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1.
Santosh Thapa Ruth Ann Luna Bruno P. Chumpitazi Numan Oezguen Susan M. AbdelRahman Uttam Garg Salma Musaad James Versalovic Gregory L. Kearns Robert J. Shulman 《CTS Clinical and Translational Science》2022,15(4):1036
Peppermint oil (PMO) is effective in the treatment of functional abdominal pain disorders, but its mechanism of action is unclear. Evidence suggests PMO has microbicidal activity. We investigated the effect of three different doses of PMO on gut microbiome composition. Thirty children (7–12 years of age) with functional abdominal pain provided a baseline stool sample prior to randomization to 180, 360, or 540 mg of enteric coated PMO (10 participants per dose). They took their respective dose of PMO (180 mg once, 180 mg twice, or 180 mg thrice daily) for 1 week, after which the stool collection was repeated. Baseline and post‐PMO stools were analyzed for microbiome composition. There was no difference in alpha diversity of the gut microbiome between the baseline and post‐PMO treatment. Principal coordinate analysis revealed no significant difference in overall bacterial composition between baseline and post‐PMO samples, as well as between the PMO dose groups. However, the very low abundant Collinsella genus and three operational taxonomic units (one belonging to Collinsella) were significantly different in samples before and after PMO treatment. The Firmicutes/Bacteroidetes ratio was lower in children who received 540 mg of PMO compared to the 180 mg and 360 mg dose groups (p = 0.04). Network analysis revealed separation between pre‐ and post‐PMO fecal samples with the genus Collinsella driving the post‐PMO clusters. PMO administration appeared to impact only low abundance bacteria. The 540 mg PMO dose differentially impacted the Firmicutes/Bacteroidetes ratio. A higher dose and/or longer duration of treatment might yield different results. Study Highlights
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2.
Edwin Lam Yi Ting Lien Walter K. Kraft Douglas F. Stickle Beth Piraino Jingjing Zhang 《CTS Clinical and Translational Science》2022,15(3):649
It is unclear if the pharmacokinetics of vancomycin are the same during automated peritoneal dialysis (APD), where cycler exchanges may affect the systemic, peritoneal, and urinary disposition of drug. We conducted a prospective pharmacokinetic study evaluating the pharmacokinetics of vancomycin in plasma, dialysis fluid, and urine in peritonitis‐negative patients on APD. Patients underwent four drug‐free exchanges with 1.5% or 2.5% dextrose following the initial dwell period. Plasma, dialysis fluid, and urine was collected over the course of 7 days for pharmacokinetic analysis. Four patients completed the study with no adverse events. Following a median (range) dwell of 14.6 (14.2–17.6 h), the mean (±SD) observed maximum plasma concentration was 28.7 ± 4.9 mg/L with a mean bioavailability of 98.5 ± 1.4% prior to starting the cycler. The overall mean total plasma clearance estimated from study start to completion was 7.6 ± 1.2 ml/min. Mean total clearance during the dialytic exchange was 13.6 ± 4.9 ml/min. In patients with residual renal function, the mean vancomycin renal clearance was 3.1 ± 1.5 ml/min, representing 21.4%–58.9% of the overall total plasma clearance during the study period. Despite the small sample size, this pilot study suggests that the dwell time has important implications for systemic vancomycin exposure, time to therapeutic plasma concentration, and dosing. Dose is driven by dwell time, whereas the cycler determines the dosing interval. Rapid exchanges from APD will determine the frequency of dosing rather than the adequacy of absorption when vancomycin is given in the peritoneum. Study Highlights
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3.
