Pharmacokinetic Relationships Research Articles

Approval of Mycophenolate Mofetil for Prophylaxis of Organ Rejection in Pediatric Recipients of Heart or Liver Transplants: A Regulatory Perspective.

On June 6, 2022, the FDA expanded the indications for mycophenolate mofetil (MMF) to include the prophylaxis of organ rejection in combination with other immunosuppressants in pediatric recipients of allogeneic heart or liver transplants aged 3 months and older. The approved oral dosing regimen for these patients was a starting dose of 600 mg/m2 with titration up to a maximum of 900 mg/m2 twice daily. Data to support efficacy in pediatric patients were derived from established pharmacokinetic (PK) relationships across approved populations, a PK study in pediatric liver transplant recipients, and information from the Scientific Registry of Transplant Recipients database. Information supporting safety was based on comparing mycophenolic acid (MPA) exposure with that in pediatric kidney transplant recipients, the published literature, and post-marketing safety reports. Efficacy in pediatric patients was established based on extrapolation of efficacy from studies in adult liver, adult heart, and pediatric kidney transplant populations, and similarity in MPA exposure between pediatric and adult patients. Review of the data supported an oral dosing regimen for pediatric heart transplant and liver transplant recipients consisting of a starting dose of 600 mg/m2 up to a maximum of 900 mg/m2 b.i.d. A dosage range for MMF is recommended recognizing that the MMF dose may be modified in clinical practice for myriad factors. The dosage recommendations in the labeling for pediatric liver and pediatric heart transplant patients are intended to permit individualized dosing based on clinical assessment of these factors.

Challenging the status quo: a framework for mechanistic and human-relevant cardiovascular safety screening.

Traditional approaches to preclinical drug safety assessment have generally protected human patients from unintended adverse effects. However, these assessments typically occur too late to make changes in the formulation or in phase 1 and beyond, are highly dependent on animal studies and have the potential to lead to the termination of useful drugs due to liabilities in animals that are not applicable in patients. Collectively, these elements come at great detriment to both patients and the drug development sector. This phenomenon is particularly problematic in the area of cardiovascular safety assessment where preclinical attrition is high. We believe that a more efficient and translational approach can be defined. A multi-tiered assessment that leverages our understanding of human cardiovascular biology, applies human cell-based in vitro characterizations of cardiovascular responses to insult, and incorporates computational models of pharmacokinetic relationships would enable earlier and more translational identification of human-relevant liabilities. While this will take time to develop, the ultimate goal would be to implement such assays both in the lead selection phase as well as through regulatory phases.

Nonlinear Pharmacokinetics of Topical Flurbiprofen Gel in a Phase I Study Among Chinese Healthy Adults.

PDX-02 (Flurbiprofen sodium) is a topical nonsteroidal anti-inflammatory drug in gel formulation for local analgesia and anti-inflammation. A Phase I clinical trial was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of PDX-02 gel in Chinese healthy adults. The trial comprised three parts: (1) a single-dose ascending study with three dose levels (0.5%, 1% to 2% PDX-02 gel) applied on a 136 cm2 skin area; (2) a multiple-dose study with either 1% or 2% PDX-02 gel applied on a 136 cm2 skin area for 7 consecutive days; and (3) a high dose group with 2% PDX-02 gel on an 816 cm2 skin area and a frequent multiple dose group with 2% PDX-02 gel on a 272 cm2 skin area four times a day for 7 consecutive days. The safety, tolerability and pharmacokinetics of the PDX-02 gel were evaluated in each part. A total of sixty participants completed the trial, with all adverse events recovered and all positive skin reaction being transient and recovered. The overall absorption of topical PDX-02 gel was slow with a mean peak time exceeding 9h. The elimination rate remained consistent between dose groups. A less-than-dose-proportional nonlinear pharmacokinetics relationship was observed within the studied dose range, and this is likely due to the autoinduction of skin first-pass metabolism. The topical PDX-02 gel showed favorable safety and tolerability in both single and multiple dosing studies, with a less-than-dose-proportional nonlinear pharmacokinetics observed.

