Drug Clearance Research Articles

Evaluating the protective effects of dexamethasone and electrospun mesh combination on primary human mixed retinal cells under hyperglycemic stress

Chronic inflammation is a leading cause of neurodegeneration and vision loss in hyperglycemia-associated conditions such as diabetic retinopathy. Corticosteroid injections are widely used for treatment but suffer from limitations such as rapid drug clearance, short drug half-lives and frequent administration. While drug release from biomaterial carriers can overcome these shortcomings, evaluating the combined effects of corticosteroids and polymeric matrices under hyperglycemic stress is an important step towards aiding translation. In this study, we investigated the effects of dexamethasone (DEX) and electrospun mesh combination on primary human mixed retinal cells under normal and hyperglycemic culture conditions. DEX-incorporated poly(lactide-co-glycolide) (PLGA) meshes were prepared and characterized for architecture, chemistry, drug distribution and in vitro release. The meshes exhibited cumulative in vitro drug release of 39.5 % over 2 months at a near constant rate. Under normal culture conditions, DEX-PLGA meshes promoted significantly higher viability of mixed retinal cells than the control groups but without adverse phenotypic activation. Under hyperglycemic conditions, DEX supplementation resulted in higher viability than the control, although the highest viability was achieved only when DEX was added to cells cultured on PLGA fibers. The combination of DEX and PLGA fibers also promoted higher mRNA expression of the antioxidant GSH under hyperglycemia. Importantly, the largest reduction in the production of pro-inflammatory cytokines viz., MMP-9, IL-6, IL-8 and VEGF-R1 was observed for the DEX and PLGA combination. Our study reveals a combined effect of DEX and electrospun fibers in combating hyperglycemia-driven pro-inflammatory responses, which can aid the development of DEX-loaded electrospun implants for diabetes-driven retinal conditions.

A fractional order impedance model for heterogeneous drug distribution in obese patients during general anesthesia

Personalised pharmacokinetic models imply stepping away from the classical assumption of homogeneous drug mixing in various tissue compartments in the body, with a particular impact on obese patients. In this work, the pharmacokinetic compartmental model structure is revisited to account for non-uniform distribution of uptake/clearance time constants in patients as a nonlinear function of body mass index. Simulations are confirming expected patterns of drug distribution in the body and can account for post-anesthesia side effects up to 72 hours. We apply spectroscopy to extract the complex impedance in fat tissue samples. The data is modelled by a Cole-Cole model, where parameters of the fractional order impedance model are optimized using a genetic algorithm. The findings suggest that fat tissue will exhibit anomalous diffusion when drug uptake and clearance are present.

A Standardized Protocol for Extraction and Homogenization of Ocular Tissues.

The eye is a complex organ composed of multiple tissues in anterior and posterior eye segments. Malfunctions of any of these tissues can lead to ocular diseases and loss of vision. A detailed understanding of the ocular anatomy and physiology in animal models and humans contributes to the development of ocular drugs by enabling studies on drug delivery and clearance routes, pharmacokinetics, and toxicity. This protocol provides step-by-step instructions for the extraction and homogenization of ocular tissues for enzymatic and proteomics analyses. Key features • Suitable protocol for the extraction and isolation of ocular tissue from humans and laboratory animals (rabbit, pig, rat, mouse) while minimizing cross-contamination. • Hard or soft tissue homogenates can be prepared efficiently using a Bead Ruptor homogenizer. • Allows to determine the protein contents in prepared homogenates.

When to consider intra-target microdosing: physiologically based pharmacokinetic modeling approach to quantitatively identify key factors for observing target engagement.

Intra-Target Microdosing (ITM), integral to Phase 0 clinical studies, offers a novel approach in drug development, effectively bridging the gap between preclinical and clinical phases. This methodology is especially relevant in streamlining early drug development stages. Our research utilized a Physiologically Based Pharmacokinetic (PBPK) model and Monte Carlo simulations to examine factors influencing the effectiveness of ITM in achieving target engagement. The study revealed that ITM is capable of engaging targets at levels akin to systemically administered therapeutic doses for specific compounds. However, we also observed a notable decrease in the probability of success when the predicted therapeutic dose exceeds 10mg. Additionally, our findings identified several critical factors affecting the success of ITM. These encompass both lower dissociation constants, higher systemic clearance and an optimum abundance of receptors in the target organ. Target tissues characterized by relatively low blood flow rates and high drug clearance capacities were deemed more conducive to successful ITM. These insights emphasize the necessity of taking into account each drug's unique pharmacokinetic and pharmacodynamic properties, along with the physiological characteristics of the target tissue, in determining the suitability of ITM.

