Determination Of Pharmacokinetics Research Articles

Study APV20002: Safety and Efficacy Results Through Week 684 for Pediatric Participants Living with HIV-1 Treated with Ritonavir-Boosted Fosamprenavir Oral Solution-Based Antiretroviral Therapy.

APV20002 was a multicenter, international, open-label study that began in 2003 investigating the pharmacokinetics, efficacy, and safety of ritonavir-boosted fosamprenavir (FPV/r) oral solution (OS) in combination with nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) in participants living with HIV-1 aged 4 weeks to <2 years with a primary endpoint at Week 48 (48W). Participants in APV20002 could continue in the study post-48W until FPV OS was locally available in their countries. Children were required to discontinue after reaching >39 kg or if FPV OS had no clinical benefit. Fifty-nine participants were enrolled; 5/59 received a single FPV OS visit for pharmacokinetic determinations. Most (38/54; 70%) were antiretroviral experienced; 39/59 participants had >48 weeks on treatment, 4/39 of whom discontinued after 48 weeks due to an adverse event (AE). At 48W, 88% of participants had HIV-1 RNA <400 copies/mL by Observed analysis; the proportion with HIV-1 RNA <400 copies/mL remained high (84%-100%) through Week 684. The median CD4+ cell count was 1,235 cells/mm3 [n = 51] at baseline, 1,690 cells/mm3 (n = 41) at Week 48, and 1,280 cells/mm3 (n = 21) at Week 180. From baseline to Week 684, 54/59 (92%) participants had ≥1 treatment-emergent AE regardless of causality; 42/59 (71%) had a treatment-emergent grade 2-4 AE, predominantly maximum toxicity: grade 2; 21/59 (36%) and 21/59 (36%) had severe or grade 3/4 AEs. From baseline to Week 684, 14/54 (26%) participants met virologic failure (VF) criteria, 9/14 before 48W. HIV from 1/9 VFs through 48W developed treatment-emergent reduced susceptibility to FPV and 1/9 to lamivudine/emtricitabine. Post-48W, 4/5 participants with VF had phenotype results; all were still susceptible to all study drugs at VF. In conclusion, FPV OS-based ART was efficacious and generally well tolerated in this long-running pediatric study through 684 weeks of treatment, with a safety profile consistent with experience in adults and older children.

Study APV20002: Safety and Efficacy Results Through Week 684 for Pediatric Participants Living With HIV-1 Treated With Ritonavir-Boosted Fosamprenavir Oral Solution-Based Antiretroviral Therapy.

APV20002 was a multicenter, international, open-label study that began in 2003 investigating the pharmacokinetics, efficacy, and safety of ritonavir-boosted fosamprenavir (FPV/r) oral solution (OS) in combination with nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) in participants living with HIV-1 aged 4 weeks to <2 years with a primary endpoint at Week 48 (48W). Participants in APV20002 could continue in the study post-48W until FPV OS was locally available in their countries. Children were required to discontinue after reaching >39 kg or if FPV OS had no clinical benefit. Fifty-nine participants were enrolled; 5/59 received a single FPV OS visit for pharmacokinetic determinations. Most (38/54; 70%) were antiretroviral-experienced; 39/59 participants had >48 weeks on treatment, 4/39 of whom discontinued after 48 weeks due to an adverse event (AE). At 48W, 88% of participants had HIV-1 RNA <400 copies/mL by Observed analysis; the proportion with HIV-1 RNA <400 copies/mL remained high (84%-100%) through Week 684. The median CD4+ cell count was 1235 cells/mm3 [n=51] at baseline, 1690 cells/mm3 (n=41) at Week 48, and 1280 cells/mm3 (n=21) at Week 180. From baseline to Week 684, 54/59 (92%) participants had ≥1 treatment-emergent AE regardless of causality; 42/59 (71%) had a treatment-emergent grade 2-4 AE, predominantly maximum toxicity: grade 2; 21/59 (36%) and 21/59 (36%) had severe or grade 3/4 AEs. From baseline to Week 684, 14/54 (26%) participants met virologic failure (VF) criteria, 9/14 before 48W. HIV from 1/9 VFs through 48W developed treatment-emergent reduced susceptibility to FPV and 1/9 to lamivudine/emtricitabine. Post-48W, 4/5 participants with VF had phenotype results; all were still susceptible to all study drugs at VF. In conclusion, FPV OS-based ART was efficacious and generally well tolerated in this long-running pediatric study through 684 weeks of treatment, with a safety profile consistent with experience in adults and older children.