Naoaki Hashimoto Kosuke Doki Satoru Kawano Kazutaka Aonuma Masaki Ieda Masato Homma 《CTS Clinical and Translational Science》2022,15(3):771
Amiodarone and its main metabolite, desethylamiodarone (DEA), are highly distributed to serum lipoproteins such as very‐low‐density lipoprotein (VLDL) and low‐density lipoprotein (LDL), which are the carriers of triglyceride and cholesterol. This study aimed to investigate the association of serum concentrations of amiodarone and DEA with the levels of serum lipids in terms of drug distribution to lipoprotein fractions in patients with hyperlipidemia. Total serum concentrations of amiodarone and DEA were examined in 116 patients receiving amiodarone for tachyarrhythmias. The concentration‐to‐dose (C/D) ratio of amiodarone positively correlated with the level of serum triglyceride (rs = 0.541, p < 0.001) and was higher in the hypertriglyceridemic state than in normotriglyceridemic state (479 ± 211 vs. 320 ± 161, p < 0.001). No correlation was found between the C/D ratio of DEA and serum triglyceride levels (rs = 0.272), although higher values were observed in the hypertriglyceridemic state (322 ± 125 vs. 285 ± 143, p < 0.001). In the hypertriglyceridemic state, the distribution of amiodarone increased in LDL/VLDL fraction and decreased in high‐density lipoprotein and albumin fractions. The ratio of serum amiodarone to serum DEA, a metabolic ratio of amiodarone, positively correlated with serum triglyceride levels (rs = 0.572, p < 0.001) and was higher in the hypertriglyceridemic state, suggesting that amiodarone metabolism decreased in hyperlipidemia. The results of this study reveal that serum concentrations of amiodarone increase in the hypertriglyceridemic state through the increased lipoprotein‐binding and decreased metabolism of amiodarone. Study Highlights
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4.
Debora Curci Marianna Lucaf Adriana Cif Martina Fabris Matteo Bramuzzo Stefano Martelossi Raffaella Franca Giuliana Decorti Gabriele Stocco 《CTS Clinical and Translational Science》2021,14(6):2184
Infliximab is commonly used in inflammatory bowel disease (IBD), however, differences in clinical response among patients are common. Several studies have considered the possibility that these differences are caused by genetic variability even if no unique marker has been yet identified in pediatric patients. We evaluated the impact of two candidate single‐nucleotide polymorphisms (SNPs) rs396991 in FCGR3A and rs1800629 in TNFα genes on infliximab response in an Italian cohort of 76 pediatric patients with IBD. Results showed that patients with the variant FCGR3A allele had a reduced clinical response at the end of induction (p value = 0.004), at 22 weeks (p value = 0.001), and at 52 weeks of treatment (p value = 0.01). A significant association between the FCGR3A variant and median infliximab levels measured during maintenance therapy was also observed: patients with wild type genotype had higher infliximab levels compared to patient with variant allele. Furthermore, patients with the variant allele had a higher probability to produce antidrug antibodies (ADAs). No association was found among the TNFα SNP, clinical response, and infliximab levels. This study addressed for the first time in pediatric patients with IBD, the association of FCGR3A SNP, infliximab response, and ADA production. Study Highlights
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5.
Rui Zhu Hubert Chen Joshua Galanter Gaohong She Fang Cai Matthew R. Durk Yixuan Zou Liuxi Chen Jane R. Kenny Shweta Vadhavkar Simon Warren Glyn Taylor Olivia Hwang Avi Eliahu Chris Wynne Ryan Owen 《CTS Clinical and Translational Science》2022,15(5):1225
Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. 99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma Cmax similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration. Study Highlights
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6.