Cancer and Chronic Kidney Disease

Chronic kidney disease (CKD) and cancer are two serious and increasingly prevalent diseases. They are interconnected in multiple ways and bidirectionally: cancer can directly or indirectly cause CKD through adverse effects of therapies; conversely, CKD can be a risk factor for cancer. Both conditions may coexist in a patient. The number of cancer patients undergoing hemodialysis is on the rise, presenting a growing challenge for oncologists, nephrologists, and pharmacists worldwide, as there are approximately one million hemodialysis patients. In hemodialysis patients, the concerns are twofold: their renal function is impaired, exposing them to the risk of overdosing and adverse effects. Simultaneously, careful planning of treatment administrations concerning dialysis sessions is necessary to avoid premature drug clearance by dialysis, preventing underdosing and consequently treatment inefficacy. In this article, we present a case of a patient with chronic renal insufficiency undergoing hemodialysis for 16 years, who developed breast cancer. Through this case, we illustrate the challenges encountered in managing such patients and provide a literature review summarizing recommendations.

Population Pharmacokinetic Modeling and Simulation of Pudexacianinium (ASP5354) for Dose Setting of a Phase 2 First-in-Patient Study: A Novel Imaging Agent for Intraoperative Ureter Visualization during Abdominopelvic Surgery.

Pudexacianinium (ASP5354) chloride is an indocyanine green derivative designed to enable enhanced ureter visualization during surgery. The objective of the present analysis was to determine appropriate doses of pudexacianinium for a phase 2, dose-ranging study (NCT04238481). Real-time urine pudexacianinium concentration is considered a good pharmacodynamic surrogate marker, since ureter visualization likely depends on its concentration in the ureter. Using plasma and urine concentrations of pudexacianinium from a phase 1 single-ascending-dose (0.1-24.0mg) study in healthy participants, a 3-compartment population pharmacokinetic model with a urine output compartment was developed and effectively described the concentration-time profiles. The individual estimated glomerular filtration rates had a significant impact on drug clearance. Simulations suggested that a 1.0mg intravenous injection would achieve target urine concentrations over 1μg/mL (determined from previous nonclinical studies) for 3 hours postdose, assuming a urine production rate of 1.0mL/min. Based on this simulation, doses of 0.3, 1.0, and 3.0mg were proposed for the phase 2 study. The observed plasma concentrations were generally consistent with model predictions. For urine, although only limited data could be obtained due to the difficulties of spot urine collection from surgical patients, intraoperative ureter visualization was successful at 1.0 and 3.0mg.

Identification of cytochrome P450 2C18 and 2C76 in tree shrews: P450 2C18 effectively oxidizes typical human P450 2C9/2C19 chiral substrates warfarin and omeprazole with less stereoselectivity

Cytochromes P450 (P450s or CYPs), especially the CYP2C family, are important drug-metabolizing enzymes that play major roles in drug metabolism. Tree shrews, a non-rodent primate-like species, are used in various fields of biomedical research, notably hepatitis virus infection; however, its drug-metabolizing enzymes have not been fully investigated. In this study, tree shrew CYP2C18, CYP2C76a, CYP2C76b, and CYP2C76c cDNAs were identified and contained open reading frames of 489 or 490 amino acids with high sequence identities (70–78 %) to human CYP2Cs. Tree shrew CYP2C76a, CYP2C76b, and CYP2C76c showed higher sequence identities (79–80 %) to cynomolgus CYP2C76 and were not orthologous to any human CYP2C. Phylogenetic analysis revealed that tree shrew CYP2C18 and CYP2C76s were closely related to rat CYP2Cs and cynomolgus CYP2C76, respectively. Tree shrew CYP2C genes formed a gene cluster similar to human CYP2C genes. All four tree shrew CYP2C mRNAs showed predominant expressions in liver, among the tissue types examined; expression of CYP2C18 mRNA was also detected in small intestine. In liver, CYP2C18 mRNA was the most abundant among the tree shrew CYP2C mRNAs. In metabolic assays using human CYP2C substrates, all tree shrew CYP2Cs showed metabolic activities toward diclofenac, R,S-omeprazole, paclitaxel, and R,S-warfarin, with the activity of CYP2C18 exceeding that of the other CYP2Cs. Moreover, tree shrew CYP2C76 enzymes metabolized progesterone more efficiently than human, cynomolgus, or marmoset CYP2Cs. Therefore, these novel tree shrew CYP2Cs are expressed abundantly in liver, encode functional enzymes that metabolize human CYP2C substrates, and are likely responsible for drug clearances.