Dynamic Interplay of Age and Protein Malnutrition on the Pharmacokinetic Profile of Acetaminophen in Wistar Rats

Abstract Objectives Age and protein malnutrition (PMN) are well-known determinants of drug pharmacokinetics. The combined influence of age and nutrition on the pharmacokinetics of acetaminophen (APAP) remains insufficiently explored; therefore, this study investigates the role of age and PMN on APAP pharmacokinetics. Materials and Methods Wistar rat weanlings were divided into four groups. Groups ND-5 (n = 6) and ND-18 (n = 6) were fed with normal diet (ND, 18% protein) and groups LPD-5 (n = 6) and LPD-18 (n = 6) were fed with low-protein diet (LPD, 10%) for 5 and 18 months, respectively. Blood samples were collected at different time intervals (0, 0.5, 1, 3, 6, 24, 36, and 48 hours), and plasma was separated and analyzed for APAP using high-performance liquid chromatography. Pharmacokinetic data was analyzed by the noncompartmental model using Phoenix WinNonlin 8.3 software. Results The pharmacokinetic parameters of APAP were elevated in both LPD groups compared with their age-matched controls. The average area under the curve was increased by approximately 131% (LPD-5) and 17.57% (LPD-18), and the average maximum plasma concentrations (Cmax) was increased by 33.5% (LPD-5) and 26.3% (LPD-18) compared with their respective age-matched controls. The average mean retention time was approximately 114% (LPD-5) and 17.4% (LPD-18) higher than their respective age-matched controls, whereas the clearance rate (Cl/F) and volume distribution (Vz/F) of the drug were significantly lower. Consequently, there was a 68.5% (ND-5) and 4.73% (ND-18) prolongation in the mean half-life of APAP. Conclusion The altered pharmacokinetics may arise from the intricate interplay of dietary and age influences on physiology, protein binding, and cytochrome P450enzyme activity/expression. However, the exact reason requires further investigation for a better understanding of vulnerable populations.

Derivatization-free determination of chiral plasma pharmacokinetics of MDMA and its enantiomers

3,4-Methylenedioxymethamphetamine (MDMA) is an entactogen with therapeutic potential. The two enantiomers of MDMA differ regarding their pharmacokinetics and pharmacodynamics but the chiral pharmacology of MDMA needs further study in clinical trials. Here, an achiral and an enantioselective high performance liquid chromatography–tandem mass spectrometry method for the quantification of MDMA and its psychoactive phase I metabolite 3,4-methylenedioxyamphetamine (MDA) in human plasma were developed and validated. The analytes were detected by positive electrospray ionization followed by multiple reaction monitoring. The calibration range was 0.5–500 ng/mL for the achiral analysis of both analytes, 0.5–1,000 ng/mL for chiral MDMA analysis, and 1–1,000 ng/mL for chiral MDA analysis. Accuracy, precision, selectivity, and sensitivity of both bioanalytical methods were in accordance with regulatory guidelines. Furthermore, accuracy and precision of the enantioselective method were maintained when racemic calibrations were used to measure quality control samples containing only one of the enantiomers. Likewise, enantiomeric calibrations could be used to reliably quantify enantiomers in racemic samples. The achiral and enantioselective methods were employed to assess pharmacokinetic parameters in clinical study participants treated with racemic MDMA or one of its enantiomers. The pharmacokinetic parameters assessed with both bioanalytical methods were comparable. In conclusion, the enantioselective method is useful for the simultaneous quantification of both enantiomers in subjects treated with racemic MDMA. However, as MDMA and MDA do not undergo chiral inversion, enantioselective separation is not necessary in subjects treated with only one of the enantiomers.

