Pharmacokinetic Considerations Research Articles

Natural products as anticancer agents and enhancing their efficacy by a mechanism-based precision approach

Traditional medicines and their active ingredients and some natural products and derived analogs have been used for treating multiple diseases including cancer. Among these compounds cytotoxic agents such as bleomycin, paclitaxel and vincristine block essential pathways and genes required for cancer cell growth and these agents have diverse clinical applications. Dietary phenolics including flavonoids and related compounds are associated with multiple health benefits however most individual dietary compounds and other natural products that show promising anticancer activity in preclinical studies exhibit minimal clinical effectiveness and this is particularly true for cancer. Many of the compounds perform poorly in clinical trials due to pharmacokinetic consideration and limited uptake (e.g., curcumin) and these are issues that can be addressed. The clinical effectiveness of flavonoids and many other natural product-derived anticancer compounds can also be enhanced by a more targeted approach. This would include identifying a significant response/gene or target in a specific cancer and then identifying the optimal compound. In this review, I have discussed a limited number of targets including non-oncogene addiction genes such as Sp transcription factors, reactive oxygen species (ROS) or the orphan nuclear receptor 4A (NR4A) sub-family. Thus, the most active compound for these responses could be used only for treating patients that are ROS-inducible or highly express targets such as Sp1 or NR4A sub-family members. A mechanism-based precision medicine approach should enhance the clinical efficacy of dietary and related natural products as anticancer agents and decrease toxic side effects for some combination therapies.

Evaluating the Role of Susceptibility Inducing Cofactors and of Acetaminophen in the Etiology of Autism Spectrum Disorder

More than 20 previously reported lines of independent evidence from clinical observations, studies in laboratory animal models, pharmacokinetic considerations, and numerous temporal and spatial associations indicate that numerous genetic and environmental factors leading to inflammation and oxidative stress confer vulnerability to the aberrant metabolism of acetaminophen during early development, leading to autism spectrum disorder (ASD). Contrary to this conclusion, multivariate analyses of cohort data adjusting for inflammation-associated factors have tended to show little to no risk of acetaminophen use for neurodevelopment. To resolve this discrepancy, here we use in silico methods to create an ideal (virtual) population of 120,000 individuals in which 50% of all cases of virtual ASD are induced by oxidative stress-associated cofactors and acetaminophen use. We demonstrate that Cox regression analysis of this ideal dataset shows little to no risk of acetaminophen use if the cofactors that create aberrant metabolism of acetaminophen are adjusted for in the analysis. Further, under-reporting of acetaminophen use is shown to be a considerable problem for this analysis, leading to large and erroneously low calculated risks of acetaminophen use. In addition, we argue that factors that impart susceptibility to acetaminophen-induced injury, and propensity for acetaminophen use itself, can be shared between the prepartum, peripartum, and postpartum periods, creating additional difficulty in the analysis of existing datasets to determine risks of acetaminophen exposure for neurodevelopment during a specific time frame. It is concluded that risks of acetaminophen use for neurodevelopment obtained from multivariate analysis of cohort data depend on underlying assumptions in the analyses, and that other evidence, both abundant and robust, demonstrate the critical role of acetaminophen in the etiology of ASD.

Antibody-Drug Conjugates in the Pipeline for Treatment of Melanoma: Target and Pharmacokinetic Considerations.

Melanoma is an aggressive, rapidly developing form of skin cancer that affects about 22 per 100,000 individuals. Treatment options for melanoma patients are limited and typically involve surgical excision of moles and chemotherapy. Survival has been improved in recent years through targeted small molecule inhibitors and antibody-based immunotherapies. However, the long-term side effects that arise from taking chemotherapies can negatively impact the lives of patients because they lack specificity and impact healthy cells along with the cancer cells. Antibody-drug conjugates are a promising new class of drugs for the treatment of melanoma. This review focuses on the development of antibody-drug conjugates for melanoma and discusses the existing clinical trials of antibody-drug conjugates and their use as a melanoma treatment. So far, the antibody-drug conjugates have struggled from efficacy problems, with modest effects at best, leading many to be discontinued for melanoma. At the same time, conjugates such as AMT-253, targeting melanoma cell adhesion molecule, andmecbotamab vedotin targeting AXL receptor tyrosine kinase, are among the most exciting for melanoma treatment in the future.

Obstructive Sleep Apnea and Acute Lower Respiratory Tract Infections: A Narrative Literature Review.

