Plasma Drug Levels Research Articles

Changes in Psychotropic Drug Blood Levels After SARS-CoV-2 Vaccination: A Two-Center Cohort Study.

Limited evidence from case reports suggests that coronavirus disease 2019 (COVID-19) vaccination may interact with the treatment outcomes of psychiatric medications. Apart from clozapine, reports on the effect of COVID-19 vaccination on other psychotropic agents are scarce. This study aimed to investigate the impact of COVID-19 vaccination on the plasma levels of different psychotropic drugs using therapeutic drug monitoring. Plasma levels of psychotropic agents, including agomelatine, amisulpride, amitriptyline, escitalopram, fluoxetine, lamotrigine, mirtazapine, olanzapine, quetiapine, sertraline, trazodone, and venlafaxine, from inpatients with a broad spectrum of psychiatric diseases receiving COVID-19 vaccinations were collected at 2 medical centers between 08/2021 and 02/2022 under steady-state conditions before and after vaccination. Postvaccination changes were estimated as a percentage of baseline. Data from 16 patients who received COVID-19 vaccination were included. The largest changes in plasma levels were reported for quetiapine (+101.2%) and trazodone (-38.5%) in 1 and 3 patients, respectively, 1 day postvaccination compared with baseline levels. One week postvaccination, the plasma levels of fluoxetine (active moiety) and escitalopram increased by 31% and 24.9%, respectively. This study provides the first evidence of major changes in the plasma levels of escitalopram, fluoxetine, trazodone, and quetiapine after COVID-19 vaccination. When planning COVID-19 vaccination for patients treated with these medications, clinicians should monitor rapid changes in bioavailability and consider short-term dose adjustments to ensure safety.

Synthesis and Preclinical Development of a Promising Novel Romidepsin Nanoparticle for the Treatment of Peripheral T‐Cell Lymphoma (PTCL)

Introduction: The HDAC inhibitors are important drugs for the treatment of PTCL. While these drugs produce ORR of 25–30% with short PFS, responses can last over a year. There is still debate on the optimal ways to use HDAC inhibitors. Most HDAC inhibitors are oral with prolonged AUC of exposure. Romidepsin (R) is administered IV and exhibits a half-life of only 3 hours, though biological effects on chromatin may persist for 24–48 hours. A failed Phase 4 study led to the withdrawal of R for R/R PTCL. In an effort to try and create improved alternatives to R with better efficacy and safety, we deployed a proprietary nanochemistry platform to synthesize NanoRomidepsin (NR) particles, identifying a lead molecule that is comparable to or better than the predecessor R. Methods: Using a combinatorial strategy of solvent screening and polymer chemistry, we developed a first-in-class NR therapeutic with a unique and specific Drug/ Polymer/Surfactant ratio. We utilized dynamic Light Scattering (DLS), cryo-electron microscopy (EM) and liquid chromatography-mass spectrometry (LC-MS) to characterize the size, morphology, and drug encapsulation efficiency of the NR nanoparticles. Cell viability, flow cytometry and western blotting (WB) were performed to determine the effect of NR on cytotoxicity, apoptosis, and histone acetylation across a panel of PTCL cell lines. The maximum tolerated dose of NR was based on an in vivo single-dose and repeated dose toxicity study. Pharmacokinetic studies were performed in mice treated at ½ MTD with quantitation of plasma drug levels by LC-MS. Results: Cryo-EM and DLS confirmed that NR had a poly-dispersity index (PDI) between 0.16 to 0.27 and a z-average of 60–70 nm, indicating uniform size and homogenous particle distribution in the desired ranges. The cell viability assays demonstrated that R and NR produced comparable cytotoxicity (IC50 in range of 0.7–1.9 nM). Flow cytometry and WB analysis demonstrated that NR induced apoptosis and increased acetylation of H3/H4 in a time and concentration-dependent manner. In vivo single-dose and repeated dose toxicity assays revealed a clear correlation between dose and weight loss and/or clinical score in both R and NR treated groups. Pharmacokinetic analyses revealed a substantially greater AUC for NR, which was 3- and 25-fold higher compared to R for IP and IV routes of administration respectively. Interestingly, the markedly greater AUC for NR did not appear to be associated with increased in vivo toxicity. Conclusions: We have synthesized a lead nanotherapeutic of R that will be translated to the clinic. In keeping with other nanotherapeutic drugs, nanosizing drugs tend to increase their volume of distribution (Vd), AUC and markedly improve their tolerability. Large scale in vivo modeling of NR is underway. Data on the development and differentiation of our lead NR asset will be presented, as will the strategy for clinical development. The research was funded by: IVY grant, Translational Orphan Blood Cancer Research Initiative Fund Keyword: Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.