Novel Cytochrome P450 2C119 Enzymes in Cynomolgus and Rhesus Macaques Metabolize Progesterone, Diclofenac, and Omeprazole.

Cynomolgus and rhesus macaques are used in drug metabolism studies due to their evolutionary and phylogenetic closeness to humans. Cytochromes P450 (P450s or CYPs), including the CYP2C family enzyme, are important endogenous and exogenous substrate-metabolizing enzymes and play major roles in drug metabolism. In cynomolgus and rhesus macaques, six CYP2Cs have been identified and characterized, namely, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2C76, and CYP2C93. In this study, CYP2C119, a new CYP2C, was identified and characterized in cynomolgus and rhesus macaques. Cynomolgus and rhesus CYP2C119 contained open reading frames of 489 amino acids with high sequence identities to human CYP2C8 and to cynomolgus and rhesus CYP2C8. Phylogenetic analysis showed that cynomolgus and rhesus CYP2C119 were closely related to cynomolgus and rhesus CYP2C8. In cynomolgus and rhesus genomes, CYP2C genes, including CYP2C119, form a cluster. Among the tissues analyzed, cynomolgus CYP2C119 mRNA was predominantly expressed in liver. Hepatic expressions of CYP2C119 mRNA in four cynomolgus and two rhesus macaques varied, with no expression in one rhesus macaque. Among the CYP2C mRNAs, CYP2C119 mRNA was expressed less abundantly than CYP2C8, CYP2C9, CYP2C19, and CYP2C76 mRNAs but more abundantly than CYP2C18 mRNA. Recombinant cynomolgus and rhesus CYP2C119 catalyzed progesterone 16α-, 17α-, and 21-hydroxylation and diclofenac and omeprazole oxidations, indicating that CYP2C119 is a functional enzyme. Therefore, the novel CYP2C119 gene, expressed in macaque liver, encodes a functional enzyme that metabolizes human CYP2C substrates and is likely responsible for drug clearances. SIGNIFICANCE STATEMENT: Cytochrome P450 2C119 was found in cynomolgus and rhesus macaques, in addition to the known P450 2C8, 2C9, 2C18, 2C19, 2C76, and 2C93. Cynomolgus and rhesus CYP2C119 contain open reading frames of 489 amino acids with high sequence identity to human CYP2C8. Cynomolgus CYP2C119 mRNA is predominantly expressed in the liver. Recombinant CYP2C119 catalyzed progesterone hydroxylation and diclofenac and omeprazole oxidations. Therefore, the novel CYP2C119 gene expressed in the macaque liver encodes a functional enzyme that metabolizes human CYP2C substrates.

Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections.

Ceftobiprole is a fifth-generation cephalosporin used for different Gram-positive bacterial infections. A population pharmacokinetic analysis was conducted in real-life clinical patients to assess the adequacy of current dosages. Population pharmacokinetics was conducted using non-linear mixed effect modeling. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) of free trough or steady-state concentration over MIC (fCtrough/MIC or fCss/MIC) ≥ 1 or ≥4 associated with both the standard and intensified dosing regimens adjusted for renal function. Cumulative fraction of response (CFR) against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were also calculated. A total of 132 patients with 503 concentrations were included. Most of them (107/132, 81.1%) had hospital- or community-acquired pneumonia, endocarditis, and bacteremia. A three-compartment model adequately fitted ceftobiprole concentration-time data. Estimated glomerular filtration rate significantly affected drug clearance. Monte Carlo simulations showed that the optimal target of fCtrough/MIC or fCss/MIC ≥ 4 is achieved only with the use of the standard dosages administered by continuous infusion (CI) against MRSA infections in patients with preserved renal function. Intensified dosages administered by CI are needed in patients with impaired renal function and/or augmented renal clearance against MRSA and in patients with preserved renal functions against MRSE.

