We compared drug-related hepatic effects by applying proteomics along with transcriptomics and histology. We found that monotherapy effects on hepatic proteomics were limited but significant changes were seen with polypharmacy (93% unique to polypharmacy). Polypharmacy altered the hepatic expression of proteins involved in immunity, and in drug, cholesterol, and amino acid metabolism, accompanied by higher serum drug levels than monotherapies. Deprescribing not only reversed some effects but also caused irreversible and novel changes in the hepatic proteome. Furthermore, our study identified several hepatic protein co-expressed modules that are associated with clinically relevant adverse geriatric outcomes, such as mobility, frailty, and activities of daily living. This study highlights the complex molecular changes following aging, chronic polypharmacy, and deprescribing. Further exploration of these mechanistic pathways may inform management of polypharmacy and deprescribing in older adults.

Safety assessment of sapropterin dihydrochloride: real-world adverse event analysis based on the FDA adverse event reporting system (FAERS)

ObjectiveSapropterin dihydrochloride is the first drug for the therapy of phenylketonuria, which is a rare disease that occurs one of 10,000–15,000 newborns. As a result, detailed and comprehensive reports on the safety of sapropterin in large, real-world populations are required. The purpose of this study is to undertake a complete analysis of sapropterin’s adverse events (AEs) using the FDA Adverse Event Reporting System (FAERS) database.MethodsWe retrieved reports of adverse events with sapropterin as the principal suspect from FAERS between the first quarter of 2008 and the first quarter of 2024. The Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Bayesian Confidence Propagation Neural Network (BCPNN) were utilized to detect AE signals.ResultsThe study collected 4,953 suspected AE cases from the FAERS database, with sapropterin as the major suspect. A total of 130 positive signals were obtained utilizing the ROR, PRP, and BCPNN. The FAERS database revealed that common clinical AEs of sapropterin included vomiting, upper respiratory infection, rhinorrhea, and a reduction in amino acid concentrations. Furthermore, we detected probable unexpected adverse events (AEs) using disproportionality analysis, including gastroesophageal reflux disease, flatulence, influenza, ear infection, viral infection, pharyngitis streptococcal, spontaneous abortion, and nephrolithiasis.ConclusionBy analyzing huge amounts of real-world data from the FAERS database, we found potential novel AEs of sapropterin using disproportionate analysis. It is advantageous for healthcare professionals and pharmacists to focus on efficiently managing sapropterin’s high-risk adverse events, improving drug levels in clinical settings, and ensuring patient medication safety.

Are Environmental Levels of Nonsteroidal Anti-Inflammatory Drugs a Reason for Concern? Chronic Life-Cycle Effects of Naproxen in Zebrafish.

The nonsteroidal anti-inflammatory drug naproxen (NPX) is among the most consumed pharmaceuticals worldwide, being detected in surface waters within the ng to μg/L range. Considering the limited chronic ecotoxicity data available for NPX in aquatic ecosystems, the present study aimed at evaluating its impact in the model organism Danio rerio, following a full life-cycle exposure to environmentally relevant concentrations (0.1 to 5.0 μg/L). An integration of apical endpoints, i.e., survival, growth, and reproduction, with gonad histopathology and gene transcription (RNA-seq) was performed to provide additional insights into the mode of action (MoA) of NPX. NPX decreased zebrafish growth and reproduction and led to histopathological alterations in gonads at concentrations as low as 0.1 μg/L. At the molecular level, 0.7 μg/L of NPX led to a disruption in gonads transcription of genes involved in several biological processes associated with reproduction, mainly involving steroid hormone biosynthesis and epigenetic/epitranscriptomic machineries. Collectively, these results show that environmentally realistic concentrations of NPX affect zebrafish reproduction and associated signaling pathways, indicating that current hazard and risk assessment data for NPX underestimate the environmental risk of this pharmaceutical.