Interaction of Statins with Grapefruit Juice

Grapefruit juice, which discovered to interact with felodipine for the first time, is now known to interact with more that 80 drugs. Statins are among the drugs that interact with grapefruit juice. Grapefruit juice-statin interactions were first investigated in 1998 in human pharmacokinetic studies with lovastatin and simvastatin. The pharmacokinetic and pharmacodynamic basis of the interaction has been extensively investigated in studies. Flavonoids and furanocoumarins, the main components of grapefruit juice, have been reported to cause drug interactions. Furthermore, statin-grapefruit juice interactions occur mostly through inhibition of cytochrome-3A4 (CYP3A4), to a lesser extent through inhibition of P-glycoprotein (P-gp) and organic anion transporting polypeptides (OATPs). Changes in plasma drug levels as a result of interaction may increase the side-effect of statins or reduce their therapeutic efficacy. Therefore, patients using statins are generally advised to avoid grapefruit juice consumption.

Use of paliperidone palmitate half-yearly release in patients diagnosed with psychotic disorder: profile and satisfaction of use

IntroductionThe lack of insight can be present among patients with a diagnosis of schizophrenia, which often results in lack of adherence to pharmacological treatments1 and, subsequently, in treatment discontinuation and relapses2. This vicious pattern leads to further clinical deterioration, impaired functioning, and reduced quality of life 3. There is a plethora of evidence supporting the fact that long-acting injectable and depot antipsychotics can increase adherence to treatment, reduce the risk of discontinuation and hospital admissions4. It is also known that low fluctuations between peaks and lows in plasma drug levels could be related to a better tolerability profiles5. A new paliperidone palmitate prolonged release formulation, which is administered twice annually, has been approved as maintenance treatment for patients with schizophrenia who are already stable on the monthly or quarterly prolonged release paliperidone palmitate6.ObjectivesWe aimed to evaluate the transition of monthly and quarterly paliperidone palmitate to the new six-monthly formulation and patients’ satisfaction with it in a real-world clinical setting.MethodsWe collected a basic epidemiologic questionnaire, responses to a query about local pain after administration, and the Drugs Attitude Inventory (DAI).ResultsA total of 21 patients from an outpatient clinic for severe mental disorders with a long evolution of their disease in Salamanca, Spain, were included. All of them had a DSM5-TR diagnosis of Schizophrenia. Sixteen were male and 5 female. The mean age was 42.6 years. 14 were receiving quartlery paliperidone palmitate (10 with high doses (525 mg) and 4 with moderate doses (350 mg)) and 7 were on monthly injections (6 with high doses (150 mg) and 1 with a moderate dose (100 mg)). Those receiving moderate doses of quarterly or monthly paliperidone palmitate were administered 700 mg of six-monthly paliperidone palmitate; 1000 mg were injected to those with higher doses. The mean score on the DAI scale was 8. Only one patient reported an increase in local pain after the injection, and another reported dissatisfaction with the administration in the gluteus instead of the deltoid muscle. The first administration of the new formulation in our site was on June 26th; to date none of these patients have required hospital admission due to relapse.ConclusionsSix-monthly prolonged release paliperidone palmitate seems to be an effective maintenance treatment for schizophrenia. In addition, this new formulation is well received and tolerated by patients previously on monthly or quarterly formulations of the same drug.Disclosure of InterestNone Declared

Pengembangan dan Validasi Metode Bioanalisis Trimetoprim dalam Sampel Plasma dan Urin Manusia Simulasi Menggunakan KCKT-PDA

To monitor trimethoprim levels (TMP) in humans, a validated, simple, and cost-efficient analytical method is needed to be applied regularly. However, most of the methods used to establish TMP levels in urine and plasma use complex instrumentation. Therefore, in this study, a simpler High-Performance Liquid Chromatography-based (HPLC) method was developed. The separation was carried out using a GIST® C18 column (150 × 4.6 mm, 5 μm) at a temperature of 35°C which was fed by a mobile phase in the form of an acetic acid solution pH 2.5: acetonitrile (87:13, v / v) at a speed of 1.4 ml/min. Detection was performed with Photodiode Array Detector (PDA) at wavelengths of 254 nm and 243 nm to quantify TMP in urine and plasma samples respectively. The preparation of urine and plasma sequentially was carried out by the liquid-liquid extraction (ECC) method using ethyl acetate and the protein precipitation using acetonitrile. This method proved to be selective, linear (R=0.997), accurate with %error ≤ 10.29% at LLOQ level and above LLOQ value %error ≤ 10.45%, precision with %RSD ≤ 11.79% at LLOQ level and %RSD ≤ 10.82% above LLOQ. In addition, this method is quite sensitive for pharmacokinetic studies in the urine and monitoring of TMP levels in the blood with LLOQ 5 mg/L in both urine and plasma. The stability of trimethoprim in solution, urine, and plasma was conducted to ensure storage time. The developed method is proven to be valid and can be applied in pharmacokinetic studies and monitoring of trimethoprim drug levels in urine and plasma.