Research progress on chemical constituents and pharmacological effects of Glechomae Herba and prediction of its Q-markers

Glechomae Herba, the dried aerial part of Glechoma longituba(Labiatae), has the effects of promoting urination, draining dampness, and relieving stranguria. It has received wide attention in recent years owing to the satisfactory efficacy on lithiasis. Amid the in-depth chemical and pharmacological research, it has been found that Glechomae Herba has antibacterial, anti-inflammatory, antioxidant, antithrombotic, hepatoprotective, cholagogic, antitumor, hypoglycemic, and lipid-lowering effects. The main chemical constituents are volatile oils, flavonoids, terpenoids, phenylpropanoids, and organic acids. This paper summarized the chemical constituents and pharmacological effects of Glechomae Herba. Based on genetic relationship of plants, the characteristics, efficacy, and pharmacokinetics of the chemical constituents, and the potential of these constituents as quality markers(Q-markers), it was summed up that ursolic acid, caffeic acid, rosmarinic acid, luteolin-7-O-diglucuronide, apigenin, apigenin-7-O-diglucuronide, apigetrin, and glechone can be the candidate Q-markers of Glechomae Herba.

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial.

Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation. This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II. Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each). Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.

Stereoselective interaction of tolvaptan with amiodarone under racemic metabolic impact by CYP3A5 genotypes in heart failure patients.

The diuretic effect of tolvaptan is largely blood level-dependent although it does exhibit interindividual differences according to cytochrome P450 (CYP) 3A5 genotype. This study aimed to investigate the pharmacokinetic relationship between plasma tolvaptan and its monohydroxylate enantiomers and the factors affecting their metabolism in heart failure patients. Japanese heart failure patients (n = 88) receiving oral tolvaptan (median dosage 7.5mg/day) were enrolled. Blood samples were collected prior to the dosing on day 6 or later after first administration to determine the plasma concentrations of tolvaptan and its monohydroxylate enantiomers. Gene polymorphisms of CYP3A5, carbonyl reductase (CBR) 1/3, and ATP-binding cassette subfamily B member (ABCB) 1 were analyzed for their impact on tolvaptan pharmacokinetics. Serum laboratory test values and concomitant use of amiodarone were evaluated as factors related to tolvaptan metabolism. The median of the sum of the 5S- and 5R-tolvaptan plasma concentrations was 48.9 (range, 15.3-100) ng/mL. CYP3A5 genotypes significantly affected the concentration ratio of all enantiomeric metabolites to tolvaptan, while the other metabolic-related gene polymorphisms had no influence. A negative correlation was found between serum albumin and the enantiomeric ratio of tolvaptan and monohydroxylate DM-4111. Concomitant use of amiodarone increased the plasma levels of whole tolvaptan but significantly decreased the metabolic ratios of 5R-tolvaptan. 5S-tolvaptan was selectively synthesized from ketone MOP-21826 by CBR1 with a substantially smaller reaction velocity compared to tolvaptan monohydroxylation by CYP3A4/5. This study clarified the racemic impact of CYP3A5 genotypes on tolvaptan metabolism. Amiodarone may stereoselectively interact with R-forms rather than S-forms of tolvaptan.

Abstract B027: Modeling the emergence of therapy resistance with fitness seascapes

Abstract One approach to the study of therapy resistance is through an evolutionary lens, where novel sub-types emerge through a random process and are selected for by an increased fitness. Computational models are used to understand the parameter spaces that facilitate resistance, optimize therapy regimens, and predict the evolutionary trajectory. Fitness landscapes are structures that map genotype to fitness and are commonly used in computational models of evolution. Most fitness landscape models assume the environment is constant. However, this obscures evolutionary trade-offs that depend on environmental change, i.e., where a resistant mutant trades a lower growth rate in the absence of drug in exchange for drug resistance. Furthermore, a disease agent population in a patient will never experience a constant drug concentration; the drug concentration will vary according to pharmacokinetic effects and spatial relationships to blood vessels. Here, we explored fitness seascapes as an extension to fitness landscapes. Fitness seascapes model a variable genotype-phenotype mapping. In this work, we used fitness seascapes that map genotypes to drug dose-response curves. In contrast to fitness landscapes, the fitness rank-order of genotypes changes as a function of drug concentration, representing evolutionary tradeoffs. Using a novel computational platform, we showed that modeling evolutionary tradeoffs with fitness seascapes dramatically impacted the evolutionary trajectory of a population subject to changing drug concentrations. We also showed how mutant selection windows, a commonly studied structure in evolutionary medicine, are embedded in fitness seascapes. Using an empirical fitness seascape measured in genetically engineered S. cerevisiae, we then explored the utility of fitness seascapes in two in silico experiments. In the first experiment, we subjected an evolving population to varying rates of change of drug concentration, finding that populations experiencing a lower rate of change were more likely to become resistant, while those experiencing a higher rate of change were more likely to go extinct. This aligns with similar previously published in vitro experiments. Next, we simulated patients undergoing therapy with varying levels of drug regimen nonadherence using a pharmacokinetic model. We found that a higher rate of drug regimen nonadherence was associated with a higher rate of resistance, while a higher rate of adherence was associated with a higher rate of elimination of the disease agent. Future work may reveal patterns of nonadherence that promote resistance. Here, we have demonstrated the utility of fitness seascapes in studying resistance. Our results highlight the importance of evolutionary trade-offs when modeling the emergence of resistance under varying drug concentrations. These results have implications for diseases across kingdoms, including viral and bacterial infections and cancer. In the future, fitness seascapes may be used to optimize drug dosing regimens or understand differences in metabolism in silico. Citation Format: Eshan S. King, Emily Dolson, Jacob G. Scott. Modeling the emergence of therapy resistance with fitness seascapes [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B027.