A Narrative Review of Chromatographic Bioanalytical Methods for Quantifying Everolimus in Therapeutic Drug Monitoring Applications

Background: Methods for measuring drug levels in the body are crucial for improving therapeutic drug monitoring (TDM) and personalized medicine. In solid-organ transplants, TDM is essential for the management of immunosuppressive drugs to avoid toxicity and organ rejection. Everolimus is a commonly used immunosuppressant with a small range of safe doses; therefore, it is important to adjust the dose according to each patient's needs. Therefore, reliable methods are required to accurately measure everolimus levels. This study aims to conduct a comprehensive and updated narrative review of chromatographic bioanalytical methods for everolimus quantification. Methods: The authors searched for original research articles published between 2013 and 2023 in Scopus and PubMed and found 295 articles after removing duplicates. Based on their titles and summaries, 30 articles were selected for a detailed review and 25 articles were included in the final analysis. Results: Among the 25 studies, 16 used protein precipitation, mainly with methanol, to prepare the samples, 12 used high-performance liquid chromatography, 11 used ultra-performance liquid chromatography, and 2 used both. Almost all the studies (24 of 25) used tandem mass spectrometry for detection, whereas only 1 used ultraviolet. Conclusions: This comprehensive review of bioanalytical methods for measuring everolimus using chromatography is a useful resource for researchers developing bioanalytical methods for TDM applications. Future trends in everolimus measurement include achieving lower detection limits, owing to the trend of reducing drug doses in therapy by improving sample extraction techniques and using more sensitive methods.

Standing between the elite and street fields: Young people from affluent communities dealing with drugs

Sociology has a rich tradition studying ‘elite’ and ‘street’ social spaces, but rarely considers spaces between these fields and the social actors within them. This article fills that gap by examining the life stories of affluent Oslo youth engaged in illegal drug dealing. Participants had access to economic, social, and cultural capital in both elite and street social space. Making money in legitimate and illegitimate ways kept participants relatively marginal in both spaces. Having social networks among street-oriented peers and among elites facilitated drug dealing but also allowed them an exit from drug crimes when needed. They were educated and often employed, but also had high levels of drug and street cultural competence. This left them relatively estranged from their affluent background milieu leading to persistence in drug dealing. I argue that illegal drug markets among the affluent can be viewed as an in-between social space, that ‘elite’ or ‘street’ youth are likely best conceptualized as existing on a sociocultural spectrum between fields and provide a Bourdieusian framework to study social actors who stand between fields and the impact this may have on their lives.

Subclinical hypothyroidism and plasma levels of commonly prescribed anti-seizure medications

Background: Epilepsy remains the most common neurological problem worldwide. Most commonly prescribed antiseizure medications (ASMs) like phenytoin, sodium valproate, and carbamazepine show high inter-individual variability in bioavailability due to genetic and epigenetic factors resulting in either therapeutic failure or toxicity. In our study, we aim to determine the association between subclinical hypothyroidism and the plasma levels of these commonly prescribed ASMs, leading to either therapeutic failure or adverse drug reactions. Methods: We collected demographic data, details about the antiepileptic medication, and plasma levels of ASMs (phenytoin, carbamazepine, and sodium valproate) from patients on antiseizure medications who came for routine therapeutic drug monitoring (TDM). High-performance liquid chromatography (HPLC) estimated plasma levels of the antiseizure medications as per the TDM laboratory standard operating procedure (SOP) and thyroid function test (TSH) by a standard enzyme-linked immune-sorbent assay (ELISA) kit. Results: Of the 158 patients who had TDM, 75.31% were taking sodium valproate, 15.18% were on phenytoin, and 9.49% were on carbamazepine monotherapy. In our study, we found that 12 patients (7.59%) had TSH levels between 4 to 10 mIU/l, indicating subclinical hypothyroidism (SCH). The plasma drug levels of all 12 patients who had SCH were found to be below the therapeutic range. Conclusions: This study has established a significant association between ASMs, particularly sodium valproate, and thyroid dysfunction, specifically SCH, in patients with epilepsy. Our findings suggest that prolonged ASM therapy can lead to thyroid disturbances, warranting careful monitoring of thyroid function in these patients.

Measuring the impact: Severity of harm from laboratory errors in 195 tests.

This study aimed to objectively assess the potential severity of harm associated with erroneous results in 195 laboratory tests by surveying 514 specialist physicians and medical biochemistry experts. The survey obtained participants' (75 medical biochemists, 439 clinicians) opinions on severity of harm for the erroneous results of 195 tests. The comprehensive list of errors and their effects on test results were obtained from the literature, and then matched with severity of harm scores, from 1 (negligible effect) to 5 (life-threatening injury/death), obtained from the survey responses. Participants perceived tests such as cardiac biomarkers, blood gases, coagulation parameters (activated partial thromboplastin time, prothrombin time, international normalized ratio, and dimerized plasmin fragment D), critical ions (potassium, sodium), toxic trace elements (lead, mercury), and specific serum drug levels (lithium, digoxin) to have a greater potential for patient harm in case of errors. Medical biochemistry specialists assigned higher severity scores to some laboratory tests, including total bilirubin, pseudocholinesterase, platelet indices, and some drug levels (cyclosporine, methotrexate, vancomycin). A substantial agreement (91%) was observed between medical biochemists and clinicians in terms of the most frequently chosen severity of harm score. The study provided objective severity scores and identified high-risk tests for targeted quality improvement.

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

Formulation and Evaluation of Controlled Release Tablet Using Thyme and Rosemary for Osteoporosis

Osteoporosis is a common public health problem which currently affected millions of people worldwide. Osteoporosis is mainly associated with Ovarian hormone deficiency following menopause is till now a most common reason of age-related bone loss. There are tablets that are available in the market, which shows the side effect such as nausea, heart burn, gastric problem after the continuous use of medicine. These side effects led to the avoidance of such medicine. Using herbal plant such as thyme and rosemary as an alternative of those drug will help to reduce these effects. Hence, selected to develop a Controlled Release Tablet of Rosemary and Thyme. Tablet is the most popular among all dosage forms existing today because of its convenience of self-administration, compactness and easy manufacturing. Developing the tablet using thyme and rosemary in the form of controlled release drug will help to prolonged the effect of the medicine. As precision of dosing, to improve the bioavailability of the drug and to maintain the constant level of drug in the plasma become important to provide the long-term effect to the patient. It will also provide the patience compliance as well as prolonged the effect of drug in the patient’s body.

Multi-assessed green sustainable chromatographic resolution of nicotine and caffeine; application to in-vitro release from a new quick mist mouth spray co-formula

The availability of well-established analytical methods is crucial to cope with the fast-ongoing research for the development of new drug delivery formulations. In this work, a rapid highly green chromatographic method was developed for the simultaneous determination of nicotine (NIC) and caffeine (CAF) to be applied for an in-vitro release study from a newly prepared quick mist mouth spray co-formula (QMS), as a complementary synergistic fast-onset relief of cravings during smoking cessation. The chromatographic resolution was accomplished on a cyano column using isocratically delivered (1.0 mL/ min) glycerol: orthophosphoric acid (OPA) (0.2 M) adjusted to pH 3.0 using 0.05 M triethylamine (5:95, v/v) and UV detection at 260 nm. Well resolved peaks of NIC and CAF were eluted at 2.1 and 3.9 min (Rs = 5.64), with linear responses between 0.1 and 20.0 µg/mL and 0.2–40.0 µg/mL, and detection limits of 0.03 and 0.07 µg/mL for NIC and CAF, respectively. The developed method showed good analytical performance (accuracy, precision, robustness, and selectivity) as well as superiority in practicality and ecological profile compared to reported methods applying GAPI, analytical eco-scale, AGREE, BAGI, and whiteness metric tool. The developed method was successfully applied for NIC and CAF determination in their pharmaceutical preparations, and artificial saliva with no significant differences from reported method results (F-test and t-test). Moreover, an in-vitro release study of NIC and CAF from QMS was performed employing the developed method that revealed diffusion-controlled release, compared to mixed diffusion/ polymer chain relaxation for marketed single component formulation, showing the superiority of QMS in reducing drug level fluctuations of NIC and CAF and improving their bioavailability.Graphical

A Comprehensive Review of Self-Nanoemulsifying Systems in the Delivery of Herbal Drugs.

Self-nanoemulsifying drug delivery systems (SNEDDS) are an isotropic mixture of oils, co-surfactants, and surfactants and can form fine O/W Nanoemulsions in aqueous media. These components are advantageous in terms of improved solubility and bioavailability. Limited permeability, solubility, and bioavailability remain a significant challenge in developing herbal drugs. This review explores the potential of self-nanoemulsifying drug delivery systems (SNEDDS) as a promising strategy to overcome this problem. The SNEDDS is considered a novel technique for the delivery of low water-soluble drugs. It can bypass the first-pass metabolism, resulting in steady and sustained drug levels in the systemic circulation. The present article provides a comprehensive overview of the SNEDDS formulation of herbal drugs. It includes their composition, characterization, in vitro and in vivo studies conducted in various disease conditions, and pharmacokinetic studies.

Apixaban dosing in hemodialysis - can drug level monitoring mitigate controversies?

BackgroundInconsistent study results and contradictory recommendations from health authorities regarding the use of apixaban in patients on hemodialysis have generated considerable uncertainty among clinicians, making investigations of appropriate dosing an unmet need.MethodsWe analyzed pre-dialysis apixaban drug levels from a tertiary care dialysis unit, comparing 2.5 mg once versus twice daily dosing. We applied mixed-effects models including dialysis modality, adjusted standard Kt/V, ultrafiltration, and dialyzer characteristics. We included an exploratory analysis of bleeding events and compared the drug levels of our dialysis patients to those from non-CKD reference populations taking the standard dose of 5 mg twice daily.ResultsWe analyzed 143 drug levels from 24 patients. Mean (SD) age at first drug level measurement was 64.7 (15.9) years (50 % female), median (IQR) follow-up was 12.5 (5.5 – 21) months. For the apixaban 2.5 mg once and twice daily groups, median (IQR) drug levels were 54.4 (< 40 – 72.1) and 71.3 (48.8 – 104.1) ng/mL respectively (P < 0.001). Levels were below the detection limit in 30 % (with 2.5 mg once daily) and 14 % (with 2.5 mg twice daily) respectively. Only dosing group (twice versus once daily) was independently associated with higher drug levels (P = 0.002). Follow-up did not suggest accumulation. The 95th percentile of drug levels did not exceed those of non-CKD populations taking 5 mg twice daily. Median (IQR) drug levels before a bleeding (8 episodes) were higher than those without a subsequent bleeding: 111.6 (83.1 – 129.3) versus 54.8 (< 40 – 77.1) ng/mL (P < 0.001). Concomitant antiplatelet therapy was used in 86% of those with bleeding events versus 6% without bleeding events (P < 0.001).ConclusionsDrug monitoring may be a contributory tool to increase patient safety. Despite non-existing target ranges, drug levels on both edges of the spectrum (e.g. below detectability or beyond the 95th percentiles of reference populations) may improve decision-making in highly individualized risk-benefit analyses.

Comprehensive Pharmacokinetic Evaluation of High Melanin Binder Levofloxacin in Rabbits Shows Potential of Topical Eye Drops for Posterior Segment Treatment.

The purpose of this work was to understand the impact of melanin binding on ocular pharmacokinetics after administration of a high-binder model drug via different administration routes. We applied levofloxacin to pigmented and albino rabbits as eye drops (single and multiple), as well as by intravitreal and intravenous injections. Ocular tissues and plasma were analyzed for levofloxacin concentrations with liquid chromatography-mass spectrometry (LC-MS/MS), and pharmacokinetic parameters were calculated. The data show enrichment of levofloxacin and weeks-long retention in pigmented tissues. Upon intravitreal injection, the area under the curve (AUC) values in pigmented tissues were about 9 to 15 times higher than the respective values in the albino rabbits, but this difference expanded to 255- to 951-fold following topical eye drop administration. Multiple dosing of eye drops led to substantial accumulation of levofloxacin in the pigmented tissues: AUC values were 3 to 12 times higher than after intravitreal injection. The AUCs were much lower after single topical or intravenous drug administrations. High drug levels (0.1-35 µM) were always observed in the neural retinas of pigmented eyes; the highest exposure was seen after intravitreal administration followed by multiple doses of topical drops. Single topical instillation and intravenous injections to the albino rabbits resulted in vitreal bioavailability values of 0.009% and 0.003%, respectively. Melanin binding can be used to achieve targeted drug delivery and extended retention in pigmented ocular tissues. The results from topical multiple dosing experiments suggest that eye drop treatment may yield drug exposures and responses comparable to intravitreal delivery, even in the retinal pigment epithelium and choroid.

Recent Advancement of Novel Drug Delivery Systems for Topical Anaesthesia Formulations

Abstract: In recent years, there have been exciting developments in improving how we deliver anaesthesia through the skin. Nanotechnology is a key player, using tiny particles to encapsulate and transport anaesthetic agents, ensuring a controlled and steady release. This helps overcome challenges like inconsistent absorption and short-lasting effects seen with traditional methods. Transdermal patches are gaining attention too; they release drugs slowly and steadily, eliminating the need for frequent reapplication while maintaining a constant drug level at the application site. Smart polymers are bringing innovation by responding to specific triggers, enabling on-demand drug release. This allows for personalized anaesthesia based on individual patient needs. In recent years, there have been exciting developments in improving how we deliver anaesthesia through the skin. Nanotechnology is a key player, using tiny particles to encapsulate and transport anaesthesia agents, ensuring a controlled and steady release. This helps overcome challenges like inconsistent absorption and other short-lasting effects seen with traditional methods. Microemulsion systems, made of water, oil, surfactants, and co-surfactants, are another promising approach. They enhance drug solubility and availability, providing a stable environment for including anaesthesia agents. Transdermal patches are gaining attention too; they release drugs slowly and steadily, eliminating the need for frequent reapplication and maintaining a constant drug level at the application site. Smart polymers are bringing innovation by responding to specific triggers, enabling on-demand drug release. This allows for personalized anaesthesia based on individual patient needs. Together, these advancements mark a significant shift towards more effective, patient-friendly, and personalized topical anaesthesia delivery systems.

Management of Busulfan-Induced Lung Injury in Pediatric Patients with High-Risk Neuroblastoma

Background/Objectives: Integrating the cytotoxic drug busulfan into a high-dose chemotherapy regimen prior to autologous hematopoietic stem cell rescue in patients with high-risk neuroblastoma has improved the survival of children battling this deadly disease. Busulfan-induced toxicities can, however, be severe. Here, we describe the diagnosis and successful treatment of acute pulmonary injury by total-body-weight-adjusted busulfan therapy in two children with high-risk neuroblastoma. Case series: Patient 1 developed life-threatening biphasic acute respiratory failure on days +60 and +100 after busulfan therapy, requiring intubation and invasive mechanical ventilation. Despite intensive anti-inflammatory and immunomodulatory therapy, including systemic corticosteroids, topical inhalation regimens, azithromycin, nintedanib and extracorporal photopheresis, patient 1 required extended intensive care measures and non-invasive respiratory support for a total of 20 months. High-resolution computed tomography showed diffuse intra-alveolar and interstitial patterns. Patient 2 developed partial respiratory failure with insufficient oxygen saturation and dyspnea on day +52 after busulfan therapy. Symptoms were resolved after 6 months of systemic corticosteroids, topical inhalation regimens and azithromycin. High-resolution computed tomography showed atypical pneumonic changes with ground-glass opacities. While both patients fully recovered without evidence of pulmonary fibrosis, cancer therapy had to be paused and then modified until full recovery from busulfan-induced lung injury. Conclusions: Busulfan-induced lung injury requires prompt diagnosis and intervention. Symptoms and signs are nonspecific and difficult to differentiate from other causes. Therapeutic busulfan drug level monitoring and the identification of patients at risk for drug overdosing through promoter polymorphisms in the glutathione S-transferase alpha 1 gene encoding the main enzyme in busulfan metabolism are expected to reduce the risk of busulfan-induced toxicities.

Beta-Lactam Antibiotic Exposure During Pediatric Extracorporeal Membrane Oxygenation: Retrospective Cohort Analysis of Drug Levels Using Standard Dosing, 2018–2020

Objectives: Children on extracorporeal membrane oxygenation (ECMO) are at high risk of infection that may worsen prognosis. Even though treatment with beta-lactam antibiotics is frequent, dosing is not adapted to altered pharmacokinetic and pharmacodynamic characteristics of children on ECMO. There is, therefore, a risk of inadequate drug levels when using standard dosing. In this study, we aimed to describe beta-lactam exposures of children on ECMO using current dosing and to identify factors associated with inadequate exposure. The optimal pharmacokinetic/pharmacodynamic target was considered as a plasma concentration four times above the minimum inhibitory concentration throughout the dosing interval target. Design: Two-center retrospective cohort study. Setting: Two PICUs in Paris, France. Patients: Children (from birth to 18 yr) undergoing venovenous or venoarterial ECMO, from 2018 to 2020. Interventions: None. Measurements and Main Results: There were 57 patients who received 11 different beta-lactams, with 226 plasma concentrations analyzed. A total of 32 infections were documented. Overall, 133 of 226 concentrations (58.8%) were insufficient, primarily in samples from children younger than 28 days (p = 0.035), with low body weight (p = 0.013), or in instances of hypoalbuminemia (p = 0.011) and increased renal clearance (p = 0.032). Supratherapeutic concentrations were observed in 25 of 226 samples (11.1%), associated with being taken from patients with renal impairment (p &lt; 0.01). Conclusions: In this retrospective cohort of pediatric ECMO cases, there is an associated risk of underexposure when prescribing conventional dosing of beta-lactams, which are likely associated with renal impairment and fluid overload. Prospective testing of therapeutic drug monitoring combined with pharmacokinetic/pharmacodynamic models should be tested as a risk-reduction strategy in this vulnerable population.

Subsequent Indications in Oncology Drugs: Pathways, Timelines, and the Inflation Reduction Act.

Recent research has raised questions about potential unintended consequences of the Inflation Reduction Act's Drug Price Negotiation Program (DPNP), suggesting that the timelines introduced by the law may reduce manufacturer incentives to invest in post-approval research towards additional indications. Given the role of multiple indications in expanding treatment options in patients with cancer, IRA-related changes to development incentives are especially relevant in oncology. This study aimed to describe heterogeneous drug-level trajectories and timelines of subsequent indications in a cohort of recently approved, multi-indication oncology drugs, including overall, across subgroups of drugs characterized by the timing and pace of additional indications, and by drug type (i.e., small molecule vs. biologic). This cross-sectional study evaluated oncology drugs first approved by the FDA from 2008 to 2018 and later approved for one or more additional indications. Numbers, types, and approval timelines of subsequent indications were recorded at the drug level, with drugs grouped by quartile based on the pacing of post-approval development (i.e., "rapid pace" to "measured pace"). Multi-indication oncology drugs (N = 56/86, 65.1%) had one or more subsequent indication approved in a new: cancer type (60.7%), line of treatment (50.0%), combination (41.1%), mutation (32.1%), or stage (28.6%). The median time between FDA approvals for indications increased from 0.6 years (IQR: 0.48, 0.74) in the "rapid pace" group to 1.6 years (IQR: 1.32, 1.66), 2.4 years (IQR: 2.29, 2.61), and 4.9 years (IQR: 3.43, 6.23) in the "moderate," "measured-moderate," and "measured" pace groups, respectively. Drugs in the "rapid pace" group often received their first subsequent indication approval within 9 months of initial approval (median: 0.7 years; IQR: 0.54, 1.59), whereas the "measured pace" group took a median of 5.7 years (IQR: 3.43, 6.98). Across all multi-indication drugs, the median time to the most recent approval for a subsequent indication was 5.5 years (IQR: 3.18, 7.95). One quarter (25%) of drugs were approved for their most recent subsequent indication after the time at which they would be DPNP-eligible. Approval histories of new oncology drugs demonstrate the role of post-approval indications in expanding treatment options towards new cancer types, stages, lines, combinations, and mutations. Heterogeneous clinical development pathways provide insights into potential unintended consequences of IRA-related changes surrounding post-approval research and development.