Determination of pharmacokinetics of acetaminophen and assessment of impact to animal health following serial liver biopsies in cynomologus monkeys

Determination of pharmacokinetics of acetaminophen and assessment of impact to animal health following serial liver biopsies in cynomologus monkeys

Interplay of Ritonavir-Boosted Oral Cabazitaxel with the Organic Anion-Transporting Polypeptide (OATP) Uptake Transporters and Carboxylesterase 1 in Mice.

Intravenously administered chemotherapeutic cabazitaxel is used for palliative treatment of prostate cancer. An oral formulation would be more patient-friendly and reduce the need for hospitalization. We therefore study determinants of the oral pharmacokinetics of cabazitaxel in a ritonavir-boosted setting, which reduces the CYP3A-mediated first-pass metabolism of cabazitaxel. We here assessed the role of organic anion-transporting polypeptides (OATPs) in the disposition of orally boosted cabazitaxel and its active metabolites, using the Oatp1a/b-knockout and the OATP1B1/1B3-transgenic mice. These transporters may substantially affect plasma clearance and hepatic and intestinal drug disposition. The pharmacokinetics of cabazitaxel and DM2 were not significantly affected by Oatp1a/b and OATP1B1/1B3 activity. In contrast, the plasma AUC0-120min of DM1 in Oatp1a/b-/- was 1.9-fold (p < 0.05) higher than that in wild-type mice, and that of docetaxel was 2.4-fold (p < 0.05) higher. We further observed impaired hepatic uptake and intestinal disposition for DM1 and docetaxel in the Oatp-ablated strains. None of these parameters showed rescue by the OATP1B1 or -1B3 transporters in the humanized mouse strains, suggesting a minimal role of OATP1B1/1B3. Ritonavir itself was also a potent substrate for mOatp1a/b, showing a 2.9-fold (p < 0.0001) increased plasma AUC0-120min and 3.5-fold (p < 0.0001) decreased liver-to-plasma ratio in Oatp1a/b-/- compared to those in wild-type mice. Furthermore, we observed the tight binding of cabazitaxel and its active metabolites, including docetaxel, to plasma carboxylesterase (Ces1c) in mice, which may complicate the interpretation of pharmacokinetic and pharmacodynamic mouse studies. Collectively, these results will help to further optimize (pre)clinical research into the safety and efficacy of orally applied cabazitaxel.

Importance of Drug Transporters as Determinants of Pharmacokinetics of Drugs

Importance of Drug Transporters as Determinants of Pharmacokinetics of Drugs

Molecular modelling, Synthesis and Antiproliferative Evaluation of New Phenyldiazenyl)-Pyrazol Schiff Base Derivatives

Lung cancer is the most prevalent worldwide. In addition, it is also the most common cause of cancer-related deaths worldwide, with around 1.8 million new cases annually. With a 5-year survival rate of fewer than 20%. Cytotoxic medicines are commonly employed in cancer treatment. Although the medicine improves patients' quality of life, several disadvantages diminish its efficacy. This necessitates developing new effective strategies that target tumors with minimal adverse effects. This research aims to overcome these issues by synthesizing a new series of phenyldiazenyl)-pyrazol schiff base derivatives by utilizing the molecular docking (GOLD) suite program and the pharmacokinetic properties determination by utilizing (Swiss) ADME suite; The most appropriate-fitting compounds were subsequently produced and confirmed using spectrum analysis (FTIR, 1HNMR, and 13 CNMR). MTT in vitro assay were performed to assess of antiproliferative activities against A549 lung cancer cell lines. The antiproliferative study showed that compound 3a had an inhibitory concentration (IC50 of 17.37 µM) on lung cancer cells (A549), which was significantly higher inhibitory activity than Erlotinib (IC50 = 25.06 µM). While compound 3b had an inhibitory activity comparable to the reference drug's, The IC50 values for compounds 3c, 3d, and 3e were 47.48, 45.56, and 33.05 µM, respectively