Olumide B. Gbolahan Bert H. ONeil Autumn J. McRee Hanna K. Sanoff John K. Fallon Philip C. Smith Anastasia Ivanova Dominic T. Moore Julie Dumond Gary N. Asher 《CTS Clinical and Translational Science》2022,15(5):1304
Curcumin inhibits UDP‐glucuronyltransferases, a primary metabolic pathway for cancer chemotherapeutic agents like irinotecan. Concurrent administration of both agents may exacerbate irinotecan toxicity. We conducted this phase I study to determine the safety of concurrent curcumin and irinotecan administration. Ten participants with advanced solid tumors received one of four doses (1, 2, 3, and 4 g) of a curcumin phosphatidylcholine complex (PC) orally daily, and 200 mg/m2 of i.v. infusion irinotecan on days 1 and 15 of a 28‐day cycle, to determine the maximum tolerated dose (MTD) of PC. Thirteen participants received 4 g of PC (MTD) to assess the effect on the pharmacokinetic (PK) properties of irinotecan and its metabolites, SN‐38 and SN‐38G. Irinotecan, SN‐38, and SN‐38G exposure equivalence with and without curcumin was assessed using area under the plasma concentration‐time curves from 0 to 6 h (AUC0‐6h). Safety assessments and disease responses were also evaluated. The combination of irinotecan and PC was well‐tolerated. Because there was no dose limiting toxicity, the maximum dose administered (4 g) was defined as the recommended phase II dose of PC. PC did not significantly alter the plasma exposure and other PK properties of irinotecan and its metabolites. There was no apparent increase in the incidence of irinotecan‐associated toxicities. The objective response rate was 3/19 (22%, 95% confidence interval [CI]: 5–39%), median progression free survival and overall survival (n = 23) were 4 months (95% CI: 2.9–8.9 months) and 8.4 months (95% CI: 3.7 – not evaluable [NE]), respectively. Future studies are required to evaluate the efficacy of this combination. Study Highlights
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7.
Jeannine S. McCune Ryotaro Nakamura Denis OMeally Timothy W. Randolph Brenda M. Sandmaier Aleksandra Karolak David Hockenbery Sandi L. Navarro 《CTS Clinical and Translational Science》2022,15(5):1215
The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the drug‐metabolizing enzymes that metabolize CY to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY’s cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY), and 24 h after the first dose of PT‐CY (24‐h post‐CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre‐CY time point, no EMCs were associated at FDR less than 0.1. At pre‐HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre‐graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24‐h post‐CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY. Study Highlights
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8.
Aaron Lazorwitz Christina L. Aquilante Jonathan A. Shortt Jeanelle Sheeder Stephanie Teal Christopher R. Gignoux 《CTS Clinical and Translational Science》2021,14(5):1713
To compare etonogestrel pharmacokinetic and pharmacodynamic outcomes by both self‐reported race/ethnicity and genetically determined ancestry among contraceptive implant users. We conducted a secondary analysis of our parent pharmacogenomic study of 350 implant users. We genotyped these reproductive‐aged (18–45 years) women for 88 ancestry‐informative single nucleotide polymorphisms. We then assigned each participant a proportion value for African (AFR), European (EUR), and Indigenous American (AMR) ancestry based on reference population data. We correlated genetic ancestry with self‐reported race/ethnicity and utilized genetic ancestry proportion values as variables for previously performed association analyses with serum etonogestrel concentrations and progestin‐related side effects (e.g., bothersome bleeding and subjective weight gain). We successfully estimated genetically determined ancestry for 332 participants. EUR, AFR, and AMR ancestry were each highly correlated with self‐reported White/non‐Hispanic race (r = 0.64, p = 4.14 × 10−40), Black/African American race (r = 0.88, p = 1.36 × 10−107), and Hispanic/Latina ethnicity (r = 0.68, p = 4.03 × 10−47), respectively. Neither genetically determined ancestry nor self‐reported race/ethnicity were significantly associated with serum etonogestrel concentrations. AFR ancestry and self‐reported Black race had similar associations with reporting monthly periods (odds ratio [OR] 2.18, p = 0.09 vs. OR 2.22, p = 0.02) and having received treatment for bothersome bleeding (OR 5.19, p = 0.005 vs. OR 4.73, p = 2.0 × 10−4). In multivariable logistic regression for subjective weight gain, AMR ancestry dropped out of the model in preference for self‐reported Hispanic/Latina ethnicity. We found no new associations between genetically determined ancestry and contraceptive implant pharmacodynamics/pharmacokinetics. Self‐reported race/ethnicity were strong surrogates for genetically determined ancestry among this population of contraceptive implant users. Our data suggest that self‐reported race/ethnicity, capturing societal and cultural aspects, remain important to the investigation of progestin‐related side effects. Study Highlights
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9.