Both obstructive sleep apnea (OSA) and acute lower respiratory tract infections (LRTIs) are important global health issues. The pathophysiological links between OSA and LRTIs include altered immune responses due to chronic intermittent hypoxia and sleep fragmentation, increased aspiration risk, and a high burden of comorbidities. In this narrative review, we evaluated the current evidence on the association between OSA and the incidence and outcomes of acute LRTIs in adults, specifically community-acquired pneumonia and viral pneumonia caused by influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Studies have demonstrated that OSA patients are more likely to develop bacterial pneumonia and exhibit a higher risk of invasive pneumococcal disease. The risk intensifies with the severity of OSA, influencing hospitalization rates and the need for intensive care. OSA is also associated with an increased risk of contracting influenza and suffering more severe disease, potentially necessitating hospitalization. Similarly, OSA contributes to increased COVID-19 disease severity, reflected by higher rates of hospitalization, longer hospital stays, and a higher incidence of acute respiratory failure. The effect of OSA on mortality rates from these infections is, however, somewhat ambiguous. Finally, we explored antibiotic therapy for OSA patients with LRTIs, addressing care settings, empirical regimens, risks, and pharmacokinetic considerations. Given the substantial burden of OSA and its significant interplay with acute LRTIs, enhanced screening, targeted vaccinations, and optimized management strategies for OSA patients should be prioritized.

Pharmacokinetic and pharmacodynamic considerations with psychiatric disorders and migraines.

Pharmacokinetic and pharmacodynamic considerations with psychiatric disorders and migraines.

Central Nervous System Medications: Pharmacokinetic and Pharmacodynamic Considerations for Older Adults.

Most drugs have not been evaluated in the older population. Recognizing physiological alterations associated with changes in drug disposition and with the ultimate effect, especially in central nervous system-acting drugs, is fundamental. While considering pharmacokinetics, it should be noted that the absorption of most drugs from the gastrointestinal tract does not change in advanced age. There are only few data about the effect of age on the transdermal absorption of medications such as fentanyl. Absorption from an intramuscular injection may be similar in older adults as in younger patients. The distribution of lipophilic drugs (such as diazepam) is increased owing to a relative increase in the percentage of body fat, causing drug accumulation and prolonged drug elimination following cessation. Phase I drug biotransformation is variably decreased in aging, impacting elimination, and hepatic drug clearance has been shown to decrease in older individuals by 10-40% for most drugs studied. Lower doses of phenothiazines, butyrophenones, atypical antipsychotics, antidepressants (citalopram, mirtazapine, and tricyclic antidepressants), and benzodiazepines (such as diazepam) achieve the same extent of exposure. For renally cleared drugs with no prior metabolism (such as gabapentin), the glomerular filtration rate appropriately estimates drug clearance. Important pharmacodynamic changes in older adults include an increased sedative effect of benzodiazepines at a given drug exposure, and a higher sensitivity to mu opiate receptor agonists and to opioid adverse effects. Artificial intelligence, physiologically based pharmacokinetic modeling and simulation, and concentration-effect modeling enabling a differentiation between the pharmacokinetic and the pharmacodynamic effects of aging might help to close some of the gaps in knowledge.

Manganese- and Platinum-Driven Oxidative and Nitrosative Stress in Oxaliplatin-Associated CIPN with Special Reference to Ca4Mn(DPDP)5, MnDPDP and DPDP.

Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative-nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [Ca4Mn(DPDP)5; PledOx®], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying Ca4Mn(DPDP)5 in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with Ca4Mn(DPDP)5, a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with Ca4Mn(DPDP)5. The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca4Mn(DPDP)5 may be explained by redox interactions between Pt2+ and Mn2+ and subtle oxidative-nitrosative chain reactions. In peripheral sensory nerves, Pt2+ presumably leads to oxidation of the Mn2+ from Ca4Mn(DPDP)5 as well as from Mn2+ in MnSOD and other endogenous sources. Thereafter, Mn3+ may be oxidized by peroxynitrite (ONOO-) into Mn4+, which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O2•-) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt2+-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca4Mn(DPDP)5 mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt2+-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt2+ outcompetes Mn2+ and endogenous Zn2+ in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt2+ by DPDP, which in turn suggests that Mn2+ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN.