Masked Randomized Trial of Epinephrine versus Vasopressin in an Ovine Model of Perinatal Cardiac Arrest.

Current neonatal resuscitation guidelines recommend the use of epinephrine for bradycardia/arrest not responding to ventilation and chest compressions. Vasopressin is a systemic vasoconstrictor and is more effective than epinephrine in postnatal piglets with cardiac arrest. There are no studies comparing vasopressin with epinephrine in newly born animal models with cardiac arrest induced by umbilical cord occlusion. Objective: To compare the effect of epinephrine and vasopressin on the incidence and time to return of spontaneous circulation (ROSC), hemodynamics, plasma drug levels, and vasoreactivity in perinatal cardiac arrest. Design/Methods: Twenty-seven term fetal lambs in cardiac arrest induced by cord occlusion were instrumented and resuscitated following randomization to epinephrine or vasopressin through a low umbilical venous catheter. Results: Eight lambs achieved ROSC prior to medication. Epinephrine achieved ROSC in 7/10 lambs by 8 ± 2 min. Vasopressin achieved ROSC in 3/9 lambs by 13 ± 6 min. Plasma vasopressin levels in nonresponders were much lower than responders after the first dose. Vasopressin caused in vivo increased pulmonary blood flow and in vitro coronary vasoconstriction. Conclusions: Vasopressin resulted in lower incidence and longer time to ROSC compared to epinephrine in a perinatal model of cardiac arrest supporting the current recommendations for exclusive use of epinephrine in neonatal resuscitation.

Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use

The rapid onset of action of nifedipine causes a precipitous reduction in blood pressure leading to adverse effects associated with reflex sympathetic nervous system (SNS) activation, including tachycardia and worsening myocardial and cerebrovascular ischemia. As a result, short acting nifedipine preparations are not recommended. However, importantly, there are no modified release preparations of nifedipine authorised for paediatric use, and hence a paucity of clinical studies reporting pharmacokinetics data in paediatrics. Pharmacokinetic parameters may differ significantly between children and adults due to anatomical and physiological differences, often resulting in sub therapeutic and/or toxic plasma concentrations of medication. However, in the field of paediatric pharmacokinetics, the use of pharmacokinetic modelling, particularly physiological-based pharmacokinetics (PBPK), has revolutionised the ability to extrapolate drug pharmacokinetics across age groups, allowing for pragmatic determination of paediatric plasma concentrations to support drug licensing and clinical dosing. In order to pragmatically assess the translation of resultant dissolution profiles to the paediatric populations, virtual clinical trials simulations were conducted. In the context of formulation development, the use of PBPK modelling allowed the determination of optimised formulations that achieved plasma concentrations within the target therapeutic window throughout the dosing strategy. A 5 mg sustained release mini-tablet was successfully developed with the duration of release extending over 24 h and an informed optimised dosing strategy of 450 µg/kg twice daily. The resulting formulation provides flexible dosing opportunities, improves patient adherence by reducing frequent administration burden and enhances patient safety profiles by maintaining efficacious levels of consistent drug plasma levels over a sustained period of time.

Abstract WP219: Repurposing The K Ca 3.1 Inhibitor Senicapoc For Treatment Of Acute Ischemic Stroke