Discovery of the Aminated Quinoxalines as Potential Active Molecules

Background: In recent years, as the biological activity of the quinoxaline skeleton has been revealed in numerous studies, interest in synthesizing new prototype molecules for the treatment of many chronic diseases, especially cancer, has increased. Methods: The desired alkoxy substituted aminoquinoxalines (AQNX1-9) were synthesized by the reaction of QNX and alkoxy substituted aryl amines such as 2-methoxyaniline, 4-methoxyaniline, 2- ethoxyaniline, 3-ethoxyaniline, 4-ethoxyaniline, 4-butoxyaniline, 2,4-dimethoxyaniline, 3,4- dimethoxyaniline, and 3,5-dimethoxyaniline according to the previously published procedure. QNX was aminated in DMSO at 130°C. We synthesized various alkoxy-substituted aminoquinoxaline compounds (AQNX1-9) and evaluated their anticancer and antimicrobial activities in order to expand the search to related structures. In particular, two aminoquinoxaline (AQNX5 and AQNX6) compounds, coded as NSC D-835971/1 and NSC D-835972/1 by the National Cancer Institute in the USA, were screened for anticancer screening at a dose of 10-5 M on a full panel of 60 human cell lines obtained from nine human cancer cell types (leukemia, melanoma, non-small cell lung, colon, central (nervous system, ovarian, kidney, prostate, and breast cancer). objective: Therefore, we synthesized various alkoxy-substituted aminoquinoxaline compounds (AQNX1-9) and evaluated their anticancer and antimicrobial activities in order to expand the search to related structures. Results: Further in silico studies were also conducted for the compound AQNX5 (NSC D- 835971/1), which was found to be the most active antiproliferative agent, especially against leukemia cell lines. Molecular docking studies showed that AQNX5 interacted with Glu286 and Lys271 through hydrogen bonding and π-stacking interaction in the ATP binding region of Abl kinase, which is indicated as a potential target of leukemia. Besides, AQNX5 occupied the minor groove of the double helix of DNA via π-stacking interaction with DG-6. method: Especially, the two aminoquinoxalines (AQNX5 and AQNX6) with the NCI codes NSC D-835971/1 and NSC D-835972/1 selected by NCI, USA, were screened for anticancer screening at a 10-5 M dose in the full panel of 60 human cell lines derived from nine human cancer cell types (leukemia, melanoma, non-small-cell lung, colon, central nervous system, ovarian, renal, prostate, and breast cancer) at the NIH, Bethesda, Maryland, USA. Conclusion: According to in silico pharmacokinetic determination, AQNX5 was endowed with drug-like properties as a potential anticancer drug candidate for future experiments. In the light of these findings, more research will focus on aminated quinoxalines' ability to precisely target leukemia cancer cell lines. conclusion: In the light of these findings, more research will focus on aminated quinoxalines&amp;#039; ability to precisely target leukemia cancer cell lines.

Lead to hit ruthenium-cyclopentadienyl anticancer compounds: Cytotoxicity against breast cancer cells, metabolic stability and metabolite profiling