Pharmacokinetic and pharmacodynamic considerations of antibiotic therapy among critically ill adult patients with sepsis

A szepszis életet veszélyeztető, komplex klinikai állapot, melynek kezelése jelentős kihívást és számottevő költségráfordítást jelent a betegellátás számára. A szepszis által előidézett patofiziológiai változások jelentős mértékben megváltoztatják a gyógyszerek és a szervezet kölcsönhatását, megnehezítve az optimális gyógyszerelést. A kapillárisszivárgás jelensége, valamint az ellátás során alkalmazott folyadékterápia hatására megemelkedhet egyes antibiotikumok megoszlási térfogata. A hypalbuminaemia következtében megnövekedett szabad frakció a nagy fehérjekötődésű antibiotikumok gyorsabb eliminációját okozhatja. A megnövekedett perctérfogat és a vascularis ellenállás csökkenése a fiatalabb betegpopulációkban megnövekedett renalis clearance-t idézhet elő. A betegek nagyobb hányadában azonban a hipoperfúzió miatt szepszis indukálta akut veseelégtelenség jellemző, melynek hatására a renalis clearance csökken. A klinikai képet tovább árnyalja, ha vesepótló vagy extracorporalis membránoxigenizációs kezelést alkalmazunk. Az antibiotikumok fizikai-kémiai jellemzői meghatározzák, hogy a patofiziológiai változások milyen mértékben befolyásolják az egyes gyógyszermolekulák farmakokinetikai paramétereit. A várttól eltérő gyógyszer-expozíciót előidéző folyamatok ellensúlyozására a farmakokinetikai-farmakodinamikai indexek, valamint a fizikokémiai értékek ismeretében többféle klinikai stratégia áll rendelkezésre. A terápia racionális szempontok szerint történő személyre szabásával és a terápiás gyógyszerszint monitorozásával növelhető a hatékonyság, és csökkenthető az antibiotikumrezisztencia kialakulásának esélye. Orv Hetil. 2024; 165(11): 403–415.

Sparsentan, a Dual Endothelin Type A and Angiotensin II Subtype 1 Receptor Antagonist for the Treatment of Immunoglobulin A Nephropathy: Latest Trial Results, Pharmacokinetic Considerations, and Binding Profile

Immunoglobulin A nephropathy (IgAN) is one of the most common forms of primary glomerulonephritis. In some patients, it can progress rapidly, leading to proteinuria, kidney failure, and death. Standard of care is traditionally with an angiotensin converting enzyme inhibitor (ACEi), or an angiotensin II (Ang II) receptor blocker (ARB). More recently, drugs targeting both endothelin 1 (ET-1) and Ang II receptors have been developed, as overactivation of such is implicated in IgAN. Sparsentan is a dual ET Type A (ETAR) and Ang II subtype 1 receptor (AT1R) antagonist. The PROTECT study compared sparsentan with the ARB irbesartan, in patients with IgAN and with proteinuria of ≥1 g/day despite stable dose of ACEi/ARB for ≥90 days. Data presented at the 2023 American Society of Nephrology (ASN) Kidney Week showed that use of sparsentan led to sustained (>110 weeks) decreases in proteinuria, and a significantly greater preservation of kidney function, compared with irbesartan. The ongoing SPARTAN study is investigating the use of sparsentan in recently diagnosed, treatment-naïve patients with IgAN. Preliminary data in 12 patients showed rapid and sustained proteinuria reductions, with little change from baseline in estimated glomerular filtration rate (eGFR), body weight, or total body water mean at Week 36. In both studies, sparsentan was generally well-tolerated with, in PROTECT, a comparable safety profile to irbesartan. Data presented at the congress also showed that sparsentan consistently occupies AT1R at levels exceeding ETAR occupancy. This balance is hypothesised to contribute to sparsentan’s limited risk of fluid retention.

Pharmacokinetic considerations for enhancing drug repurposing opportunities of anthelmintics: Niclosamide as a case study

Recently, anthelmintics have showcased versatile therapeutic potential in addressing various diseases, positioning them as promising candidates for drug repurposing. However, challenges such as low bioavailability and a lack of a solid pharmacokinetic basis impede successful repurposing. To overcome these flaws, we aimed to investigate the key pharmacokinetic factors of anthelmintics mainly focusing on the absorption, distribution, and metabolism profiles by employing niclosamide (NIC) as a model drug. The intestinal permeability of NIC is significantly influenced by solubility and doesn't function as a substrate for efflux transporters. It showed high plasma protein binding. Also, the metabolism study indicated that NIC would have low metabolic stability by extensively undergoing the intestinal glucuronidation. Additionally, we investigated the CYP-mediated drug-drug interaction potential of NIC in both direct and time-dependent ways. NIC showed strong inhibitory effects on CYP1A2 and CYP2C8 and is not likely to become a time-dependent inhibitor. Our findings could contribute to the identification of essential factors in the pharmacokinetics of anthelmintics, potentially facilitating their repositioning.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Moderate-to-Severe Psoriasis.