Background: Acute ischemic stroke (AIS) is a leading cause of death and long-term disability. Both microglia (MG) and infiltrating macrophages (MP) are critical effector cell types in ischemic brain injury and recovery. K Ca 3.1 is a calcium-activated potassium channel that is upregulated in reactive MG and MP. Studies using either genetic deletion or pharmacological inhibition of K Ca 3.1 demonstrated that this channel is critical for pro-inflammatory activation of MG/MP as well as exacerbation of stroke pathophysiology. Senicapoc (ICA-17043) is a K Ca 3.1-specific inhibitor that has been used in human clinical trials for non-neurological indications (sickle cell anemia, asthma) and was proven safe. Here we evaluate the potential for repurposing senicapoc for AIS. Methods: Young adult male and female mice underwent 60 min middle cerebral artery occlusion (MCAO)/reperfusion. MCAO was monitored by laser doppler. Senicapoc’s pharmacokinetic (PK) profile was determined using high performance liquid chromatography - mass spectroscopy. Drug levels in plasma and brain were quantified at multiple time points post administration. Effects of senicapoc on post-stroke release of cytokines/chemokines was determined by multiplex ELISA. Inflammatory infiltrates were quantified with flow cytometry. Efficacy studies included: (i) infarct volume (MRI T2), white matter integrity (DTI) and longitudinal neurobehavioral outcomes (NBO). In-vitro chromogenic assay was used to assess senicapoc’s effect on proteolytic activity of tissue plasminogen activator (tPA). Results: Administration of senicapoc (40 mg/kg, i.p.) twice daily for seven days starting 12 h after MCAO resulted in ~55% reduction in infarct volume with corresponding improvements in NBO. Free senicapoc levels in brain ranged from 20 - 200 nM in stroked mice at 1, 4 & 12 hours following administration. All values exceeded senicapoc’s IC 50 (11 nM) for K Ca 3.1. Senicapoc, at up to 5 μM, had no effect on tPA’s proteolytic activity. Conclusions: We provide proof-of-concept data that senicapoc, administered in an extended temporal window, can markedly reduce infarct volume and improve NBO in a mouse model of AIS. Senicapoc demonstrated favorable PK and CNS penetration. It did not interfere with tPA.

Stimuli-Responsive Boron-Based Materials in Drug Delivery.

Drug delivery systems, which use components at the nanoscale level as diagnostic tools or to release therapeutic drugs to particular target areas in a regulated manner, are a fast-evolving field of science. The active pharmaceutical substance can be released via the drug delivery system to produce the desired therapeutic effect. The poor bioavailability and irregular plasma drug levels of conventional drug delivery systems (tablets, capsules, syrups, etc.) prevent them from achieving sustained delivery. The entire therapy process may be ineffective without a reliable delivery system. To achieve optimal safety and effectiveness, the drug must also be administered at a precision-controlled rate and the targeted spot. The issues with traditional drug delivery are overcome by the development of stimuli-responsive controlled drug release. Over the past decades, regulated drug delivery has evolved considerably, progressing from large- and nanoscale to smart-controlled drug delivery for several diseases. The current review provides an updated overview of recent developments in the field of stimuli-responsive boron-based materials in drug delivery for various diseases. Boron-containing compounds such as boron nitride, boronic acid, and boron dipyrromethene have been developed as a moving field of research in drug delivery. Due to their ability to achieve precise control over drug release through the response to particular stimuli (pH, light, glutathione, glucose or temperature), stimuli-responsive nanoscale drug delivery systems are attracting a lot of attention. The potential of developing their capabilities to a wide range of nanoscale systems, such as nanoparticles, nanosheets/nanospheres, nanotubes, nanocarriers, microneedles, nanocapsules, hydrogel, nanoassembly, etc., is also addressed and examined. This review also provides overall design principles to include stimuli-responsive boron nanomaterial-based drug delivery systems, which might inspire new concepts and applications.

Influence of sex on the exposure to isoniazid in patients with pulmonary tuberculosis.

Isoniazid is a key component of tuberculosis treatment. Adequate exposure is a determinant for therapeutic success; however, considerable inter- and intraindividual variations in drug plasma levels can lead to unfavorable outcomes. While some predictors of isoniazid levels are well-known, others, such as sex, yield controversial results, requiring further investigation to optimize exposure. This study investigates whether the sex of patients influences the dose administered and the concentrations of isoniazid in plasma. Levels of isoniazid were associated with the N-acetyltransferase 2 phenotypes. A total of 76 male and 58 female patients were included. Isoniazid was measured by high-performance liquid chromatography, and N-acetyltransferase 2 phenotypes were assessed using molecular techniques. The results show that the dose administered, expressed in mg/kg, was higher in females, but the plasma levels were similar between both sexes. Among patients, 46.2%, 38.8%, and 15% were slow, intermediate, and fast acetylators, respectively. As expected, isoniazid levels were associated with the acetylation phenotypes, with higher concentrations in the slow acetylators. Thus, sex-related difference in isoniazid levels is due to the body weight of patients, and the optimized dose regimen based on patient weight and acetylator phenotypes can improve the treatment outcomes.