The successful choice of hit compounds during drug development programs involves the integration of structure-activity relationship (SAR) studies with pharmacokinetic determinations, including metabolic stability assays and metabolite profiling.A panel of nine ruthenium-cyclopentadienyl (RuCp) compounds with the general formula [Ru(η5-C5H4R)(PPh3)(bipyR')]+ (with R = H, CHO, CH2OH; R' = H, CH3, CH2OH, CH2Biotin) has been tested against hormone-dependent MCF-7 and triple negative MDA-MB-231 breast cancer cells. In general, all compounds showed important cytotoxicity against both cancer cell lines and were able to inhibit the formation of MDA-MB-231 colonies in a dose-dependent manner, while showing selectivity for cancer cells over normal fibroblasts. Among them, four compounds stood out as lead structures to be further studied. Cell distribution assays revealed their preference for the accumulation at cell membrane (Ru quantification by ICP-MS) and the mechanism of cell death seemed to be mediated by apoptosis. Potential structural liabilities of lead compounds were subsequently flagged upon in vitro metabolic stability assays and metabolite profiling. The implementation of this integrated strategy led to the selection of RT151 as a promising hit compound.

The effects of formulation on the pharmacokinetics of itraconazole and amiodarone in dogs after oral administration of a combination product, commercial products, and compounded products.

This study evaluated four different formulations of itraconazole and amiodarone. Formulation 1 was Vida's combination tablet containing both active pharmaceutical ingredients (APIs). Formulation 2 was separate, commercially available human generic capsules and tablets of itraconazole and amiodarone, respectively. Formulation 3 was separate, compounded suspensions of itraconazole and amiodarone. Formulation 4 was a compounded chewable tablet of itraconazole. Eight female dogs were dosed with 5 mg/kg of itraconazole and 15 mg/kg amiodarone (except for formulation 4, which only received 5 mg/kg itraconazole) once weekly for 4 weeks using a modified Latin Square design, ensuring that all dogs received all formulations with a 7-day washout between treatments. Animals were fasted overnight prior to each dose administration, with food returned to all animals 4 h post-dose. Blood samples (3 mL) were collected pre-treatment (0) and at appropriate time points over 72 h after each dose for a total of 14 samples per dog per treatment. There was high variability in the serum concentration data within treatment groups for itraconazole. The compounded suspensions were difficult to dose due to the nature of the formulations. The volumes dosed were accurate and consistent, but the suspension was thin and settled immediately when shaking was stopped for both itraconazole and amiodarone. All serum samples following itraconazole chewable tablet administration were not detectable or just above itraconazole's LOQ and thus did not allow for pharmacokinetic determination.

Molecular Imaging to Study Antimicrobial Pharmacokinetics In Vivo.

While antimicrobials are among the most prescribed drugs, the use of some older antibiotics is not optimized for efficacy in terms of dosage, route of administration, and duration of therapy. Knowledge gaps exist regarding the heterogeneous microenvironments within different infected tissues consisting of varying bacterial loads, immune responses, and drug gradients. Positron-emission tomography-based imaging, where radiolabeled drugs are visualized within the living body, enables accurate, holistic, and real-time determination of pharmacokinetics to provide valuable, actionable data to optimize antibiotic use. Here we briefly review the concepts, history, and recent progress in the field.

Pharmacokinetics of Cannabidiol: A Systematic Review and Meta-Regression Analysis.

Background: In this review, we provide an updated assessment of available evidence on the pharmacokinetics (PK) of CBD and explore the impact of different factors on PK outcomes. Materials and Methods: This systematic review and meta-regression analysis was preregistered (PROSPERO: CRD42021269857). We systematically searched Medline, Embase, PsycInfo, and Web of Science Core Collection up to November 19, 2022. Trials of CBD in healthy adults were included if they reported at least one of the PK parameters of interest, including Tmax, Cmax, AUC0-t, AUC0-inf, and T1/2, in serum or plasma. Studies of patient populations or CBD co-administration with other medications were excluded. The National Heart, Lung, and Blood Institute's Quality Assessment Tool for Before-After Studies with no Control Group was used. Random-effects multivariable meta-regression analysis was conducted. Results: A total of 112 trial arms from 39 studies were included; 26 trial arms had a "Good" quality, 70 "Fair," and 16 "Poor." Eight arms used inhalation CBD, 29 oromucosal, 73 oral, and 2 intravenous. CBD formulations could be categorized to nanotech (n=14), oil-based (n=21), alcohol-based (n=10), water-based (n=12), Sativex (n=17), and Epidiolex® (n=22). For single-dose studies, CBD doses ranged between 2 and 100 mg in inhalation, 5-50 mg in oromucosal, and 0.42-6000 mg in oral administration. Sixty-six trial arms had only male participants or a higher number of male than female participants. The duration of the PK session was between 4 and 164 h. A higher CBD dose was associated with higher Cmax, AUC0-t, and AUC0-inf. Compared with oral administration, oromucosal administration was associated with lower Cmax, AUC0-t, and AUC0-inf. Fed status was associated with higher Cmax and AUC0-t when compared with the fasting status. A higher ratio of female participants was associated with lower Tmax in oral administration and higher Cmax. Conclusion: As expected, CBD dose, route of administration, and diet were major determinants of CBD PK with oral routes providing higher bioavailability and nanotechnology formulations a faster onset. Although CBD appeared to have a faster onset and longer duration in women, more studies are required to delineate the role of biological sex. Factors that influence CBD PK have implications for medication development and appropriate dosing in clinical practice.