Enteropathogen spectrum and effect on antimycobacterial pharmacokinetics among children with tuberculosis in rural Tanzania: a prospective cohort study

SummaryBackgroundEnteropathy is prevalent in tuberculosis-endemic areas, and it has been shown to impair intestinal absorptive function; therefore, enteropathogen burden might negatively affect antimycobacterial pharmacokinetics, particularly among malnourished children. We sought to quantify enteropathogen burden among children initiating tuberculosis treatment in rural Tanzania and determine the effect of enteropathogen burden on serum antimycobacterial pharmacokinetics.MethodsWe performed a prospective cohort study at one site in rural Tanzania as an exploratory substudy of a large multicountry cohort study. We included children younger than 15 years of age with confirmed or probable tuberculosis undergoing treatment with first-line tuberculosis therapy; children were excluded from the study if they were unable to undergo sample collection. Participants were consecutively recruited from the inpatient paediatric wards or the outpatient tuberculosis clinic at Haydom Lutheran Hospital, Tanzania. The main outcome was to quantify symptomatic enteropathogen burden and the effect on serum antimycobacterial pharmacokinetics. We quantified enteropathogen burden (defined as the sum of distinct enteropathogens detected in stool) using a multipathogen PCR capable of simultaneous detection of 37 bacterial, viral, and parasitic species or species groups from stool collected within 72 h of treatment initiation. Comprehensive clinical assessment, including presence of gastrointestinal symptoms, was performed at baseline, and serum was collected approximately 2 weeks after treatment initiation at steady state and throughout the dosing interval with concentrations of isoniazid, rifampicin, pyrazinamide, and ethambutol measured by liquid chromatography with a tandem mass spectrometry assay to quantify peak (Cmax) and total area under the concentration curve (AUC0–24), as determined by non-compartmental analysis. Enteropathogen burden was compared with pharmacokinetic measurements using bivariable and multivariable linear regression.Findings58 children were assessed for eligibilty and enrolled between June 25, 2016, and Feb 6, 2018; 44 had complete stool testing and serum pharmacokinetic data, and they were included in the analyses. 20 (45%) were female, and 24 (55%) were male. 37 (84%) had moderate or severe malnutrition. A mean of 2·1 (SD 1·3) enteropathogens were detected per participant. Target peak concentrations of rifampicin were reached in eight (18%) of 44 participants, isoniazid in 24 (54%) of 44 participants, pyrazinamide in 28 (74%) of 38 participants, and ethambutol in six (15%) of 39 participants. Compared with controlled comparisons, each summative additional bacterial enteropathogen detected was associated with a 40% lower rifampicin Cmax (95% CI −62 to −5) and a 36% lower ethambutol Cmax (−52 to −14), while viral pathogens were associated with a 51% lower isoniazid Cmax (−75 to −7). The combination of gastrointestinal symptoms and detection of an additional enteropathogen was associated with a 27% reduction in rifampicin AUC0–24 (95% CI −47 to −1).InterpretationTanzanian children undergoing tuberculosis treatment rarely attained pharmacokinetic targets; enteropathogen carriage was common and enteropathogen burden was associated with significant reductions in the concentrations of some antimycobacterial drugs. Further research should explore mechanistic relationships of individual pathogens and antimycobacterial pharmacokinetics in larger cohorts, or determine if screening for and treating enteropathogens at tuberculosis treatment initiation improves pharmacokinetic target attainment.FundingNational Institute of Allergy and Infectious Diseases, National Institutes of Health.