Hemoadsorption Therapy for Calcium Channel Blocker Overdose: A Case Report

BackgroundModern resin hemoadsorption/hemoperfusion for calcium channel blocker overdose is yet to be reported. The characteristics of calcium channel blockers make them unamenable to removal by hemodiafiltration or charcoal hemoperfusion; however, elimination, using styrene bead adsorption in an ex vivo model, has been demonstrated. Its clinical use is described. Case ReportA man in his 20s was admitted with shock into the Intensive Care Unit (ICU) after an overdose of amlodipine and risperidone. Resuscitation and supportive care were administered, but hypotension did not resolve despite the administration of intravenous fluids, infusions of calcium, adrenaline, and hyperinsulinemic-euglycemic therapy. Methylene blue was then administered to maintain the mean arterial pressures. However, the hemodynamic effect did not allow the weaning of the adrenaline. Drug clearance using hemoadsorption/hemoperfusion was attempted using a styrene resin filter (Jafron HA230; Jafron Biomedical Co., Ltd., Guangdong, China). During the two hemoperfusion sessions (6 h duration each, and 18 h apart) the patient had successfully weaned off all supportive measures, with lactate levels returning to normal and was later discharged home. At the end of each session, significant amlodipine concentrations were detected in blood aspirated from both filters, suggesting enhanced clearance. Why Should an Emergency Physician Be Aware of This?Our case illustrates a temporal relationship between resin hemoperfusion therapy, resolution of hemodynamic instability, and shock without proving causation. Significant amlodipine elimination was suggested by high concentrations found in blood from the filter. At the same time, shock resolution after initiation of hemoperfusion occurred in less than one elimination half-life of amlodipine.

Intratumoral aluminum hydroxide-anchored IL-12 drives potent antitumor activity by remodeling the tumor microenvironment.

IL-12 is a potent cytokine that can promote innate and adaptive anticancer immunity, but its clinical development has been limited by toxicity when delivered systemically. Intratumoral (i.t.) administration can expand the therapeutic window of IL-12 and other cytokines but is in turn limited by rapid drug clearance from the tumor, which reduces efficacy, necessitates frequent administration, and increases systemic accumulation. To address these limitations, we developed an anchored IL-12 designated ANK-101, composed of an engineered IL-12 variant that forms a stable complex with the FDA-approved vaccine adjuvant aluminum hydroxide (Alhydrogel). Following i.t. administration of murine ANK-101 (mANK-101) in early intervention syngeneic mouse tumors, the complex formed a depot that was locally retained for weeks as measured by IVIS or SPECT/CT imaging, while unanchored protein injected i.t. was cleared within hours. One or 2 i.t. injections of mANK-101 induced single-agent antitumor activity across a diverse range of syngeneic tumors, including models resistant to checkpoint blockade at doses where unanchored IL-12 had no efficacy. Local treatment with mANK-101 further induced regressions of noninjected lesions, especially when combined with systemic checkpoint blockade. Antitumor activity was associated with remodeling of the tumor microenvironment, including prolonged IFN-γ and chemokine expression, recruitment and activation of T and NK cells, M1 myeloid cell skewing, and increased antigen processing and presentation. Subcutaneous administration of ANK-101 in cynomolgus macaques was well tolerated. Together, these data demonstrate that ANK-101 has an enhanced efficacy and safety profile and warrants future clinical development.

Recent advances in polymeric microparticle-based drug delivery systems for knee osteoarthritis treatment.

Due to the poor bioavailability and high joint clearance of drugs, sustained delivery of therapeutic agents has proven difficult in the treatment of osteoarthritis (OA). Intra-articular (IA) drug delivery strategy is an attractive option for enhancing OA patients' prognosis, for which various polymer materials have been used as drug carriers due to their attractive delivery properties, to slow or even reverse the progress of OA by prolonging the duration of therapeutic agent residence in the joint. This article focuses on the recent developments in natural and synthetic polymer-based microsphere drug delivery systems for treating knee osteoarthritis. It evaluates the translational potential of some novel formulations for clinical application.