Population Pharmacokinetic Modeling and Determination of Individual Exposure to Avalglucosidase Alfa in Adolescent and Adult Patients With Late-Onset Pompe Disease: Analysis of Pooled Data From Phase I to III Clinical Trials.

Pompe disease is a rare genetic disorder caused by a deficiency of a lysosomal enzyme called acid alpha-glucosidase and is classified into infantile and late-onset forms. Since 2006, an enzyme replacement therapy involving alglucosidase alfa has been available. In 2021, a new enzyme replacement therapy involving avalglucosidase alfa demonstrated improved clinical benefits. In this article, the authors describe the pharmacokinetics of avalglucosidase alfa using a population pharmacokinetic approach. The population pharmacokinetic model was developed using a data set that included 75 patients and 2042 plasma drug concentrations determined through enzymatic activity assay from 3 studies (phases I/II and III) and involved 3 dose levels (5, 10, and 20 mg/kg). The analysis was performed using NONMEM software. Two sequences were observed in the plasma drug concentration profile: the first kinetic driving exposure, and after 12 hours postdose, a slight rebound addressing very low concentrations that lasted up to 2 weeks. Following model screening, a model with a central compartment with parallel linear and nonlinear elimination and 2 concatenated peripheral compartments was proposed. A putative back-redistribution of a marginal fraction of the drug from the second peripheral compartment to the central compartment may explain the slight rebound in concentration. The final model's mean bias and precision for individual predictions were -2.66% and 30.7%, respectively, and -0.433% and 38.9%, respectively, for population predictions. A concatenated 3-compartment model was developed to describe the avalglucosidase alfa concentrations in patients with late-onset Pompe disease. None of the covariates tested could explain the interindividual variability.

Daptomycin Exposure as a Risk Factor for Daptomycin-Induced Eosinophilic Pneumonia and Muscular Toxicity.

High-dose daptomycin is increasingly used in patients with bone and joint infection (BJI). This raises concerns about a higher risk of adverse events (AEs), including daptomycin-induced eosinophilic pneumonia (DIEP) and myotoxicity. We aimed to examine pharmacokinetic and other potential determinants of DIEP and myotoxicity in patients with BJI receiving daptomycin. All patients receiving daptomycin for BJI were identified in a prospective cohort study. Cases were matched at a 1:3 ratio, with controls randomly selected from the same cohort. Bayesian estimation of the daptomycin daily area under the concentration-time curve over 24 hours (AUC24h) was performed with the Monolix software based on therapeutic drug monitoring (TDM) data. Demographic and biological data were also collected. Risk factors of AEs were analyzed using Cox proportional hazards model. From 1130 patients followed over 7 years, 9 with DIEP, 26 with myotoxicity, and 106 controls were included in the final analysis. Daptomycin AUC24h, C-reactive protein, and serum protein levels were associated with the risk of AEs. The adjusted hazard ratio of DIEP or myotoxicity was 3.1 (95% confidence interval [CI], 1.48-6.5; P < .001) for daptomycin AUC24h > 939 mg/h/L, 9.8 (95% CI, 3.94-24.5; P < .001) for C-reactive protein > 21.6 mg/L, and 2.4 (95% CI, 1.02-5.65; P = .04) for serum protein <72 g/L. We identified common determinants of DIEP and myotoxicity in patients with BJI. Because the risk of AEs was associated with daptomycin exposure, daptomycin TDM and model-informed precision dosing may help optimize the efficacy and safety of daptomycin treatment in this setting. A target AUC24h range of 666 to 939 mg/h/L is suggested.