Relationship of pharmacokinetics and pharmacodynamics to apitegromab efficacy in patients with later-onset spinal muscular atrophy (Types 2 and 3 SMA): Results from the TOPAZ study

Apitegromab is an investigational, fully human, monoclonal antibody that inhibits myostatin activation by specific binding to myostatin proforms, promyostatin and latent myostatin. We will present data, from the Phase 2 TOPAZ clinical trial (NCT03921528), on the relationships of pharmacokinetics (PK) and pharmacodynamic (PD) (marker of target engagement, latent serum myostatin levels) to apitegromab efficacy.

Relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with systemic lupus erythematosus.

ObjectivesTo characterize the relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with moderate to severe SLE despite standard therapy, using pooled data from two phase 3 trials.MethodsTULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (every 4 weeks for 48 weeks). For the exposure–response analysis, BILAG-based Composite Lupus Assessment (BICLA) or SLE Responder Index [SRI(4)] response rates at week 52 in each quartile/tertile of average anifrolumab serum concentration (Cave) were compared for anifrolumab and placebo in all-comers, patients who completed treatment, and IFN gene signature (IFNGS)-high patients who completed treatment, using average marginal effect logistic regression. Relationships between exposure and key safety events were assessed graphically.ResultsOf patients in TULIP-1/TULIP-2 who received anifrolumab (150 mg, n = 91; 300 mg, n = 356) or placebo (n = 366), 574 completed treatment, of whom 470 were IFNGS high. In the exposure–efficacy analyses, BICLA and SRI(4) treatment differences favouring anifrolumab 300 mg vs placebo were observed across Cave subgroups and all analysis populations. Logistic regression identified Cave as a significant covariate for predicted BICLA response, as higher anifrolumab Cave predicted greater efficacy. There was no evidence of exposure-driven incidence of key safety events through week 52 in patients receiving anifrolumab 150 or 300 mg.ConclusionWhile higher Cave predicted greater efficacy, consistent positive benefit favouring anifrolumab 300 mg vs placebo was observed in BICLA and SRI(4) responses across Cave subgroups in the TULIP trials. There was no evidence of exposure-driven safety events.ClinicalTrial.gov numbersNCT02446912, NCT02446899

High-Trough Plasma Concentration of Afatinib Is Associated with Dose Reduction.

Simple SummaryAfatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). We examined the relationship between the trough plasma concentrations of afatinib and adverse effects, including diarrhea, rash, stomatitis and mucositis. The dose reduction of afatinib was associated with the trough plasma concentration of afatinib in this paper. As a result, we clarified that a higher trough plasma concentration induced adverse events, and there was a threshold to reduce the dosage or not. Monitoring plasma concentrations of afatinib is useful to predict the adverse effects of afatinib and to support quality of life in patients with EGFR-mutated advanced NSCLC.Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, p = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy.

Abstract 2451: A novel single domain antibody targeting TIGIT for cancer use in combination therapies

Abstract T-cell immunoglobulin and ITIM domains (TIGIT) has emerged as another popular checkpoint receptor that negatively regulates T-cell functions. TIGIT is upregulated by immune cells, such as activated T cells, natural killer cells, and regulatory T cells. TIGIT binds to two ligands, CD155 (PVR) and CD112 (PVRL2, nectin-2), that are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment. Beyond CTLA4 and PD1, TIGIT therapies recently demonstrated great combo potential in the clinic along with well-tolerated toxicity profile. Here we present HLX53, a novel single domain antibody (sdAb) targeting TIGIT with differentiated format, binding epitope, and functional activity. HLX53 binds to TIGIT and blocks CD155 and CD112 with sub-nanomolar affinity. In mixed lymphocyte reaction assay (MLR), HLX53 significantly increased IL2 secretion compared to Tiragolumab and Vibostolimab analogues. HLX53's IL2 induction seems to require an adequate bridging effect between T-cell and antigen-presenting cell via Fc-FcγR engagement, further promoting the maturation of antigen-specific T-cell. In vivo, HLX53 exhibits a better tumor inhibition than Tiragolumab analogue and shows synergy in combination with anti-PD-L1 antibody in MC38 model. In addition to its unique epitope/MOA, HLX53 being a sdAb has a shorter half-life and thus potentially a better tumor penetration and a differentiated PK/PD profile. Understanding pharmacokinetic and pharmacodynamic relationships enables a dosing regimen providing adequate target coverage and superior tumor eradication. Citation Format: Botong Hua, Ming Yang, Jie Xue, Chen Dong, Yi-Ting Mao, Ou Li, Eric Cheung, Hassan Issafras, Wenfeng Xu, Weidong Jiang. A novel single domain antibody targeting TIGIT for cancer use in combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2451.