Matthias Hoch Tirtha Sengupta Florence HourcadePotelleret 《CTS Clinical and Translational Science》2022,15(6):1406
Asciminib, a first‐in‐class BCR‐ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP), is a new treatment option for patients with chronic myeloid leukemia who no longer benefit from currently approved tyrosine kinase inhibitors. In vitro, asciminib reversibly inhibits cytochrome P450 (CYP) 3A4/5, CYP2C9, and CYP2C8. This phase I, open‐label, two‐stage study in healthy participants evaluated the effect of asciminib (40 mg b.i.d. at steady‐state) as a potential perpetrator on single‐dose pharmacokinetics of a two‐drug cocktail containing midazolam (CYP3A substrate) and warfarin (CYP2C9 substrate) in stage 1 (n = 22), and of repaglinide (CYP2C8 substrate) in stage 2 (n = 25). For midazolam plus asciminib versus midazolam, geometric mean (G mean) ratios (90% confidence interval) for midazolam area under the curve from zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 1.28 (1.15, 1.43) and 1.11 (0.96, 1.28), respectively. For warfarin plus asciminib versus warfarin, G mean ratios for S‐warfarin AUCinf and Cmax were 1.41 (1.37, 1.45) and 1.08 (1.04, 1.13), respectively. Results for R‐warfarin were in line with those for S‐warfarin. For repaglinide plus asciminib versus repaglinide, G mean ratios for AUCinf and Cmax were 1.08 (1.02, 1.14) and 1.14 (1.01, 1.28), respectively. The treatments were generally well tolerated, and the asciminib safety profile was consistent with previous studies of asciminib in the absence of probe substrates. Overall, the results indicate that asciminib (40 mg b.i.d.) is a weak inhibitor of CYP3A and CYP2C9 and has no meaningful effect on CYP2C8. Study Highlights
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10.
Glauco Henrique Balthazar Nardotto Valdes Roberto Bollela Adriana Rocha Oscar Della Pasqua Vera Lucia Lanchote 《CTS Clinical and Translational Science》2022,15(2):514
There are contrasting findings regarding the effect of HIV on the pharmacokinetics of first‐line anti‐tubercular drugs (FLATDs) due to a lack of prospective controlled clinical studies, including patients with tuberculosis (TB) and patients with TB living with HIV. This study aims to assess the effect of HIV coinfection and antiviral therapy on the plasma exposure to FLATDs in patients with TB. HIV negative (TB‐HIV− group; n = 15) and HIV positive (TB‐HIV+ group; n = 18) adult patients with TB were enrolled during the second month of FLATDs treatment. All TB‐HIV+ patients were on treatment with lamivudine, tenofovir (or zidovudine), and raltegravir (or efavirenz). Serial blood sampling was collected over 24 h and FLATDs pharmacokinetic parameters were evaluated using noncompartmental methods. In the TB‐HIV+ patients, dose‐normalized plasma exposure area under the curve from zero to 24 h (nAUC0–24; geometric mean and 95% confidence interval [CI]) values at steady‐state to rifampicin, pyrazinamide, and ethambutol were 18.38 (95% CI 13.74–24.59), 238.21 (95% CI 191.09–296.95), and 18.33 (95% CI 14.56–23.09) µg∙h/ml, respectively. Similar plasma exposure was found in the TB‐HIV− patients. The geometric mean and 90% CI of the ratios between TB‐HIV− and TB‐HIV+ groups suggest no significant pharmacokinetic interaction between the selected antivirals and FLATDs. Likewise, HIV coinfection itself does not appear to have any effect on the plasma exposure to FLATDs. Study Highlights
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11.
Vidya Perera Zhaoqing Wang Joseph Luettgen Danshi Li Mary DeSouza Michael Cerra Dietmar Seiffert 《CTS Clinical and Translational Science》2022,15(2):330
Milvexian (BMS‐986177/JNJ‐70033093) is a small molecule, active‐site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two‐part, double‐blind, placebo‐controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200‐ and 500‐mg panels investigated the pharmacokinetic impact of a high‐fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once‐ or twice‐daily) or placebo for 14 days. All milvexian dosing regimens were safe and well‐tolerated, with only mild treatment‐emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half‐life (T1/2) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose‐proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose‐dependent fashion. In MAD panels, steady‐state milvexian plasma concentration was reached within 3 and 6 dosing days with once‐ and twice‐daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development. Study Highlights
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12.
Ki Young Huh Yewon Choi Jim Nissel Maria Palmisano Xiaomin Wang Liangang Liu Francisco RamirezValle Howard Lee 《CTS Clinical and Translational Science》2021,14(4):1505
We performed a two‐part study to evaluate the pharmacokinetics, safety, and tolerability of oral apremilast, a phosphodiesterase 4 inhibitor indicated for the treatment of psoriasis, in healthy Korean adult men. In part 1, there were 12 subjects who randomly received a single oral dose of apremilast at 20, 30, or 40 mg in each of 3 periods in a crossover fashion. In part 2, there were 16 subjects who randomly received 30 mg of apremilast or its matching placebo in a ratio of 3:1 twice daily for 14 days. Apremilast was rapidly absorbed (maximum concentration: ~2–3 h postdose), and eliminated according to a monoexponential pattern with a terminal‐phase elimination half‐life of 8–9 h. The exposure to apremilast increased in a dose‐proportional manner and accumulation was 1.6‐fold at steady‐state. Apremilast was well‐tolerated after a single oral administration and multiple oral administrations in Korean adult men; all of the treatment‐emergent adverse events were mild and recovered without sequelae. In conclusion, apremilast was safe and well‐tolerated in healthy Korean adult men when administered single oral doses of 20, 30, or 40 mg or when administered multiple oral doses of 30 mg b.i.d. for 14 days. Overall exposures increased in an approximate dose proportional manner in healthy Korean adult men. Study Highlights
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13.
Xiaojie Wu Sheng Feng Jing Zhang Wenhong Zhang Yuchen Zhang Mingfen Zhu Miriam Triyatni Na Zhao Qingyan Bo Yuyan Jin 《CTS Clinical and Translational Science》2022,15(1):195
The objectives of this phase I study are to assess the safety, tolerability, and pharmacokinetics (PKs) of RO7049389 in healthy Chinese volunteers (HVs) and evaluate potential ethnic differences in the safety and PKs using data from this study and the first‐in‐human study (in which most of the HVs were non‐Asian). HVs randomly received a single dose of 200–600 mg of RO7049389 or a placebo in a single ascending dose (n = 28) or multiple doses of 200–400 mg of RO7049389 or a placebo in multiple ascending doses (n = 24). Safety and tolerability were monitored throughout the study. Serial blood samples were collected for PK analysis. RO7049389 was safe and well‐tolerated in the HVs. The time to maximum concentration ranged from 1.5 to 3.0 h, and terminal half‐life ranged from 3.66 to 14.6 h. A single dose of 200–600 mg and multiple doses of 200–400 mg exhibited nonlinear PKs. In general, the safety profiles were comparable between non‐Asian and Asian HVs, but the plasma exposure of RO7049389 in Chinese HVs was higher than that in non‐Asian HVs. The data generated from this study will provide guidance for future clinical studies on RO7049389 in Chinese/Asian patients with hepatitis B virus. Study Highlights
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14.
Matthew P. Kosloski George D. Kalliolias Christine R. Xu Sivan Harel ChingHa Lai Wenjun Zheng John D. Davis Mohamed A. Kamal 《CTS Clinical and Translational Science》2022,15(2):384
Itepekimab is a monoclonal antibody that targets interleukin (IL‐33) and has been shown to reduce airway inflammation and associated tissue damage in preclinical studies. We assessed the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamic profiles of single‐ascending and multiple‐ascending doses of itepekimab in two randomized, double‐blind, placebo‐controlled phase I studies. Healthy adults (N = 40) were randomized to the single‐dose study and patients with moderate asthma (N = 23) to the multiple‐dose study. Itepekimab was administered intravenously (0.3, 1, 3, or 10 mg/kg infusion) or subcutaneously (150 mg) in the single‐dose study and subcutaneously (75 or 150 mg weekly for 4 weeks) in the multiple‐dose study. Itepekimab exhibited linear PKs across studies and dose‐proportional increases in mean maximum concentration in serum and area under the concentration–time curve following single intravenous or multiple subcutaneous doses. Itepekimab demonstrated mean subcutaneous bioavailability of 59–73% and a long terminal half‐life (30.0–31.6 days). IL‐33 concentrations in most healthy participants and patients with asthma were undetectable at baseline. Following administration of itepekimab in both studies, total IL‐33 concentrations increased and blood eosinophils decreased, both with durable effect. Itepekimab was well‐tolerated in both studies with no detection of treatment‐emergent anti‐drug antibody responses. Study Highlights
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15.
Ryota Tanaka Yosuke Suzuki Hiroshi Watanabe Takashi Fujioka Kenshiro Hirata Toshitaka Shin Tadasuke Ando Hiroyuki Ono Ryosuke Tatsuta Hiromitsu Mimata Toru Maruyama Hiroki Itoh 《CTS Clinical and Translational Science》2021,14(5):2034
Because tacrolimus is predominantly metabolized by CYP3A, the blood concentration/dose (C/D) ratio is affected by CYP3A5 polymorphism. Parathyroid hormone (PTH) expression increases in secondary hyperparathyroidism, which is frequently associated with end‐stage renal disease. Recently, PTH has been shown to downregulate CYP3A expression at mRNA level. In this study, we examined the influence of CYP3A5 polymorphism on and association of serum intact‐PTH (iPTH) level with blood tacrolimus concentration in patients with end‐stage renal disease just before kidney transplantation. Forty‐eight patients who satisfied the selection criteria were analyzed. Subjects were classified into two phenotype subgroups: CYP3A5 expressor (CYP3A5*1/*1 and *1/*3; n = 15) and CYP3A5 nonexpressor (CYP3A5*3/*3; n = 33). The blood tacrolimus C/D (per body weight) ratio was significantly lower in CYP3A5 expressors than that in CYP3A5 nonexpressors. A significant positive correlation was found between tacrolimus C/D and iPTH concentrations (r = 0.305, p = 0.035), and the correlation coefficient was higher after excluding 20 patients co‐administered CYP3A inhibitor or inducer (r = 0.428, p = 0.023). A multiple logistic regression analysis by stepwise selection identified CYP3A5 polymorphism and serum iPTH level as significant factors associated with tacrolimus C/D. These results may suggest the importance of dose design considering not only the CYP3A5 phenotype but also serum iPTH level when using tacrolimus in patients who undergo renal transplantation. Study Highlights
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16.
Joseph F. Grippo Ilia Folitar Sharon Passe Qiudi Jiang Ignacio Rodriguez Scott H. Fettner Elizabeth Calleja 《CTS Clinical and Translational Science》2021,14(4):1524
RO6870868 is an oral prodrug of the toll‐like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first‐in‐human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200–2000 mg). Single oral doses were generally well‐tolerated with a predictable safety profile associated with dose‐dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half‐life ranging 2–6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC0‐∞) increasing proportionally with dose. A pattern of dose and time‐dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose‐dependent manner with adequate safety and tolerability. Single‐dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B. Study Highlights
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17.