Effect of Concurrent Administration of Herbs on the Pharmacokinetics of Drugs: A Review

Herbal medicines are currently in high demand, and their popularity is steadily increasing as an alternative medicine. This is as a result of their perceived effectiveness, fewer side effects and relatively low cost. They are being used simultaneously with therapeutic drugs for the treatment and management of numerous medical conditions, but due to the complex mixture of bioactive constituents they are capable of affecting the pharmacokinetics and pharmacodynamics of conventional drugs when administered concurrently. Of serious concern is the concurrent consumption of herbal products and conventional drugs. Herb–drug inter-action (HDI) is the single most important clinical consequence of this practice. Using a structured assessment procedure, the evidence of HDI presents with varying degree of clinical significance. While the potential for HDI for a number of herbal products is inferred from non-human studies, certain HDIs are well established through human studies and documented case reports. This herb-drug interactions (HDIs) may lead to modifications in plasma drug levels resulting in therapeutic failure of the drug or, alternatively, it may cause drug-induced toxicity. The main routes proposed for HDIs include cytochrome P450 (CYP450)-mediated inhibition or induction and transport and flow proteins. In our review, some herbal medicines used for the treatment of various diseases were highlighted and case reports of their pharmacokinetics and pharmacodynamics herb-drug interactions were analyzed. Therefore, this review can be a quick reference tool for physicians, pharmacists and other healthcare professionals involved in therapy, and counseling towards appropriate use of drugs to maximize clinical outcomes.

Impact of personalised dosing based on quantification of drug plasma levels on the efficacy and safety of treatment with escitalopram

Impact of personalised dosing based on quantification of drug plasma levels on the efficacy and safety of treatment with escitalopram

Is psilocybin an effective antidepressant and what is its Mechanism of action?

Goodwin etal.1 report a single 25mg dose of psilocybin has an antidepressant effect short-term in medication-resistant depression. Unanswered questions include drug blood level as a guide to dose, psychedelic effects relationship to antidepressant benefit, and potential suicide risk of psilocybin.

Influence of fecal microbial transplant (FMT) between male and female rats on methamphetamine-induced hyperthermia

Objective To investigate the effect of bidirectional fecal microbial transplant (FMT) between male and female rats on methamphetamine (MA)-induced hyperthermia. Methods FMT was performed between male and female rats prior to MA (10 mg/kg, sc) treatment. Core body temperature, plasma drug and norepinephrine (NE) levels were measured and compared between treatment groups. 16S rRNA gene sequencing of bacterial communities between male and female rats was performed. Results MA treatment resulted in significantly higher core body temperatures in male groups (control and FMT-treated) compared to MA-treated female groups (control and FMT-treated). Plasma concentrations of MA and amphetamine were higher in females than males. Whereas, plasma norepinephrine (NE) levels were not different between male and female rats 90 minutes after MA treatment. At the phyla level, the microbiome of male and female control rats were dominated by Firmicutes and Bacteroidetes. Males had a higher relative abundance of Firmicutes and lower relative abundances of Bacteroidetes than females. The FMT procedure changed the recipient group towards their donor with males getting closer to their donors than females. In the control groups following MA treatment, Firmicutes increased and Bacteroides decreased in females and males. Conversely, in the FMT treatment groups following MA treatment, Firmicutes decreased while Bacteroidetes increased in females and males. Conclusions Although definite differences in the structure and diversity of the gut microbiome were observed using 16S rRNA gene sequencing of bacterial communities between male and female rats, these differences do not seem to contribute to the sex-based differences in MA-induced hyperthermia.

1123. EDP-235, A Potent and Once-daily Oral Antiviral, Demonstrates Excellent Penetration into Macrophages and Monocytes, with the Potential for Mitigation of Cytokine Storm in High-Risk COVID-19 Patients