Pharmacokinetic relationships in psychotropic drugs effects

The review discusses relationships between pharmacokinetic parameters and effects of psychotropic drugs, both in preclinical studies and clinical practice. The identification of such correlations can serve as a basis for understanding the complex system of relationships between pharmacokinetic and pharmacodynamic mechanisms in the manifestation of the action of this group of drugs and allows us to use the data of pharmacokinetic studies to optimize therapeutic approaches in medical practice.

Modeling relationship of pharmacokinetics, in vitro potency, and α4β7 receptor occupancy with intestinal cell trafficking in a gut-homing mouse model of IBD with MORF-057

Abstract Objective: MORF-057 is an orally bioavailable, selective, and potent small molecule inhibitor of α4β7 integrin being developed for inflammatory bowel diseases (IBD) that is currently in phase 1 clinical testing. We have previously presented work that characterized its nonclinical pharmacologic profile. The current study integrates data to generate a pharmacokinetic (PK) and pharmacodynamic (PD) model of MORF-057. Methods: To determine in vivo potency, MORF-057 was tested in murine gut homing assays and the PD response was determined relative to the non-protein bound drug in mouse plasma. A cell adhesion assay (CAA) for α4β7 was refined to enable detection of picomolar-level sensitivity. Murine receptor occupancy (RO) assays for α4β7 and α4β1 were established under physiologic conditions, and MORF-057 was evaluated for its potency and selectivity in fresh mouse whole blood. These datasets were used to build and validate predictive models of PD response. Results: MORF-057 strongly inhibited the homing of α4β7hi cells to murine gut lymphoid tissues with an IC90 of 7.9 nM. MORF-057 showed high potency in CAA with an IC90 of 8.8 nM. Similarly, RO assays confirmed MORF-057 to be a highly potent inhibitor of α4β7 in mouse whole blood with an IC90 of 20.5 nM and over 1500-fold selectivity vs. α4β1. The predictive models built upon these datasets revealed a strong PK-PD relationship of α4β7 inhibitors in vivo. Conclusions: We observed consistently high potency of MORF-057 across multiple assay platforms. Integrated modeling based on these assays, particularly the RO assay, successfully predicted the PD response to MORF-057. These data begin to establish the relationship between PK, target engagement, and PD with MORF-057.

Split-bolus injection protocol with optimized timings of contrast medium injection and CT scanning for 3D CT angio-venography before laparoscopic gastrectomy.

To propose an optimization method of contrast medium injection for the split-bolus protocol based on the contrast medium pharmacokinetics and investigate the utility of the optimized split-bolus protocol in 3D CT angio-venography for laparoscopic gastrectomy. A pharmacokinetic relationship between injection duration and time to the peak enhancement was taken into account in the protocol design. The first 20 consecutive patients underwent a multi-phase scan with a single-bolus injection (single-bolus protocol), and the next 20 underwent the proposed split-bolus protocol. CT attenuations of the arteries and veins and dose-length products (DLPs) were compared between the two protocols. Two radiologists visually assessed arterial and venous depictions and the misregistrations. Mean arterial CT attenuations were not significantly different between the two protocols. Though mean venous CT attenuations for the split-bolus protocol were 7-11% lower than those of the single-bolus protocol, they were visually evaluated as similar. The mean DLP of the split-bolus protocol was 46% lower than that of the single-bolus protocol. Misregistration between the arteries and veins occurred 35-80% during the single-bolus protocol, but was not indicated in the split-bolus protocol. The split-bolus protocol with optimized timing was more effective for providing improved image quality with reduced radiation dose compared with the single-bolus protocol in 3D CT angio-venography for laparoscopic gastrectomy.

The assessment of drug safety for the fetus.

Long standing concerns regarding the use of medications during pregnancy and their unknown effects on fetal development and child health suggests the need for modified study methods regarding the establishment of drug safety for the fetus. This Current Commentary highlights several pharmacological study method limitations and offers suggestions for the establishment of drug safety for the fetus. For example, extensive phase 1 pharmacology studies are needed to assess the complex pharmacokinetic relationships between mother and fetus in order to determine injurious doses to the fetus throughout pregnancy. In addition, long term randomized clinical trials are needed to assess the effects medications may have on children following exposure during gestation.

Abstract LB-133: Correlative analysis of pharmacokinetics and pharmacodynamics of RGX-104, a first-in-class Liver-X-Receptor (LXR) agonist, and clinical outcomes in patients with advanced solid tumors

Abstract RGX-104, a first-in-class small-molecule LXR agonist modulates innate immunity and cancer progression via transcriptional activation of ApoE. ApoE protein suppresses tumor cell invasion and angiogenesis, and also depletes circulating and tumoral myeloid derived suppressor cells (MDSC), leading to T cell activation.A multivariate approach was used to address pharmacokinetic (PK) and pharmacodynamic relationships of RGX-104 in a phase 1 dose escalation study in patients with relapsed/refractory solid tumors. The study entailed multiple escalation arms with RGX-104 as monotherapy and in combination with nivolumab, ipilimumab, or docetaxel. Various markers including intratumoral ApoE and its receptor LRP1 in biopsy specimens, gene expression of LXR-targets in whole blood, serum markers including cytokines and lipids, as well as immune cell types such as MDSC, CD8 T-cells, and neutrophils in peripheral blood from patients were monitored at several time points. PK metrics were tracked to assess dose response relationships. Clinical outcomes such as objective response, time to disease progression, and duration on therapy were used for exploratory correlative analyses. A generally dose dependent increase in steady state exposure to RGX-104 was observed among all cohorts; the lowest efficacious exposure among patients with partial response was ~14,000 ng*h/mL. Treatment with RGX-104 at doses ranging from 120 mg BID to 240 mg BID induced expression of LXR targets, ApoE [2.7X (p=0.008) to 7.1X (p=0.007)] and ABCA1 [ 6.3X (p=1.20E-03) to 7X (p=8.1E-04] over baseline in a generally dose-dependent manner as assessed in whole blood. Similarly, MDSC depletion, ranging from 70%-90% relative to baseline, was observed in patients treated with RGX-104 along with concomitant CD8 T-cell activation; similar effects were noted in patients in combination cohorts. A model to explore dose dependency of change in immune cell types suggested that baseline levels of MDSC were most predictive of the magnitude of MDSC reduction after treatment, and that favorable clinical outcomes correlate with the extent of MDSC reduction and T cell activation. Low baseline levels of tumoral ApoE were associated with greater clinical benefit, with almost all patients with stable disease or partial response exhibiting ApoE tumor positive score of ≤20%; these patients also exhibited low/negative PD-L1 (<1%) staining, revealing a target specific tumor biomarker and PD-L1 subset that could support prospective patient selection. These and additional markers will be tracked in expansion cohorts of RGX-104 in combination with pembrolizumab and carboplatin/pemetrexed for 1st line treatment of patients with metastatic non-small cell lung cancer (PD-L1 <1%) and in combination with docetaxel for 2nd line treatment of patients with small cell lung cancer. Citation Format: Monica Mita, Alan Mita, Erika Hamilton, Gerald S. Falchook, Michael Postow, Bartosz Chmielowski, Russell J. Schilder, James Strauss, Emerson Lim, Shubham Pant, Angela Jain, Oliver Rixe, Rebecca Redman, Kevin B. Kim, Tomislav Dragovich, R. Donald Harvey, Igor Puzanov, Nimisha Schneider, Renee Deehan, Tobi Guennel, Joe Lin, Sohail Tavazoie, Roger Waltzman, Eric Rowinsky, Michael Szarek, Subhasree Sridhar, Robert Busby, Narayan Lebaka, Celia Andreu, Isabel Kurth, David Darst, Masoud Tavazoie, Syed Raza, Robert Wasserman, Foster C. Gonsalves. Correlative analysis of pharmacokinetics and pharmacodynamics of RGX-104, a first-in-class Liver-X-Receptor (LXR) agonist, and clinical outcomes in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-133.

Review on the Clinical Pharmacology of Hydroxychloroquine Sulfate for the Treatment of COVID-19.

As the number of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infected people is greatly increasing worldwide, the international medical situation becomes very serious. Potential therapeutic drugs, vaccine and stem cell replacement methods are emerging, so it is urgent to find specific therapeutic drugs and the best treatment regimens. After the publications on hydroxychloroquine (HCQ) with anti- SARS-COV-2 activity in vitro, a small, non-randomized, open-label clinical trial showed that HCQ treatment was significantly associated with reduced viral load in patients with coronavirus disease-19 (COVID-19). Meanwhile, a large prophylaxis study of HCQ sulfate for COVID-19 has been initiated in the United States. HCQ offered a promising efficacy in the treatment of COVID-19, but the optimal administration is still being explored. We used the keyword "hydroxychloroquine" to conduct a literature search in PubMed to collect relevant literature on the mechanism of action of HCQ, its clinical efficacy and safety, pharmacokinetic characteristics, precautions for clinical use and drug interactions to extract and organize information. This paper reviews the mechanism, clinical efficacy and safety, pharmacokinetic characteristics, exposureresponse relationship and precautions and drug interactions of HCQ, and summarizes dosage recommendations for HCQ sulfate. It has been proved that HCQ, which has an established safety profile, is effective against SARS-CoV-2 with sufficient pre-clinical rationale and evidence. Data from high-quality clinical trials are urgently needed worldwide.

Pharmacokinetic linearity of naproxen and efficacy of naproxen sodium at various doses .

Naproxen sodium (NAPSO) is commonly used in a variety of pain conditions. There are several strengths of NAPSO available over the counter (OTC). Most published data are based on single or multiple doses using 220 mg, hence there is a need to assess the analgesic efficacy of other strengths of NAPSO used in the OTC setting. We reviewed published and unpublished studies of naproxen (NAP) and NAPSO to establish the pharmacokinetic relationship between dosage, plasma concentration, and efficacy, and to compare the analgesic efficacy of NAPSO 220, 440, and 550 mg or NAP 500mg versus placebo and active comparators. Increasing OTC doses of NAP are associated with linear pharmacokinetics, i.e., plasma levels of NAP increase proportionately with dosage. Accordingly, the therapeutic efficacy of higher doses of NAP or NAPSO is greater than lower doses. All OTC doses of NAP and NAPSO are significantly more effective than placebo. Higher strengths are as effective or more effective than lower strengths, and at least comparable to other active treatments. The pharmacokinetic linearity associated with NAP means that data on efficacy for the lower OTC doses of NAPSO can be extrapolated to the higher OTC doses. Thus, it is given that NAPSO 275 and 550mg will be at least as effective as or superior to the lower doses of 220 and 440 mg.

Interactions between Hormonal Contraception and Anti-Retroviral Therapy: An Updated Review.

Hormonal contraception provides women living with HIV the ability to control their fertility and avoid pregnancy-related morbidity. Due to shared metabolic pathways, there has been concern over drug-drug interactions between hormonal contraception and anti-retroviral therapy, which may affect the drugs' safety and efficacy. This article aims to provide an updated review of the most recent data around hormonal contraceptives and anti-retroviral therapy. Prior data have suggested possible pharmacologic interactions between certain hormonal contraceptives and anti-retroviral therapy. The most significant interactions implicated include those between progestin-based contraceptive implants and efavirenz as well as between combined hormonal contraceptives and protease inhibitors. Most past studies, however, feature small sample sizes with few clinical outcomes reported. Recent data since 2017 have largely affirmed prior studies on this topic, showing possible pharmacokinetic relationships between certain contraceptives and anti-retrovirals. Notably, while the effectiveness of progestin-based contraceptives, specifically the implant, appears reduced with efavirenz use, the overall effectiveness may remain higher than most other contraceptive methods. Larger studies are needed to provide further guidance before contraceptive-prescribing recommendations can be changed.