Pivi Hirvensalo Aleksi Tornio Tuija Tapaninen Maria PaileHyvrinen Mikko Neuvonen Janne T. Backman Mikko Niemi 《CTS Clinical and Translational Science》2022,15(2):409
The aim of this study was to search for associations of genetic variants with celiprolol pharmacokinetics in a large set of pharmacokinetic genes, and, more specifically, in a set of previously identified candidate genes ABCB1, SLCO1A2, and SLCO2B1. To this end, we determined celiprolol single‐dose (200 mg) pharmacokinetics and sequenced 379 pharmacokinetic genes in 195 healthy volunteers. Analysis with 46,064 common sequence variants in the 379 genes did not identify any novel genes associated with celiprolol exposure. The candidate gene analysis showed that the ABCB1 c.3435T>C and c.2677T/G>A, and the SLCO1A2 c.516A>C variants were associated with reduced celiprolol area under the plasma concentration‐time curve (AUC0–∞). An alternative analysis with ABCB1 haplotypes showed that, in addition to SLCO1A2 c.516A>C, three ABCB1 haplotypes were associated with reduced celiprolol AUC0–∞. A genotype scoring system was developed based on these variants and applied to stratify the participants to low and high celiprolol exposure genotype groups. The mean AUC0–∞ of celiprolol in the low exposure genotype group was 55% of the mean AUC0–∞ in the high exposure group (p = 1.08 × 10−11). In addition, the results showed gene‐gene interactions in the effects of SLCO1A2 and ABCB1 variants on celiprolol AUC0–∞ (p < 5 × 10−6) suggesting an interplay between organic anion transporting polypeptide 1A2 and P‐glycoprotein in celiprolol absorption. Taken together, these data indicate that P‐glycoprotein and organic anion transporting polypeptide 1A2 play a role in celiprolol pharmacokinetics. Furthermore, patients with ABCB1 and SLCO1A2 genotypes associated with low celiprolol exposure may have an increased risk of poor blood‐pressure lowering response to celiprolol. Study Highlights
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18.
Krista R. Schaefer Jaedon P. Avey Michael R. Todd Julie A. Beans Denise A. Dillard Laura M. Shireman Timothy A. Thornton Rachel F. Tyndale Kenneth E. Thummel Renee F. Robinson Katrina G. Claw 《CTS Clinical and Translational Science》2021,14(6):2474
Prevalence of smoking is higher in Alaska Native and American Indian (ANAI) populations living in Alaska than the general US population. Genetic factors contribute to smoking and cessation rates. The objective of this study was to compare CYP2A6 genetic variation and CYP2A6 enzyme activity toward nicotine in an ANAI population. ANAI (N = 151) people trying to quit smoking were recruited. DNA samples were genotyped for CYP2A6 variants *1X2A, *1B, *2, *4, *9, *10, *12, and *35. Multiple nicotine metabolites were measured in plasma and urine samples, including cotinine and 3′‐hydroxycotinine used to determine CYP2A6 activity (e.g., nicotine metabolite ratio [NMR]). We calculated summary statistics for all of the genotypes and metabolites and assigned CYP2A6 activity scores based on known information. We studied the association of CYP2A6 variants with the NMR and smoking histories. The overall frequency of the CYP2A6*1B gain of function allele was high in the ANAI versus non‐ANAI populations in other studies. Both *4 null and *9 decrease of function alleles had frequencies similar to previous studies of ANAI populations. In a multivariate analysis, the genotype‐inferred CYP2A6 activity score was associated with both plasma and urine NMR (p value = 8.56E‐08 and 4.08E‐13, respectively). Plasma NMR was also associated with duration of smoking (p value < 0.01) but not urinary total nicotine equivalents uncorrected for creatinine (TNE9uc) or biological sex. Urine NMR was significantly associated (p value < 0.01) with TNE9uc. Variation in NMR in this ANAI population is explained in part by CYP2A6 genetic variation. Study Highlights
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19.