Abstract Background Macrophages, including lung alveolar macrophages (AM), and monocytes are the first lines of defense against SARS-CoV-2. Several reports have suggested that SARS-CoV-2 can hijack AM and monocytes for replication and viral spread, which may, in turn, drive the cytokine storm associated with severe COVID-19. Herein, we describe one of many advantageous features that EDP-235, a novel and potent SARS-CoV-2 3C-like protease (3CLpro) inhibitor under development as a once-daily oral antiviral therapy for COVID-19, displays - excellent penetration into macrophages and monocytes. Methods Intracellular uptake of EDP-235 was tested side-by-side with nirmatrelvir in rat lung AM, human monocytes and human macrophages. To determine the in vivo drug distribution into lung AM, rats were dosed orally with 25 mg/kg of EDP-235 or nirmatrelvir and plasma and AM drug levels were analyzed by LC/MS/MS. Results The ratios of intracellular to extracellular concentrations of EDP-235 in rat lung AM, human monocytes and human macrophages were 22.8, 22.7 and 30.5, respectively. In contrast, nirmatrelvir had ratios of 1.2 to 1.5 in these cells. Consistent with the in vitro observations, EDP-235 showed favorable rat AM penetration with an AUC0-24 ratio of 28.4 (AM over plasma), and nirmatrelvir had much less rat AM penetration with an AUC0-24 ratio of 0.5 (AM over plasma). EDP-235 had respective AUC0-24 values of 9.6 and 271.9 h·μg/mL in rat plasma and AM, while the AUC0-24 values of nirmatrelvir in rat plasma and AM were 2.7 and 1.2 h·μg/mL, respectively. Conclusion EDP-235, a novel and potent SARS-CoV-2 3CL protease inhibitor, demonstrated excellent penetration into monocytes and macrophages, including lung AM. EDP-235 has the potential to eliminate the viral replication of SARS-CoV-2 in these critical immune cells, thus mitigating macrophage-mediated cytokine storm in high-risk COVID-19 patients. Clinical trials with EDP-235 for COVID-19 treatment and prevention are ongoing. Disclosures All Authors: No reported disclosures.

Optimising the Therapeutic Interval for Biologics in Patients with Psoriasis.

In our clinical experience, more than half of patients do not present a complete response to biologic drugs, or drug loses its efficacy over time. Plasma determinations of drug and anti-drug antibodies levels are an objective tool for optimisation in these patients; however, established therapeutic ranges are not suitable, so the objective of this study was to study these patients and optimise their healthcare. We have made a retrospective, observational study, using data of plasma levels of drugs and anti-drugs antibodies of infliximab, adalimumab or Etanercept, we summarise all data and make a study of sensitivity, specificity, positive and negative predictive value on current therapeutic ranges. We have found a statistically significant association between subtherapeutic levels and therapeutic failure in psoriasis treated with infliximab and adalimumab. New ranges were found with higher sensitivity than the established ones, we propose 2-10 µg/mL therapeutic range for infliximab, 3-11 µg/mL for adalimumab, and 1-7 µg/mL for etanercept. In conclusion, levels of drug and anti-drug antibodies are a decisive tool for predicting therapeutic response. The current therapeutic ranges may have minimum values that are excessively high, owing to which lowering them significantly increases the sensitivity of the test in all cases, and negative predictive value in the case of etanercept. Further prospective studies are needed to prove the usefulness of these new ranges.

The use of Ctrough for the therapeutic drug monitoring of olaparib in patients with ovarian cancer.

Olaparib is the poly-[Adenosine diphosphate ribose (ADP-ribose)] polymerase inhibitor (PARPI) used in maintenance therapy of patients with platinum-sensitive ovarian cancer with mutations in breast cancer genes 1/2 (BRCA1/2). Oncologists still do not have recommendations of treatment depending on efficient plasma concentrations of the PARP inhibitor. The aim of the study was the assessment of plasma trough concentrations of olaparib at steady state (Ctrough) in ovarian cancer patients. The severity of olaparib adverse effects (AEs) was noted. The retrospective study involved 33 patients [mean standard deviation (SD)]; age 57.0 (8.4) years; weight 68.7 (13.7) kg; and body mass index (BMI) 26.4 (4.9) kg/m2, with ovarian cancer treated with olaparib (tablets in dose 300 mg/12 h, 250 mg/12 h, 200 mg/12 h or capsules 400 mg/12 h, 200 mg/12 h, 100 mg/12 h). Plasma drug levels were measured by HPLC-UV method (λ = 254 nm; Symmetry C8 column; gradient flow). The severity of olaparib AEs was assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale. Drug interactions were analyzed. In total, 130 measurements (n) of Ctrough were determined in 33 patients (median sample frequency per patient was 4). The olaparib Ctrough in patients with AEs was 87.840-7,213.262 ng/mL [coefficient of variation (CV) = 91%], in patients without AEs 48.021-7,073.350 ng/mL (CV = 88%). AEs were the following: fatigue (modest, n = 4, severe, n = 2), anemia (grade G1 n = 66, G2 n = 6, G3 n = 3), neutropenia (grade G1 n = 15, G2 n = 4), prediabetes (n = 1). There was a correlation between Ctrough and olaparib-induced fatigue (p = 0.0015). The lower values of dose-adjusted olaparib concentrations (p = 0.0121) and dose/kg-adjusted olaparib concentrations (p = 0.0389) were correlated with higher grade of neutropenia. There was a correlation between Ctrough, expressed as ng/ml, ng/ml/mg or ng/ml/mg/kg, and fatigue degree, but not anemia. Patients with neutropenia had statistically significant lower plasma concentrations of olaparib.