Biohybrid Nanoparticle-Based In Situ Monitoring of In Vivo Drug Delivery.

Nanomaterials have gained huge attention worldwide owing to their unique physicochemical characteristics which enable their applications in the field of biomedicine and drug delivery systems. Although nanodrug delivery systems (NDDSs) have better target specificity and bioavailability than traditional drug delivery systems, their behavior and clearance mechanisms in living subjects remain unclear. In this regard, the importance of bioimaging methods has come to the forefront for investigating the biodistribution of nanocarriers and discovering drug release mechanisms in vivo. In this review, we introduce several examples of biohybrid nanoparticles and their clinical applications, focusing on their advantages and limitations. The various bioimaging methods for monitoring the fate of nanodrugs in biological systems and the future perspectives of NDDSs have also been discussed.

Formation and clearance of TNF-TNF inhibitor complexes during TNF inhibitor treatment.

Millions of patients with inflammatory diseases are treated with tumour necrosis factor (TNF) inhibitors (TNFi). Individual treatment response varies, in part related to variable drug clearance. The role of TNF-TNFi complexes in clearance of the different TNFi is controversial. Moreover, mechanistic insight into the structural aspects and biological significance of TNF-TNFi complexes is lacking. We hypothesized a role for Fc-mediated clearance of TNF-TNFi immune complexes. Therefore, we investigated circulating TNF-TNFi complexes upon treatment with certolizumab-lacking Fc tails-in comparison with adalimumab, golimumab, infliximab and etanercept. Drug-tolerant ELISAs were developed and used to quantify TNF during adalimumab, golimumab, etanercept, certolizumab and infliximab treatment in patients with inflammatory arthritis or ulcerative colitis for a maximum follow-up of 1 year. Effects on in vitro TNF production and Fc-mediated uptake of TNF-TNFi complexes were investigated for all five TNFi. Circulating TNF concentrations were >20-fold higher during certolizumab treatment compared with adalimumab, reaching up to 23.1 ng·ml-1 . Internalization of TNF-TNFi complexes by macrophages depended on Fc valency, with efficient uptake for the full antibody TNFi (three Fc tails), but little or no uptake for etanercept and certolizumab (one and zero Fc tail, respectively). TNF production was not affected by TNFi. Total TNF load did not affect clearance rate of total TNFi. Differences in TNFi structure profoundly affect clearance of TNF, while it is unlikely that TNF itself significantly contributes to target-mediated drug disposition of TNFi.

What Should We Know about Drug Levels and Therapeutic Drug Monitoring during Pregnancy and Breastfeeding in Inflammatory Bowel Disease under Biologic Therapy?

Data on the real long-term influences of in utero drug exposure in pregnant women on childhood development are scarce and remain not well determined and depend on the duration of in utero drug exposure and maternal drug levels. Therapeutic drug monitoring (TDM) during pregnancy may help limit fetal drug exposure while maintaining an effective dose for the treatment of the underlying inflammatory bowel disease (IBD) in women. Most antibody therapies used in patients with IBD are IgG molecules which are actively transported across the placenta, especially during the third trimester of the pregnancy. Here, we propose an up-to-date clinical review to summarize the available findings of serum drug levels in maternal blood during pregnancy, in the cord blood, infants at delivery and in breast milk of patients with IBD treated with biologics. Conversely, in comparison to adalimumab (ADA) levels, which are relatively stable during pregnancy, infliximab (IFX) drug clearance decreased significantly during the last two trimesters of the pregnancy, leading to increasing drug concentrations in the blood of the pregnant women. As most guidelines recommend using live vaccines in infants at the age of one or earlier in case of negative serum drug levels in newborns, statistical models could help clinicians in making a decision to adjust the last dose of the biologic during pregnancy and to determine the optimal date to vaccinate. Altogether, data from the literature offers strong reassurance in terms of safety for anti-TNFα therapies during pregnancy not only for IBD patients who intend to conceive, but also for pregnant women and for the physicians taking care of these patients. ADA and IFX levels in breast milk are detectable, but at very low levels, and therefore, it is recommended to pursue breast feeding under anti-TNFα therapy. Our knowledge on ustekinumab or vedolizumab levels in pregnant women remains unclear and scarce. These drugs are currently not recommended for patients with IBD in clinical practice. Therefore, TDM and proactive dose adjustment are not necessary during pregnancy since its impact on making a clinical decision have not yet been clearly demonstrated in routine practice. Overall, drug concentrations in the cord blood, an infant at birth and postpartum serum concentrations in infants, due to active placental drug transfer, may have a greater impact than the limited drug transfer in breast milk during lactation on the risk of infection and developmental outcomes. Ustekinumab and vedolizumab exposure during pregnancy and lactation are both considered low risk by the recent ECCO guidelines despite the limited data that are currently available.

Outpatient administration of high-dose methotrexate in adults without drug monitoring – a case-control study of risk factors for acute kidney injury

IntroductionHigh-dose methotrexate (HDMTX) is an essential part of chemotherapy regimens for hematologic neoplasms. The incidence of acute kidney injury (AKI) after HDMTX in unmonitored outpatient infusion had not been reported in adults yet. In this study, we evaluated toxicity data after outpatient administration of HDMTX without drug monitoring. MethodsPatients 16 years old or over with acute lymphoblastic leukemia and non-Hodgkin lymphoma who received at least one outpatient infusion of HDMTX without drug level monitoring were included. This is a retrospective, nested case-control study, in which the cases comprised patients who developed AKI after HDMTX. ResultsOverall, 302 patients were included, encompassing 840 infusions. Hospitalization occurred in 8.6 %. A total of 25 patients presented AKI after HDMTX administration, corresponding to 3 % of the methotrexate (MTX) infusions and 8.3 % of the patients. HIV-associated Burkitt lymphoma was more common in patients who presented AKI (18 vs. 6.8 %, p = 0.03). Baseline factors related to AKI after HDMTX were age > 44 y, body surface area ≥ 1.76 m2, body mass index (BMI) ≥ 23.8 kg/m2, glomerular filtration rate, and thrombocytopenia (< 150×109/L). Multivariable analysis for adjusting such factors found that BMI was independently related to AKI after HDMTX (OR 3.8). Death after AKI occurred in 56 %. ConclusionOur data showed a similar rate of AKI after HDMTX to that reported in the literature, even without drug monitoring. However, patients who developed AKI in our cohort fared worse than expected, with more hospitalizations and death. A higher BMI was associated with the MTX-induced AKI in our cohort, suggesting a differential drug clearance and the need for specific guidelines for obese patients.

Bioavailability and Antihyperglycemic Effect of Four Glibenclamide Tablets: A Comparative Study

This study compared the bioavailability and antihyperglycemic effect of 5 mg glibenclamide tablets available in Sudan. Nine healthy subjects were given a 5 mg dose of either micronized glibenclamide tablets (Euglucon®) or conventional non-micronized glibenclamide tablets (locally manufactured items). Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 7, and 8 hours and analyzed for glucose concentrations. The maximum mean serum concentration of the drug (Cmax) and the mean time to maximum serum concentration (Tmax) were calculated, and the area under the concentration versus time curve (AUC) and the drug clearance (Cl) were also recorded. The mean glucose concentration was also determined in different time intervals. The results show no significant difference in the mean Tmax between the tested items. However, the mean Cmax is significantly higher (p 0.001) when the non-micronized tablets are taken (456 ng/mL) rather than the micronized tablets (291 ng/mL). Similarly, the mean AUC0-8h is significantly higher (p 0.001) with the non-micronized tablets (1915 ng/mL.h) than with the micronized tablets (1163 ng/mL.h). After 8 hours, the subjects in the micronized group had a drug clearance of 0.0430 L/Kg.h, and a clearance of 0.0260 L/Kg.h was recorded in the unmicronized group. Both tablets lower the mean glucose concentrations of the nine volunteers after 8 hours, 99 mg/dL for micronized tablets and 98 mg/dL for non-micronized tablets. Overall, the non-micronized glibenclamide tablet used in this study similarly lowered the glucose concentrations in healthy volunteer subjects to that of imported micronized glibenclamide tablets.

483. Pharmacokinetics of Nirmatrelvir and Ritonavir in COVID-19 Patients with Hemodialysis

Abstract Background Nirmatrelvir/ritonavir (Paxlovid) is one of the few therapeutic options for COVID-19. It is not recommended to use in patients with end-stage renal disease (ESDR), and large-scale clinical trials are needed to support its application in this population. We investigated the pharmacokinetics of nirmatrelvir/ritonavir (150 mg/100 mg twice a day) in COVID-19 patients with hemodialysis (HD). Methods SARS-Cov-2 tested positive patients with HD were included and given treatment with nirmatrelvir/ritonavir (150 mg/100 mg twice a day) for 5 days. For most patients, a 4 h-HD started 2 h after the morning dose on day 2. Blood samples were collected 4 h and 12 h after the first dose on day 1 to obtain peak and trough concentrations, respectively. And the blood samples at the start and finish time points of HD were drawn to observe the effect of dialysis on drug clearance. A tandem mass spectrometry (LC-MS/MS) method was conducted to quantify the nirmatrelvir and ritonavir concentrations. Results A total of 14 COVID-19 patients undergoing dialysis were enrolled, with 4 females and 10 males. The age was 66.6 ± 8.0 years and the body mass index (BMI) was 22.3 ± 3.5. The peak concentration of nirmatrelvir after the first dose was 4960 ± 1889 ng/mL. And the trough concentration was 2940 ± 1305 ng/mL, which was approximately 10 times above the EC90 (292 ng/mL). Nirmatrelvir concentration fell by 42% from 10426 ± 3191 ng/mL to 6035 ± 2402 ng/mL during 4 h-HD. The peak and trough concentrations of ritonavir were 816 ± 445 ng/mL and 326±201 ng/mL after the first dose, respectively. And the concentration fell by 17% during 4 h-HD. Based on the assumption of a first-order elimination kinetic, nirmatrelvir/ritonavir 150 mg/100 mg, once a day dose regimen was simulated which showed that the plasma concentration of nirmatrelvir could also achieve the target EC90 value.Figure 1.Plasma concentration of nirmatrelvir (blue circles) and ritonavir (orange circles) in COVID-19 patients with hemodialysis during the course of 150 mg/100 mg twice a day treatment. 4 h- hemodialysis was performed at 26 - 30 h after the first dose. Data are presented as the mean ± standard deviation. The open circles indicate the individual concentration data.Figure 2.Simulated plasma concentration data in dialysis patients following a single dose of 150 mg/100 mg nirmatrelvir/ritonavir. Long dashed line represents patients not on dialysis. Short dashed line represents patients receiving a 4 h - dialysis. Conclusion 150 mg/100 mg twice a day dose regimen of nirmatrelvir/ritonavir produced sufficient concentrations to reach the effective target in COVID-19 patients with HD. Simulation data suggested that a modified dose with 150 mg/100 mg once a day could also reach effective concentration. Our data provide evidence for the application of nirmatrelvir/ritonavir in patients with ESRD and further validation in large-scale investigation was needed. Disclosures All Authors: No reported disclosures