Determination of milk concentrations and pharmacokinetics of salicylic acid following acetylsalicylic acid (aspirin) administration in postpartum dairy cows

The objectives of this descriptive study were to 1) describe the pharmacokinetics of salicylic acid (SA) in the milk and plasma of postpartum dairy cattle following oral administration of ace­tylsalicylic acid (ASA) (aspirin); 2) to estimate a recommended milk withdrawal period for dairy cattle treated with ASA; and 3) to determine the impact of ASA administration on plasma prostaglandin E2 metabolite (PGEM) concentrations. Adminis­tration of non-steroidal anti-inflammatory drugs, such as the widely available drug aspirin, or acetylsalicylic acid (ASA), may improve health and milk production in postpartum dairy cows. However, plasma pharmacokinetic data for salicylic acid (SA), the active metabolite of ASA, are unrepresentative of lactating dairy cows and current treatment regimens, and there are cur­rently no published milk residue and minimal pharmacody­namic data available for ASA or SA in dairy cows.

Higher abatacept exposure after transplant decreases acute GVHD risk without increasing adverse events

AbstractIn the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 μg/mL. However, a higher Ctrough_1 (≥39 μg/mL, attained in ∼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough_1 <39 μg/mL associated with GR2-4 aGVHD risk indistinguishable from placebo (P = .37). Importantly, no significant association was found between Ctrough_1 and key safety indicators, including relapse, and cytomegalovirus or Epstein-Barr virus viremia. These data demonstrate that a higher abatacept Ctrough_1 (≥39 μg/mL) was associated with a favorable GR2-4 aGVHD risk, without any observed exposure-toxicity relationships. This trial was registered at www.clinicaltrials.gov as #NCT01743131.

Pharmacogenomic markers of metoprolol and α-OH-metoprolol concentrations: a genome-wide association study.

Aim: Few genome-wide association studies (GWASs) have been conducted to identify predictors of drug concentrations. The authors therefore sought to discover the pharmacogenomic markers involved in metoprolol pharmacokinetics. Patients & methods: The authors performed a GWAS of a cross-sectional study of 993 patients from the Montreal Heart Institute Biobank taking metoprolol. Results: A total of 391 and 444 SNPs reached the significance threshold of 5×10-8 for metoprolol and α-OH-metoprolol concentrations, respectively. All were located on chromosome 22 at or near the CYP2D6 gene, encoding CYP450 2D6, metoprolol's main metabolizing enzyme. Conclusion: The results reinforce previous findings of the importance of the CYP2D6 locus for metoprolol concentrations and confirm that large biobanks can be used to identify genetic determinants of drug pharmacokinetics at a GWAS significance level.

O46 | Determination of pharmacokinetics of doxycycline in broilers with Escherichia coli infection and kept under field conditions

Journal of Veterinary Pharmacology and TherapeuticsVolume 46, Issue S1 p. 50-50 ORAL PRESENTATIONS O46 | Determination of pharmacokinetics of doxycycline in broilers with Escherichia coli infection and kept under field conditions First published: 11 June 2023 https://doi.org/10.1111/jvp.13212Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume46, IssueS1Special Issue: 15th International Congress of the European Association for Veterinary Pharmacology and Toxicology held Bruges, Belgium, July 2–5, 2023June 2023Pages 50-50 RelatedInformation

Abstract 5060: Tucatinib does not alter oxaliplatin PK or associated renal function: An OCT2 and MATE transport inhibition study

Abstract Background: Oxaliplatin (OX)-containing regimens are frequently utilized to treat gastrointestinal (GI) cancers. OX is eliminated predominately via urinary excretion (GFR and active tubular secretion). The contribution of active transport via OCT2 and MATE1/2-K to OX clearance is not fully understood. Tyrosine kinase inhibitors (TKIs) are frequently found to interact with OCT2/MATE transporters; however, a gap in knowledge remains between their clinical potential to impact OX pharmacokinetics (PK) and in turn, impact renal function. Tucatinib (TUC) is a highly selective human epidermal growth factor receptor 2 (HER2)-directed TKI approved in multiple regions in combination with trastuzumab and capecitabine for adult patients with metastatic HER2+ breast cancer and is currently being investigated in other HER2+ tumors. TUC inhibits OCT2/MATE-mediated transport of metformin and creatinine in vitro and in vivo. In this study, we investigated the impact of TUC on OX plasma PK, OX renal clearance (Clr), and renal function. Methods: In vitro inhibition of OCT2/MATE-mediated transport of OX by TUC was assessed in OCT2, MATE1, or MATE2-K-expressing MDCK-II cells. SGNTUC-024 (NCT04430738) is a Ph1b/2 clinical study in patients with HER2+ GI cancers evaluating the impact of TUC on the safety and PK of OX. Patients received TUC 150 mg (Cohort 1A) or 300 mg (Cohort 1B) BID starting on C1D8 of a 2-week cycle in combination with modified FOLFOX6/7. Intensive PK was collected in plasma and urine for OX alone (C1D1) or with steady-state TUC (C2D1). Total plasma platinum (Pt, analyzed as a surrogate for OX and catabolites), plasma Pt ultrafiltrate (PUF, unbound), and urine Pt were quantitatively analyzed via ICP-MS. Serum Cystatin C (CysC) was measured as a pharmacodynamic (PD) renal function marker in Cohorts 1A and 1B. Results: TUC inhibited in vitro OX transport by MATE1 (IC50 = 0.0639 µM), MATE2-K (IC50 = 0.0382 µM), and OCT2 (IC50 = 0.491 µM). In 11 patients, total Pt and PUF AUC0-8h geometric mean ratio (GMR) and 90% confidence intervals (CI) between patients who received OX alone compared to in combination were 1.1 (0.98, 1.3) and 1.0 (0.78, 1.4) in Cohort 1A (n=4) and 1.1 (0.96, 1.2) and 1.0 (0.98, 1.1) in Cohort 1B (n=7), respectively. OX GM (%CV) renal clearance (Clr,0-8h in mL/min) and fraction excreted 24h post-dose (fe,0-24h) were similar with and without TUC in both Cohort 1A (C1D1 Clr0-8h = 277 (33), fe,0-24h = 22% (17); C2D1 Clr0-8h = 249 (78), fe,0-24h = 21% (15)) and Cohort 1B (C1D1 Clr0-8h = 189 (37), fe,0-24h = 17.7% (16); C2D1 Clr0-8h = 177 (40), fe,0-24h = 16.6% (35)). Reversible slight increases in CysC (normalized to baseline) on day 3 of each cycle, irrespective of tucatinib, were observed. Conclusions: This investigation of in vitro and in vivo determinants of OX PK demonstrates that TUC does not alter the renal clearance of oxaliplatin nor renal function when OX is administered in combination with TUC. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, Vineet Kumar, Michelle Ubowski, JoAl G. Mayor, Layth I. Abdulrasool, Clark M. Henderson, Joseph A. Ware, Christopher J. Endres. Tucatinib does not alter oxaliplatin PK or associated renal function: An OCT2 and MATE transport inhibition study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5060.