Formulation Development & Evaluation of Controlled Drug Delivery System: An Overview

The therapeutic effect is brought about by the drug delivery system dispensing the active medicinal ingredient. Due to fluctuations in plasma drug levels, traditional drug delivery devices have poor bioavailability and cannot generate a continuous release. The drug must also be supplied at a tightly regulated rate and to the correct location for it to be most effective and safe. To solve the problems inherent in the current methods of administering medication, scientists are working on perfecting controlled drug delivery systems. Controlled pharmaceutical delivery systems have come a long way in the last twenty years, from bulk distribution to nanoscale precision to smart, patient-specific dosing. The paper's initial portion provides background knowledge on drug delivery methods, emphasizing pharmacokinetics. The article also discusses the pros and cons of more conventional drug delivery methods. Controlled drug delivery systems' design factors, categorizations, and schematics are also discussed in length. In addition, recent advances in nano-drug delivery, targeted, and innovative drug delivery utilizing stimuli-responsive, intelligent biomaterials are discussed. The limitations of regulated medicine distribution and some possible solutions are discussed at the end of the study.

Utilization of Pharmacogenomics in Assessment of Tolerability and Efficacy of BTK Inhibitors

Background: Oral inhibitors of Bruton's tyrosine kinase (BTKi) are used for a number of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL). Despite excellent hematologic responses often seen with this class of medications, discontinuation may occur due to progression or intolerable side effects. It is not fully understood why some patients develop adverse events and discontinue BTKi therapy. A previous study suggested and association between intolerance to BTKi or phosphoinositide 3-kinase (PI3K) inhibitors in CLL patients with genetic polymorphisms in cytochrome P450 enzymes. Polymorphisms in CYP3A and CYP2D6 affect the metabolism of these agents and may lead to higher-than-expected plasma levels, leading to more adverse events. We therefore evaluated the results of pharmacogenomic testing in Veterans treated with BTKi to determine the extent to which pharmacogenomics polymorphisms are associated with response and intolerance to BTKi therapy. Methods: We identified Veterans receiving care through the Veterans Administration (VA) who were prescribed a BTKi and had undergone pharmacogenetic testing through the Pharmacogenomic Testing for Veterans (PHASER) program, currently offered to veterans at 22 sites across the United States. We retrospectively analyzed clinical factors including time on BTKi, reasons for temporary or permanent discontinuation or dose changes, medical comorbidities, and grade of pertinent side effects associated with BTKi (arrhythmia, hypertension, bleeding, fatigue, arthralgias, rash, diarrhea) as well as use of concomitant medications known to interact with CYP3A or CYP2D6. Results: A total of 61 Veterans were identified, of which 97% (59) were male and 72% (44) were diagnosed with CLL. Of the remaining patients, three were diagnosed with MCL, three with WM/LPL, two with refractory diffuse large B cell lymphoma (DLBCL), one with MZL, and one with monoclonal gammopathy and cold agglutinin disease. Forty-three patients (70.5%) were prescribed ibrutinib, while eight were prescribed acalabrutinib and two zanubrutinib. Twelve patients (20%) permanently discontinued therapy due to intolerance and eight patients (13%) progressed. Another 10 patients temporarily discontinued therapy due to side effects or infection. Median time treated with BTKi was 6.7 months for patients discontinuing for intolerance, 30.1 months for those discontinuing for progression, and 32.9 months for those not requiring discontinuation. The majority of patients who either temporarily or permanently discontinued therapy did so due to new arrhythmia (10 patients), while other complications included infection, pancytopenia, arthralgias, and fatigue. Nearly half of patients were concurrently taking another medication also metabolized through the CYP3A or CYP2D6. Of the 20 patients who progressed or were intolerant of BTKi, 14 (70%) were identified as CYP3A5 poor metabolizers, while 6 (30%) exhibited CYP2D6 intermediate metabolizing function. In comparison, of patients who did not discontinue BTKi, 31 patients (76%) were CYP3A5 poor metabolizers and 11 patients (27%) were CYP2D6 intermediate metabolizers. Conclusions: In our cohort of patients with B cell malignancies who were prescribed BTKi, we identified those who discontinued either due to intolerable side effects or progression at a rate lower than previously reported in the Veteran population. We identified patient with pharmacogenomics polymorphisms that can affect plasma drug levels and are evaluating concurrent use of medication with can affect BTKi metabolism, as well as their effect on time to therapy discontinuation and adverse events. These results will inform the personalized selection of BTKi therapy for patients with B cell malignancies.