Psoriasis is a common inflammatory immune disorder due to chronic activation of the adaptive and innate immune responses. Therapies for psoriasis target reducing inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-17, and interleukin-22. Patients with inflammatory disorders have reduced metabolism by cytochrome P450 enzymes in the liver. The pharmacokinetic and pharmacodynamic changes due to psoriasis also have an impact on reaching therapeutic concentrations of the drug. Pharmacokinetic and pharmacodynamic data help determine the safety and clinical considerations necessary when utilizing drugs for plaque psoriasis. A literature search was performed on PubMed and Ovid MEDLINE for the pharmacokinetic and pharmacodynamic data of oral therapies and biologics utilized for moderate-to-severe plaque psoriasis. The findings from the literature search were organized into two sections: oral therapies and biologics. The pharmacokinetic and pharmacodynamic parameters in healthy patients, patients with psoriasis, and special populations are discussed in each section. The oral therapies described in this review include methotrexate, cyclosporine, apremilast, tofacitinib, and deucravacitinib. Biologics include tumor necrosis factor-alpha inhibitors, interleukin-17 inhibitors, ustekinumab, and interleukin-23 inhibitors. Clinical considerations for these therapies include drug toxicities, dosing frequency, and anti-drug antibodies. Methotrexate and cyclosporine have a risk for hepatoxicity and renal impairment, respectively. Moreover, drugs metabolized via cytochrome P450, including tofacitinib and apremilast have decreased clearance in patients with psoriasis, requiring dose adjustments. Patients treated with therapies such as adalimumab can develop anti-drug antibodies that reduce the long-term efficacy of the drug. Additionally, overweight patients benefit from more frequent dosing to achieve better psoriasis clearance.

Pharmacokinetic and Pharmacodynamic Considerations of Antibiotic Use in Neonates.

The selection of an appropriate dose of a given antibiotic for a neonate not only requires knowledge of the drug's basic pharmacokinetic (PK) and pharmacodynamic (PD) properties but also the profound effects that organ development might have on the volume of distribution and clearance, both of which may affect the PK/PD of a drug. Interest has grown in alternative antibiotic dosing strategies that are better aligned with the antibiotic's PK and PD properties. These strategies should be used in conjunction with minimum inhibitory concentration measurements and therapeutic drug monitoring to measure their potential success. They can also guide the clinician in tailoring the delivery of antibiotics to suit an individual patient's needs. Model-informed precision dosing, such as Bayesian forecasting dosing software (which incorporates PK/PD population models), may be utilized to optimize antibiotic exposure in neonatal populations. Consequently, optimizing the antibiotic dose and exposure in each newborn requires expertise in different fields. It drives the collaboration of physicians together with lab technicians and quantitative clinical pharmacologists.

1582. Dolutegravir/Rilpivirine STR Switch Study in Persons with HIV-1 and Chronic Kidney Disease: 48-week Assessment of Viral Suppression, Treatment Adherence and Quality of Life

Abstract Background Single tablet regimens (STRs) are widely utilized in HIV treatment in the Western world largely because they improve convenience of oral regimens and eliminate differential adherence. US Blacks are disproportionately impacted by HIV, and are also disproportionately affected by chronic kidney disease (CKD) for a variety of reasons, especially in their later years. For PWH and CKD, STR options are limited due to pharmacokinetic considerations. We evaluate the impact on viral suppression, adherence, treatment satisfaction and quality of life (QOL) of switching to DTG/RPV STR for a largely Black aging US cohort with HIV and CKD. Methods In this 48-week open label single arm switch study conducted in a community health center setting, adults with HIV, a GFR< 60 mL/min/1.73m2, an HIV RNA < 50 copies/mL and no known prior resistance to DTG or RPV were switched to DTG/RPV STR. HIV RNA and CD4 were monitored per standard national clinical guidance following switch. Standardized tools for medication adherence, treatment satisfaction and QOL were administered at baseline, 24 weeks and 48 weeks. We present final 48-week data. Results Between August 2019 and December 2021, 35 participants were enrolled. One dropped out after 19 weeks and one after 22 weeks due to drug-drug interaction concerns following renal transplantation. 94% of participants were Black, 57% were female and 43% were 65 years and older. At baseline, 20% had a GFR < 30 mL/min/1.73m2 per race-based calculation (36% per race-free calculation). At 48 weeks, 97% of participants maintained viral suppression with an HIV RNA < 50 copies/mL in a per protocol analysis (91% in an intent-to-treat analysis). One participant with an HIV RNA of 62 copies/mL at 48 weeks subsequently re-suppressed on DTG/RPV. 69% reported an improvement in adherence, 77% noted an improvement in treatment satisfaction and 66% reported an improvement in QOL. The only adverse event reported in >5% of participants was nausea (5.7%). There were no serious adverse events. Conclusion For this diverse aging cohort with HIV and CKD in a real-life community health center setting, DTG/RPV STR was efficacious, well-tolerated and associated with improvements in adherence, treatment satisfaction and QOL, sustained over 48 weeks. DTG/RPV is a feasible oral ARV option for PWH and CKD. Disclosures Helena Kwakwa, MD, MPH, ViiV Healthcare: Grant/Research Support

Pharmacokinetic Consideration of Venetoclax in Acute Myeloid Leukemia Patients: A Potential Candidate for TDM? A Short Communication.

Venetoclax (VNX)-based regimens have demonstrated significantly favorable outcomes in patients with acute myeloid leukemia (AML) and are now becoming the standard treatment. Tyrosine kinase inhibitors are administered at a fixed dose, irrespective of body surface area or weight. For such orally targeted therapies, real-world data have highlighted a larger pharmacokinetic (PK) interindividual variability (IIV) than expected. Even if VNX PKs have been well characterized and described in the literature, only 1 clinical trial-based PK study has been conducted in patients with AML. This study aimed to evaluate the PK of VNX in AML patients. We retrospectively analyzed all patients treated with a combination of VNX-azacitidine between January and July 2022 at our center, using at least 1 available VNX blood sample. Based on a previously published population PK model, individual PK parameters were estimated to evaluate the exposure and IIV. and Discussion. Twenty patients received VNX in combination with azacitidine, according to the PK data. A total of 93 plasma concentrations were collected. The dose of VNX was 400 mg, except in 7 patients who received concomitant posaconazole (VNX 70 mg). The patients' weight ranged from 49 kg to 108 kg (mean = 78 kg). Mean individual clearance was 13.5 ± 9.4 L/h with mean individual daily area under the concentration-time curves of 35.8 mg.h/L with significant IIV (coefficient of variation = 41.1%). Ten patients were still alive (8 in complete response), but all experienced at least 1 hematological toxicity of grade ≥ 3. Based on the observed large PK variability in the data from our real-world AML patients, the risk of drug interactions and the recommended fixed-dosage regimen of VNX therapeutic drug monitoring may be useful.

Pharmacokinetic and Pharmacodynamic Considerations of Novel Antibiotic Agents for Pediatric Infections: A Narrative Review.

Background: Currently, the escalation of microbial resistance poses a significant global challenge. Children are more susceptible to develop infections and therefore are prescribed antibiotics more frequently. The overuse and misuse of antibiotics in pediatric patients can play a considerable role in developing microbial resistance. Accordingly, many policies, including research into new antibiotic agents have been recommended to combat microbial resistance. Recent developments in novel antibiotics have shown promising results against multi-drug resistant (MDR) and extensive drug resistance (XDR) pathogens. However, as pediatric patients are typically excluded from the clinical trials of new medications, labeling and information about approved antibiotics should be improved. This study aimed to evaluate antibiotics having been introduced to the market in the last decade focusing on pediatric population. Methods: This study reviewed the published literatures on novel FDA-approved antibiotics released between 2010 and 2022. Results: Finally, seven newly approved antibiotics including ceftaroline fosamil, ceftazidime-avibactam, ceftolozane-tazobactam, ceftobiprole, imipenem-cilastatin-relebactam, meropenem-vaborbactam, and tedizolid were considered in the present review-article. All relevant data extracted from literatures, were discussed in different subtitles of "Pharmacology", "Mechanism of action", "Indication", "Dosage regimen and pharmacokinetic and pharmacodynamic properties", "Dosage adjustment in renal/liver failure", "Resistance pattern", and "Adverse drug events". Conclusion: This study reviewed available data on seven new antibiotic agents and their pharmacodynamic and pharmacokinetic properties, with a particular focus on their use in pediatric patients. The information presented in this review will be useful for healthcare professionals in selecting appropriate antibiotics for pediatric patients and for researchers in achieving the ideal therapeutic regimens.

Isosteric Replacement of Ester Linkage of Lysophospholipids with Heteroaromatic Rings Retains Potency and Subtype Selectivity.

Our group has reported various derivatives of lysophosphatidylserine (LysoPS) as potent and subtype-selective agonists for G-protein-coupled receptors (GPCRs). However, the ester linkage between the glycerol moiety and fatty acid or fatty acid surrogate is present in all of them. In order to develop these LysoPS analogs as drug candidates, appropriate pharmacokinetic consideration is essential. Here, we found that the ester bond of LysoPS is highly susceptible to metabolic degradation in mouse blood. Accordingly, we examined isosteric replacement of the ester linkage with heteroaromatic rings. The resulting compounds showed excellent retention of potency and receptor subtype selectivity, as well as increased metabolic stability in vitro.

Paving the way to environment-friendly greener anesthesia.

Health-care settings have an important responsibility toward environmental health and safety. The operating room is a major source of environmental pollution within a hospital. Inhalational agents and nitrous oxide are the commonly used gases during general anesthesia for surgeries, especially in the developing world. These greenhouse gases contribute adversely to the environmental health both inside the operating room and in the outside atmosphere. Impact of these anesthetic agents depends on the total consumption, characteristics of individual agents, and gas flows, with higher levels increasing the environmental adverse effects. The inimical impact of nitrous oxide is higher due to its longer atmospheric half-life and potential for destruction of the ozone layer. Anesthesiologist of today has a choice in the selection of anesthetic agents. Prudent decisions will help in mitigating environmental pollution and contributing positively to a greener planet. Therefore, a shift from inhalational to intravenous-based technique will reduce the carbon footprint of anesthetic agents and their impact on global climate. Propofol forms the mainstay of intravenous anesthesia technique and is a proven drug for anesthetic induction and maintenance. Anesthesiologists should appreciate growing concerns about the role of inhalational anesthetics on the environment and join the cause of environmental responsibility. In this narrative review, we revisit the pharmacological and pharmacokinetic considerations, clinical uses, and discuss the merits of propofol-based intravenous anesthesia over inhalational anesthesia in terms of environmental effects. Increased awareness about the environmental impact and adoption of newer, versatile, and user-friendly modalities of intravenous anesthesia administration will pave the way for greener anesthesia practice.

Amisulpride Augmentation in Schizophrenia Patients with Poor Response to Olanzapine: A 4-week, Randomized, Rater-Blind, Controlled, Pilot Study

IntroductionOlanzapine (OLA) is a common first-prescribed antipsychotic and has shown favorable efficacy in acutely exacerbated patients with schizophrenia. The mixed receptor activity of OLA and its greater affinity for serotonin 5-HT2A rather than dopamine D2 receptors are similar to those of clozapine. Pharmacokinetically, OLA is metabolized mainly by hepatic cytochrome enzyme P450 1A2 (CYP1A2). Because risks of antipsychotic polypharmacy include increased drug-drug interactions, pharmacokinetic considerations are important for selection of antipsychotics to be combined. Due to its pharmacological characteristics, amisulpride (AMI), another atypical antipsychotic with proven efficacy, is a promising adjuvant agent of special interest. AMI is unlikely to interact with other drugs due to the low plasma protein binding and metabolism and does not affect the activity of the CYP system. Furthermore, AMI is highly selective for dopamine D2/D3 receptors; has minimal or no affinity for D1, D4, or D5 receptors. Despite the potential benefits of the combination of OLA and AMI, only a few open-label studies have been conducted, and no randomized clinical trial has been performed to date to examine the efficacy and tolerability of the combination. Hence, the goals of this study were to test the hypothesis that AMI augmentation would improve psychotic symptoms and be well tolerated in schizophrenic patients who showed poor response to OLA monotherapy.ObjectivesThe purpose of this study was to compare the efficacy and tolerability of continued olanzapine (OLA) versus amisulpride (AMI) augmentation in schizophrenic patients with poor response to OLA monotherapy.MethodsThe present 4-week, randomized, rater-blinded study included 25 patients with schizophrenia who were partially or completely unresponsive to treatment with OLA monotherapy. Eligible subjects were randomly assigned at a 1:1 ratio to continuation of OLA monotherapy (OLA group) or OLA with AMI augmentation (AMI group). Efficacy was primarily evaluated using the Positive and Negative Syndrome Scale (PANSS) at baseline and at 1, 2, and 4 weeks.ResultsThe changes in PANSS total score and PANSS-positive subscale score were significantly different (p < 0.05) between the OLA and AMI groups. The differences between the two groups in PANSS-negative subscale, PANSS-general subscale, Brief Psychiatric Rating Scale, and Clinical Global Impression-Severity (CGI-S) scale scores were not statistically significant.ConclusionsAMI augmentation could be an effective strategy for patients with schizophrenia who show inadequate early response to OLA monotherapy.Disclosure of InterestW.-M. Bahk Grant / Research support from: Handok Pharmaceuticals, Seoul, Korea, Y. S. Woo: None Declared, S.-Y. Park: None Declared, B.-H. Yoon: None Declared, S.-M. Wang: None Declared, M.-D. Kim: None Declared

Entrectinib dose confirmation in pediatric oncology patients: pharmacokinetic considerations

PurposeEntrectinib is a central nervous system-active potent inhibitor of tropomyosin receptor kinase (TRK), with anti-tumor activity against neurotrophic NTRK gene fusion-positive tumors. This study investigates the pharmacokinetics of entrectinib and its active metabolite (M5) in pediatric patients and aims to understand whether the pediatric dose of 300 mg/m2 once daily (QD) provides an exposure that is consistent with the approved adult dose (600 mg QD).MethodsForty-three patients aged from birth to 22 years were administered entrectinib (250–750 mg/m2 QD) orally with food in 4-week cycles. Entrectinib formulations included capsules without acidulant (F1) and capsules with acidulant (F2B and F06).ResultsAlthough there was interpatient variability with F1, entrectinib and M5 exposures increased dose dependently. Lower systemic exposures were observed in pediatric patients receiving 400 mg/m2 QD entrectinib (F1) versus adults receiving either the same dose/formulation or the recommended flat dose of 600 mg QD (~ 300 mg/m2 for a 70 kg adult) due to suboptimal F1 performance in the pediatric study. The observed pediatric exposures following 300 mg/m2 QD entrectinib (F06) were comparable to those in adults receiving 600 mg QD.ConclusionsOverall, the F1 formulation of entrectinib was associated with lower systemic exposure in pediatric patients compared with the commercial acidulant formulation (F06). Systemic exposures achieved in pediatric patients with the F06 recommended dose (300 mg/m2) were within the known efficacious range in adults, confirming the adequacy of the recommended dose regimen with the commercial formulation.

Pharmacokinetic Consideration to Formulate Sustained Release Drugs: Understanding the Controlled Drug Diffusion through the Body Compartment of the Systemic Circulation and Tissue Medium-A Caputo Model

The aim of this study is to provide an overview of various models to study drug diffusion for a sustained period into and within the human body. Emphasized the mathematical compartment models using fractional derivative (Caputo model) approach to investigate the change in sustained drug concentration in different compartments of the human body system through the oral route or the intravenous route. Law of mass action, first-order kinetics, and Fick's perfusion principle were used to develop mathematical compartment models representing sustained drug diffusion throughout the human body. To adequately predict the sustained drug diffusion into various compartments of the human body, consider fractional derivative (Caputo model) to investigate the rate of concentration changing depending upon the change in the order of fractional differentiation in all the possible compartments of the body, i.e., systemic circulation and tissue compartments. Also, assigned a numerical parameter value to the rate of drug flow in different compartments to estimate the drug concentration. Results were calculated and figures were depicted by using MATLAB software (version R2020a). Illustrated graphical effects of change in concentration rate by assuming various intermediate values according to the fractional derivative (Caputo model). The resultant graphical representation concludes that considering the order of the differential equation values, the drug concentration varies depending upon its rate of constants in compartments concerning time. Considering the initial case for rough estimation where the body is indicated as a whole compartment, following division of the body into two model compartments. Whereas, the model I represents stomach, liver, and systemic blood, and model II consider arterial blood, liver tissue, and venous blood.