B-266 Therapeutic Drug Monitoring of Natalizumab and Anti-Natalizumab Antibodies

Abstract Background Natalizumab (NTZ) is a monoclonal antibody directed against the α4-integrin subunit of α4β1 and α4β7 integrins. NTZ is used to treat relapsing and remitting forms of multiple sclerosis. Although a majority of patients on standard dosing (intravenous 300 mg, every 4 weeks) reach therapeutic drug concentrations, about 10% of patients will eventually fail NTZ therapy due to the development of anti-NTZ antibodies. NTZ and anti-NTZ antibody concentrations in serum are used together to provide patient-specific pharmacokinetic and immunogenic assessment to aid in patient management. Methods Serum measurements of NTZ and anti-NTZ antibody levels are performed by lab developed electro-chemiluminescent immunoassays where assay design and principle are equivalent to biologic therapeutic drug monitoring described in our previous publication. The natalizumab drug assay is an immunoassay validated to measure free drug (pharmacodynamically active, ADA-unbound) in serum. The anti-natalizumab antibody assay utilizes a solution phase bridging method designed to measure total binding antibodies (including IgM &amp; IgG subtypes). All anti-natalizumab antibody positive samples are confirmed for drug-specificity by an additional signal suppression step. The anti-natalizumab antibody assay is quantitative and drug-tolerant, meaning that circulating drug in patient serum does not interfere with anti-NTZ detection and quantitation. Results Here, we report concomitant measurement of NTZ and anti-NTZ antibody in 160 patient serum samples. Positive anti-NTZ levels from 24 to 235 ng/mL were found in 7.5% (12/160) patients. Anti-NTZ-free samples (148/160) had NTZ drug levels ranging from undetectable (&amp;lt;1.0) to 85 ug/mL. The mean and median drug level in 90 samples (results &amp;gt;1.0) was 10.8 and 2.7, respectively. 61/90 samples had therapeutic drug concentrations (at least 2.0 ug/mL). In the presence of anti-NTZ, 67% (8/12) had undetectable drug level and (4/12) had mean and median drug levels of 1.2 and 1.3, respectively, which is 9- or 2-fold lower than the mean and median drug levels of the anti-NTZ Ab -free group. Conclusions Low serum NTZ and high anti-NTZ are associated with loss of clinical efficacy, while elevated NTZ may increase progressive multifocal leukoencephalopathy risk. Assays to measure biologic drugs and their anti-drug antibodies in patient serum may be useful tools in dose optimization and patient management.

Changes in drug crystallinity in a commercial tacrolimus amorphous formulation result in variable pharmacokinetics

Tacrolimus capsules contain the drug as the amorphous form. It is well known that drug crystallinity is a risk factor for the performance of amorphous formulations. This study investigated the impact of varying levels of crystalline drug on the pharmacokinetics of tacrolimus following oral dosing of a 5 mg capsule under fasting conditions. Two treatments with percent crystallinity of 20% and 50% were achieved by exposing a marketed generic tacrolimus product to open dish storage conditions of 35 °C and 75% relative humidity (RH) for up to 20 days. Crystallinity was monitored with X-ray powder diffraction. Prograf®, the reference listed drug (RLD), an amorphous generic drug product, and generic drug products containing 20% and 50% crystalline tacrolimus were evaluated. All four treatments were administered to healthy participants in a randomized, single-dose, four-treatment, four-period, four-way crossover study. Blood sampling occurred over 24 h. The amorphous generic tacrolimus product was determined not to be bioequivalent to the RLD. The capsules containing both 20% and 50% crystalline tacrolimus also failed the bioequivalence recommendations when compared to the amorphous generic or to the RLD. Both levels of crystalline tacrolimus resulted in BE failure for both Cmax and AUC parameters. The impact of tacrolimus crystallization was greater for maximum blood concentration (Cmax) values relative to the area-under-the-curve (AUC) values. This study demonstrates that crystalline tacrolimus formed in a marketed generic product and these changes resulted in variable pharmacokinetics which could be of significant clinical concern.