2526. Ex Vivo Assessment of Sulbactam-Durlobactam (SUL-DUR) Clearance during Continuous Renal Replacement Therapy (CRRT)

Abstract Background Optimal dosing of antibiotics in patients on CRRT is complicated by factors that can influence drug adsorption and clearance including filter type, CRRT mode, effluent rate (ER), and the drug’s properties itself. SUL-DUR is a novel combination antibiotic under development for management of Acinetobacter baumannii infections. We sought to characterize SUL and DUR adsorption and transmembrane clearance (CLTM) in an ex vivo CRRT model. Methods CLTM was determined in hemofiltration (CVVH) and hemodialysis (CVVHD) modes using the Prismaflex M100 and HF1400 hemofilter sets. One liter of heparinized bovine blood was allowed to circulate in the Prismaflex CRRT system for 10 minutes. SUL and DUR were then added to achieve a plasma concentration of 30 mg/L, the average maximum concentration achieved in humans following SUL-DUR 1g/1g q6h as a 3h infusion. Pre-filter blood, post-filter blood and effluent samples were collected at 0, 10, 30, and 60 minutes to determine SUL and DUR concentrations. Combinations of filters, modes, and replacement fluid were tested in triplicate at effluent rates of 1, 2 and 3 L/h. The sieving coefficient (SC) for CVVH and the saturation coefficient (SA) for CVVHD were calculated to determine CLTM. Adsorption was measured through a closed loop system bypassing effluent elimination. Multiple linear regression was used to determine SUL and DUR CLTM as a function of ER, filter, and mode. Results SUL and DUR adsorption was minimal at 10% for both drugs. Mean ± standard deviation initial SUL and DUR concentrations were 28.6 ± 2.5 and 27.4 ± 1.9 mg/L, respectively. The overall mean SC/SA across different modes, filters, and ERs was 1.0 and 0.9 for SUL and DUR, respectively. Multiple linear regression demonstrated that the ER was the primary driver (p&amp;lt; 0.001) of CLTM for both drugs based on the equations: SUL CLTM (L/h) = -0.0123 + (1 x ER), R2 = 0.998; DUR CLTM (L/h) = 0.0346 + (0.91 x ER), R2 = 0.958. Conclusion SUL and DUR were efficiently cleared by both CVVH and CVVHD through M100 and HF1400 filters. The clearance of both drugs during CRRT was dependent primarily on the ER. When incorporated into established population pharmacokinetic models, these data can be used to estimate CLTM and devise dosing recommendations for SUL-DUR for patients requiring CRRT. Disclosures Xiaoyi Ye, MD, Sanofi Genzyme: Honoraria David P. Nicolau, PharmD, Allergan: Advisor/Consultant|Allergan: Grant/Research Support|Cepheid: Advisor/Consultant|Cepheid: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Tetraphase: Advisor/Consultant|Tetraphase: Grant/Research Support|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support|Wockhardt: Advisor/Consultant|Wockhardt: Grant/Research Support Joseph L. Kuti, PharmD, bioMeriuex Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Merck &amp; Co, Inc: Grant/Research Support|Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support|Shionogi Inc: Honoraria

Predicting complex kidney drug handling using a physiologically-based pharmacokinetic model informed by biomarker-estimated secretory clearance and blood flow.

Kidney function-adjusted drug dosing is currently based solely on the estimated glomerular filtration rate (GFR), however, kidney drug handling is accomplished by a combination of filtration, tubular secretion, and re-absorption. Mechanistic physiologically-based pharmacokinetic (PBPK) models recapitulate anatomic compartments to predict elimination from estimated perfusion, filtration, secretion, and re-absorption, but clinical applications are limited by a lack of empiric individual-level measurements of these functions. We adapted and validated a PBPK model to predict drug clearance from individual biomarker-based estimates of kidney perfusion and secretory clearance. We estimated organic anion transporter-mediated secretion via kynurenic acid clearance and kidney blood flow (KBF) via isovalerylglycine clearance in human participants, incorporating these measurements with GFR into the model to predict kidney drug clearance. We compared measured and model-predicted clearances of administered tenofovir and oseltamivir, which are cleared by both filtration and secretion. There were 27 outpatients (age 55 ± 15 years, mean iohexol-GFR [iGFR] 76 ± 31 mL/min/1.73 m2 ) in this drug clearance study. The mean observed and mechanistic model-predicted tenofovir clearances were 169 ± 102 mL/min and 163 ± 80 mL/min, respectively; estimated mean error of the mechanistic model was 37.1 mL/min (95% confidence interval [CI]: 24-52.9), compared to a mean error of 41.8 mL/min (95% CI: 25-61.6) from regression model. The mean observed and model-predicted oseltamivir carboxylate clearances were 183 ± 104 mL/min and 179 ± 89 mL/min, respectively; estimated mean error of the mechanistic model was 42.9 mL/min (95% CI: 29.7-56.4), versus error of 48.1 mL/min (95% CI: 31.2-67.3) from the regression model. Individualized estimates of tubular secretion and KBF improved the accuracy of PBPK model-predicted tenofovir and oseltamivir kidney clearances, suggesting the potential for biomarker-informed measures of kidney function to refine personalized drug dosing.