Ishan Taneja Gregory L. Damhorst Carlos LopezEspina Sihai Dave Zhao Ruoqing Zhu Shah Khan Karen White James Kumar Andrew Vincent Leon Yeh Shirin Majdizadeh William Weir Scott Isbell James Skinner Manubolo Devanand Syed Azharuddin Rajamurugan Meenakshisundaram Riddhi Upadhyay Anwaruddin Syed Thomas Bauman Joseph Devito Charles Heinzmann Gregory Podolej Lanxin Shen Sanjay Sharma Timilsina Lucas Quinlan Setareh Manafirasi Enrique Valera Bobby Reddy Jr. Rashid Bashir 《CTS Clinical and Translational Science》2021,14(4):1578
Sepsis is a major cause of mortality among hospitalized patients worldwide. Shorter time to administration of broad‐spectrum antibiotics is associated with improved outcomes, but early recognition of sepsis remains a major challenge. In a two‐center cohort study with prospective sample collection from 1400 adult patients in emergency departments suspected of sepsis, we sought to determine the diagnostic and prognostic capabilities of a machine‐learning algorithm based on clinical data and a set of uncommonly measured biomarkers. Specifically, we demonstrate that a machine‐learning model developed using this dataset outputs a score with not only diagnostic capability but also prognostic power with respect to hospital length of stay (LOS), 30‐day mortality, and 3‐day inpatient re‐admission both in our entire testing cohort and various subpopulations. The area under the receiver operating curve (AUROC) for diagnosis of sepsis was 0.83. Predicted risk scores for patients with septic shock were higher compared with patients with sepsis but without shock (p < 0.0001). Scores for patients with infection and organ dysfunction were higher compared with those without either condition (p < 0.0001). Stratification based on predicted scores of the patients into low, medium, and high‐risk groups showed significant differences in LOS (p < 0.0001), 30‐day mortality (p < 0.0001), and 30‐day inpatient readmission (p < 0.0001). In conclusion, a machine‐learning algorithm based on electronic medical record (EMR) data and three nonroutinely measured biomarkers demonstrated good diagnostic and prognostic capability at the time of initial blood culture. Study Highlights
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20.
Desmond Y. H. Yap Jojo Hai Paul C. H. Lee Xueying Zhou Michael Lee Yu Zhang Meng Wang Xiaoxiang Chen 《CTS Clinical and Translational Science》2021,14(5):1769
Blockade of the binding between neonatal Fc receptor and IgG‐Fc reduces circulating IgG, and thus emerges as a potential therapy for IgG‐mediated autoimmune conditions. This was a double blind, randomized, single ascending dose study to evaluate the safety, pharmacokinetics, and pharmacodynamics of HBM9161 (a fully humanized Fc receptor monoclonal antibody) in healthy Chinese volunteers. Subjects were randomized to receive a single s.c. dose of HBM9161 or placebo in a 3:1 ratio in 3 dosing cohorts (340 mg, 510 mg, or 680 mg, respectively), and then followed up for 85 days. Study end points included incidence of adverse event (AE), serum drug concentration, IgG and its subclasses, and anti‐drug antibodies (ADAs). Twenty‐four subjects were randomized. Dose‐dependent reduction of total IgG occurred rapidly from baseline to reach nadir at day 11, then recovered steadily from day 11 to day 85. The mean maximum percentage reductions from baseline total IgG were 21.0 ± 9.3%, 39.8 ± 5.13%, and 41.2 ± 10.4% for subjects receiving HBM9161 340 mg, 510 mg, and 680 mg, respectively. The exposure of HBM9161 (areas under the curve [AUCs] and peak plasma concentration [Cmax]) increased in a more than dose‐proportional manner at the dose examined. All reported AEs were mild in severity. The most reported AEs in the HBM9161 groups were influenza‐like illness and rash. Two subjects developed ADA during the study period. A single s.c. dose of HBM9161 results in sustained and dose‐dependent IgG reduction, and was well‐tolerated at a dose up to 680 mg in Chinese subjects. The data warrant further investigation of its effects in IgG‐mediated autoimmune disorders. Study Highlights
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