ITK Inhibitor Induces Dose-Dependent Th1 Skewing in Normal T Cells and Is Active in Refractory T Cell Lymphomas

Introduction Interleukin 2 inducible T cell kinase (ITK) is a TEC family tyrosine kinase expressed in T cells with an important role both in T cell receptor (TCR) signaling and T helper cell differentiation. Resting lymphocyte kinase (RLK), a closely related kinase, is redundant to ITK and is involved in the differentiation of naïve T cells into Th1 T cells. ITK-/- mice exhibit defects in Th2 differentiation while retaining the ability to differentiate into Th1 cells that secrete IFNγ; whereas, double ITK/RLK knockout mice exhibit profound defects in T cell function. Th1 cells are needed for various cytotoxic T cell functions such as destruction of tumor cells. CPI-818 is a covalent inhibitor of ITK (KD 2.5nM) with > 100 fold selectivity over RLK and other TEC family kinases. CPI-818 is being evaluated in an ongoing phase 1 trial in patients (pts) with refractory T cell lymphomas (TCL). We now report that selective ITK blockade with CPI-818 induces Th1 skewing of normal T cells and demonstrates anti-tumor activity. Methods Normal human peripheral blood mononuclear cells (PBMC) were stimulated in vitro for 6 days with anti-CD3/CD28 in the presence of CPI-818. Th1 cells were measured by flow cytometry based on ratio of IFNγ:IL4 staining cells. Sezary cells were similarly stimulated in the presence of CPI-818. Peripheral blood and tumor samples were stained with antibodies to CD3, 4, 8, 183, 196, 197 and 45RA to enumerate Th1 and other T cell subsets using multicolor flow cytometry. Successive cohorts of TCL pts were treated in a phase 1 trial until disease progression with continuous oral dosing of CPI-818 100mg, 200mg, 400mg or 600mg given BID. Results T cell receptor stimulated PBMC from 12 healthy donors incubated in vitro with CPI-818 demonstrated Th1 skewing at concentrations of 0.1 to < 10uM (Figure 1). Maximal skewing was seen at 1uM; cell viability was unaffected but, proliferation was inhibited at 10uM. Similar studies using Th2 Sezary cells showed inhibition of proliferation with CPI-818 (0.5-2.5uM). Thirty-three pts with TCL with a median age of 62 yrs and median of 4 prior therapies were enrolled. Histologies included: PTCL-NOS (17), AITL (4), and CTCL (12). The most common (≥ 10%) AEs were nausea, chills, vomiting, fatigue, pyrexia, decreased appetite, pruritus, and rash. Treatment-related Grade 3+ AEs were: anemia (1), lymphocytosis (1), WBC decreased (1) and neutropenia (1). The swimmer plot (Figure 2) shows a dose-dependent relationship with an optimum dose of 200mg (N=10) producing 1 CR 25 mo; 1 PR 2+ mo; 1 nodal CR 16 mo (CTCL); 2 SD; 1 PD; 4 not yet evaluated; 6 pts remain on treatment. Pharmacokinetic and target occupancy studies for the 200mg dose showed mean plasma Cmax of 2.3uM (SD 1.9uM) and ITK target occupancy of >75%. Analysis of blood in 4 of 4 pts treated in this cohort showed increases in Th1 cells (CD3+/CD4+/CD8-/CD183+/CD196-) compared to baseline and increases in terminally differentiated T effector memory cells (TEMRA CD3+/CD4-/CD8+/CD197-/CD45RA+). Tumor biopsy from 1 patient taken during response demonstrated an increase in Th1 (0 to 40%) and TEMRA CD8+ T cells (2.83% to 18.6%). CPI-818 reduced blood eosinophils (Eos) in 3 of 3 pts in this cohort with elevated Eos count, consistent with inhibition of Th2 function. Conclusions This study demonstrates that selective inhibition of ITK, while sparing RLK, induces Th1 skewing. As expected, the effects on T cell differentiation and proliferation are dose dependent: lower doses induce Th1 skewing and higher concentrations in vitro and in vivo lead to inhibition of TCR signaling and proliferation. Tumor responses were observed in several patients receiving 200mg BID, which achieves drug plasma levels consistent with Th1 skewing observed in vitro. The increases in Th1 cells and TEMRA CD8+ cells suggest that anti-tumor activity is due to induction of a host anti-tumor response. This raises the possibility that immunomodulation with ITK blockade could be used for immunotherapy of other cancers. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal