Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine.

BACKGROUND: Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.S, is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein. METHODS: In this multicenter, placebo-controlled, phase 1-2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule. RESULTS: After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 212 to 354), regardless of vaccine dose or age group, and reached 96% by day 57 with a further increase in titers (GMT, 288 to 488) in cohort 1a. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 15, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3. CONCLUSIONS: The safety and immunogenicity profiles of Ad26.COV2.S support further development of this vaccine candidate. (Funded by Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services; COV1001 ClinicalTrials.gov number, NCT04436276.).

Codeine delays gastric emptying through inhibition of gastric motility as assessed with a novel diagnostic intragastric balloon catheter.

BACKGROUND: The use of opioids as analgesic is on the rise, despite their inhibitory effect on gastric emptying. A novel feeding catheter with integrated intragastric balloon was developed to continuously assess gastric motility, enabling to investigate the effect of opioids on motility and emptying simultaneously. We aimed to discriminate normal and pharmacologically impaired gastric motility and its impact on gastric emptying in healthy adults. METHODS: The VIPUN Gastric Monitoring System comprises a nasogastric balloon catheter and a monitoring unit. In a four-way randomized, single-blinded, cross-over study, subjects received either placebo or 58.8 mg codeine phosphate in combination with either an uninflated or an inflated (180 mL) balloon catheter. Motility-induced pressure changes were recorded for 6 hours. During the first 2 hours, nutrients were infused (225 kcal, 75 mL/h). Gastric emptying was assessed with a 13 C-octanoate breath test and expressed as gastric half-emptying time (GET½). An algorithm, designed to detect phasic contractility, converted pressure changes to a gastric balloon motility index (GBMI). Results are presented as mean(SD). KEY RESULTS: Eighteen subjects completed the investigation (32(13) years, 22(2) kg/m2 ). After codeine, GBMI was lower (0.31(0.16)) and GET½ was longer (233(57) minutes) compared with placebo (GBMI: 0.48(0.15), P < .01 and GET½: 172(12) minutes, P < .001). Within-subject ΔGET½ correlated significantly with ΔGBMI (r = -0.77 and P < .001). CONCLUSIONS AND INFERENCES: The VIPUN Gastric Monitoring System allowed to assess gastric motility safely and continuously. The correlation between pharmacologically decreased gastric emptying and motility indicates a strong link between both. Gastric motility, measured with this innovative device, can be an indicator for gastrointestinal intolerance.

Predicting iron absorption from an effervescent iron supplement in obese patients before and after Roux-en-Y gastric bypass: a preliminary study.

BACKGROUND & AIMS: Oral iron absorption is hampered in obese and bariatric patients, especially after Roux-en-Y gastric bypass (RYGB). As a result, iron deficiency, which is common in both patient groups, can be difficult to treat by oral supplements, often necessitating a switch to parenteral administration. The aim of this study was to find possible predictors of the extent of absorption of an effervescent iron gluconate oral supplement, which enables to pre-emptively identify those patients in which oral supplementation is likely to fail. METHODS: The pharmacokinetic properties of 695 mg effervescent iron gluconate (80 mg Fe2+) were assessed in 13 obese patients (female = 10; mean age ± SD: 45.2 ± 12.5years) pre- and six months post-RYGB by measuring serum iron concentrations during 24 hours and by calculating the adjusted for baseline AUC0-24h, Cmax and Tmax. A multivariate regression analysis was performed to investigate the effect of hepcidin concentration, iron and hematologic indices, personal and anthropometric characteristics on iron absorption. Subsequently, Receiver Operating Characteristic (ROC) curves were used to propose the cut-off value for hepcidin concentrations above which obese patients are unlikely to benefit from oral iron supplementation. Data are expressed as mean ± SD. RESULTS: Low iron status persisted after surgery as there was no significant difference observed in TSAT (17.3 ± 5.2 vs. 20.2 ± 6.6%), ferritin (91.8 ± 68.6 vs. 136.2 ± 176.9 µg/L) and hepcidin concentration (32.0 ± 30.1 vs. 28.3 ± 21.3 ng/mL) after RYGB. The absorption of effervescent iron gluconate was similar pre- and post-RYGB [AUC0-24h,pre-RYGB: 28.6 ± 10.8 µg/dL*h; AUC0-24h,post-RYGB: 27.5 ± 9.11 µg/dL*h (P = 0.84)]. Post-RYGB, iron AUC0-24h showed a strong negative correlation with both hepcidin concentrations and TSAT (R=-0.51; P = 0.08 and R=-0.81; P = 0.001), respectively. Pre-RYGB, there was a clear trend for the same negative correlations for hepcidin concentrations and TSAT (R=-0.47; P = 0.11 ;R=-0.41; P = 0.16), respectively. Taking pre-and post-RYGB data together, the negative correlations were confirmed for hepcidin concentrations and TSAT (R=-0.54; P = 0.004; R=-0.60; P = 0.001), respectively. The AUCROC = 0.87 (95%CI 0.71; 1.00) showed an optimal sensitivity/specificity cut-off at hepcidin concentrations of 26.8 ng/mL. CONCLUSIONS: The iron AUC0-24h showed a negative correlation with the hepcidin concentration and TSAT of obese patients, in particular post-RYGB. Therefore, our data support the use of hepcidin concentration and TSAT to distinguish potential responders from non-responders for iron supplementation particularly post-RYGB. Additionally, this study showed that the pharmacokinetic properties of iron gluconate from an effervescent tablet were unaffected by RYGB-surgery.

18F-JNJ-64413739, a Novel PET Ligand for the P2X7 Ion Channel: Radiation Dosimetry, Kinetic Modeling, Test-Retest Variability, and Occupancy of the P2X7 Antagonist JNJ-54175446.

The P2X7 receptor (P2X7R) is an adenosine triphosphate-gated ion channel that is predominantly expressed on microglial cells in the central nervous system. We report the clinical qualification of P2X7-specific PET ligand 18F-JNJ-64413739 in healthy volunteers, including dosimetry, kinetic modeling, test-retest variability, and blocking by the P2X7 antagonist JNJ-54175446. Methods: Whole-body dosimetry was performed in 3 healthy male subjects by consecutive whole-body PET/CT scanning, estimation of the normalized cumulated activity, and calculation of the effective dose using OLINDA (v1.1). Next, 5 healthy male subjects underwent a 120-min dynamic 18F-JNJ-64413739 PET/MRI scan with arterial blood sampling to determine the appropriate kinetic model. For this purpose, 1- and 2-tissue compartment models and Logan graphic analysis (LGA) were evaluated for estimating regional volumes of distribution (VT). PET/MRI scanning was repeated in 4 of these subjects to evaluate medium-term test-retest variability (interscan interval, 26-97 d). For the single-dose occupancy study, 8 healthy male subjects underwent baseline and postdose 18F-JNJ-64413739 PET/MRI scans 4-6 h after the administration of a single oral dose of JNJ-54175446 (dose range, 5-300 mg). P2X7 occupancies were estimated using a Lassen plot and regional baseline and postdose VTResults: The average (mean ± SD) effective dose was 22.0 ± 1.0 µSv/MBq. The 2-tissue compartment model was the most appropriate kinetic model, with LGA showing very similar results. Regional 2-tissue compartment model VT values were about 3 and were rather homogeneous across all brain regions, with slightly higher estimates for the thalamus, striatum, and brain stem. Between-subject VT variability was relatively high, with cortical VT showing an approximate 3-fold range across subjects. As for time stability, the acquisition time could be reduced to 90 min. The average regional test-retest variability values were 10.7% ± 2.2% for 2-tissue compartment model VT and 11.9% ± 2.2% for LGA VT P2X7 occupancy approached saturation for single doses of JNJ-54175446 higher than 50 mg, and no reference region could be identified. Conclusion:18F-JNJ-64413739 is a suitable PET ligand for the quantification of P2X7R expression in the human brain. It can be used to provide insight into P2X7R expression in health and disease, to evaluate target engagement by P2X7 antagonists, and to guide dose selection.

EUFEMED London Conference 2017: Exploratory Medicines Development: Innovation and Risk Management.

The first formal conference of the EUropean Federation for Exploratory MEdicines Development (EUFEMED) held in London was the result of a collaborative effort of its founding associations: the Association for Applied Human Pharmacology (AGAH; Germany), the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI; UK), the Belgian Association of Phase-I Units (BAPU; Belgium), and Club Phase-I (France). The conference focused on innovation and risk management in early clinical drug development. Among other innovations, immunotherapy in oncology and inflammatory diseases were discussed as well as the importance of adaptive trial designs in early clinical drug development. Consideration was given to assessing and mitigating risk in early clinical drug development, and included a preconference workshop. Different measures to minimize risks in healthy volunteers and patients in first-in-human trials were discussed in addition to the importance of non-clinical data, the need for reliable biomarkers, improved communication on adverse events (AEs) and well-trained study sites with ready access to intensive care units and clinical specialists. The need for a European-wide system for prevention of over-volunteering was also discussed. The conference provided opportunity to discuss these developments and concerns and the changing regulatory environment with stakeholders from academia, industry, and regulatory agencies including the European Medicines Agency (EMA). Presentations given by invited speakers are published on http://www.eufemed.eu/london-conference-2017/.

Drug disposition before and after gastric bypass: fenofibrate and posaconazole.

AIMS: Roux-en-Y gastric bypass (RYGB) alters the anatomical structure of the gastrointestinal tract, which can result in alterations in drug disposition. The aim of the present study was to evaluate the oral disposition of two compounds belonging to the Biopharmaceutical Classification System Class II - fenofibrate (bile salt-dependent solubility) and posaconazole (gastric pH-dependent dissolution) - before and after RYGB in the same individuals. METHODS: A single-dose pharmacokinetic study with two model compounds - namely, 67 mg fenofibrate (Lipanthyl®) and 400 mg posaconazole (Noxafil®) - was performed in 12 volunteers pre- and post-RYGB. After oral administration, blood samples were collected at different time points up to 48 h after administration. Plasma concentrations were determined by high-performance liquid chromatography in order to calculate the area under the concentration-time curve up to 48 h (AUC0-48 h ), the peak plasma concentration (Cmax) and the time to reach peak concentration (Tmax ). RESULTS: After administration of fenofibrate, no relevant differences in AUC0-48 h , Cmax and Tmax between the pre- and postoperative setting were observed. The geometric mean of the ratio of AUC0-48 h post/pre-RYGB for fenofibrate was 1.10 [95% confidence interval (CI) 0.87, 1.40; P = 0.40]. For posaconazole, an important decrease in AUC0-48 h and Cmax following RYGB was shown; the geometric mean of the AUC0-48 h post/pre-RYGB ratio was 0.68 (95% CI 0.48, 0.96; P = 0.03) and the geometric mean of the Cmax pre/post-RYGB ratio was 0.60 (95% CI 0.39, 0.94; P = 0.03). The decreased exposure of posaconazole could be explained by the increased gastric pH and accelerated gastric emptying of fluids post-RYGB. No difference for Tmax was observed. CONCLUSIONS: The disposition of fenofibrate was not altered after RYGB, whereas the oral disposition of posaconazole was significantly decreased following RYGB.

Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations.

AIMS: The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB. METHODS: A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6-8 months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB. RESULTS: After administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC(0-24 h)) was shown, although a tendency towards an increased oral exposure could be observed as the AUC(0-24 h) was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity. CONCLUSIONS: The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation.

Substantial variation in transplacental transfer of chemotherapeutic agents in a mouse model.

OBJECTIVE: Data on the transplacental transfer of chemotherapeutic agents are lacking. We aimed to measure the maternofetal transfer of cytotoxic drugs in a mouse model. STUDY DESIGN: The transplacental transfer of doxorubicin (9 mg/kg), epirubicin (11 mg/kg), vinblastine (6 mg/kg), carboplatin (50 mg/kg), paclitaxel (10 mg/kg), and cytarabine (100 mg/kg) was tested in a C57/Bl6J mouse model. Ninety minutes after intravenous (IV) drug injection on gestational day 18.5, maternal and fetal blood were collected simultaneously. Plasma drug levels were determined using high performance liquid chromatography or atomic absorption spectrometry. RESULTS: Fetal plasma concentrations of doxorubicin, epirubicin, vinblastine, and cytarabine were 5.1% ± 0.6% (n = 8), 4.8% ± 3.8% (n = 8), 13.8% ± 5.8% (n = 6), and 56.7% ± 22.6% (n = 6) of the maternal concentrations, respectively. Total platinum passed the mouse placenta easily (117.0% ± 38.9%, n = 6). Paclitaxel could not be detected in fetal plasma samples (n = 6). CONCLUSIONS: Substantial variations in transplacental transfer were noted among the tested drugs. Current findings contribute to the understanding of reported pregnancy outcomes in humans.

Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study.

OBJECTIVE: To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents. DESIGN: A preclinical and a clinical case-control trial. SETTING: Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic. POPULATION: Pregnant and nonpregnant women and baboons receiving chemotherapy. METHODS: Chemotherapy pharmacokinetics was compared between the pregnant and nonpregnant state. Standard-dosed chemotherapy regimens were administered in pregnant and nonpregnant baboons/women, followed by serial blood samplings. Drug plasma levels were determined using high performance liquid chromatography and atomic absorption spectrometry. MAIN OUTCOME MEASURES: Area under the curve (AUC), maximal plasma concentration, terminal elimination half-life, clearance and distribution volume of each drug in pregnant and nonpregnant state. RESULTS: Intraindividual comparative pharmacokinetic data were obtained for doxorubicin and paclitaxel/platinum in three and two baboons, respectively. In the clinical trial, two patients were exposed to doxorubicin and one patient was exposed to paclitaxel/platinum during and after pregnancy. Furthermore, a pooled analysis was performed based on 16 cycles of pregnant and 11 cycles of nonpregnant women. Numbers of pregnant/nonpregnant patients were 5/2, 7/5, 4/4 and 2/2 for paclitaxel, doxorubicin, epirubicin and platinum, respectively. For all drugs tested in the preclinical and clinical study, a decreased AUC and maximal plasma concentration and an increased distribution volume and clearance were observed in pregnancy. CONCLUSIONS: Although numbers were too small for statistical significance, pregnancy-associated physiologic alterations appear to lead to a decrease in plasma exposure of chemotherapeutic drugs. The importance of long-term follow-up of women treated with chemotherapy during pregnancy is underscored.

Transplacental transfer of paclitaxel, docetaxel, carboplatin, and trastuzumab in a baboon model.

BACKGROUND: The paucity of data on fetal effects of prenatal exposure to chemotherapy prompted us to study the transplacental transport of commonly used anticancer agents in a pregnant baboon model. METHODS: Single or combination chemotherapy with paclitaxel, docetaxel, carboplatin, and trastuzumab was administered to 9 baboons at a mean (SD) gestational age of 117 (26) days (paclitaxel, 100 mg/m2 [n = 2]; docetaxel, 100 mg/m2 [n = 2]; paclitaxel, 175 mg/m2 with carboplatin, area under the curve of 6 at standard dosage [n = 2] and 50% dosage [n = 1]; docetaxel, 75 mg/m2 with carboplatin, area under the curve 6 [n = 1]; and docetaxel, 75 mg/m2 with trastuzumab, 8 mg/kg [n = 1]). Serial fetal and maternal blood samples, amniotic fluid, maternal urine, and fetal and maternal tissue samples were collected for the first 76 hours after drug infusion. Levels of carboplatin were determined by atomic absorption spectrometry, docetaxel and paclitaxel by high-performance liquid chromatography, and trastuzumab by enzyme-linked immunosorbent assay. RESULTS: Fetal plasma concentrations of carboplatin averaged 57.5% (14.2%) of maternal concentrations (n = 7). Fetal plasma concentrations were 1.5% (0.8%) of maternal concentrations (n = 7). Immediately after ending the infusion, paclitaxel was not detectable in fetal tissues, whereas, after 3 hours, fetal tissues contained 15% of maternal tissue concentrations.Docetaxel could not be detected in fetal blood samples (n = 9). In the first 3 hours after docetaxel infusion, fetal tissues contained 5.0% to 50.0% of maternal tissue concentrations, whereas equal fetal and maternal tissue concentrations were found after 26 and 76 hours.The transplacental passages of trastuzumab were 85.0% and 3.0%, 2 and 26 hours after trastuzumab infusion, respectively. After 26 hours, amniotic fluid contained 36.4% of the fetal plasma concentration. Fetal tissue concentrations varied between 5.0% and 14.0% of the maternal concentration. CONCLUSION: Variable plasma and/or tissue concentrations of taxanes, carboplatin, and trastuzumab were encountered in the fetal compartment. These data are important when cancer treatment is considered during pregnancy and underline the need for long-term follow-up of children after prenatal exposure to these cytotoxic agents.

Cefazolin plasma protein binding saturability during pregnancy.

This article aims to document cefazolin (CFZ) plasma binding and its covariates during pregnancy and compare these observations with previously reported observations in nonpregnant adults. Maternal CFZ plasma samples were collected during in utero surgery. The unbound CFZ fraction was reported by median and range. Correlation (Spearman) and multiple regression were used to identify covariates (total CFZ concentration, albuminemia, gestational age) of the unbound CFZ fraction. Observations during pregnancy were compared with observations in nonpregnant adults (unpaired t test, multiple regression). Plasma (N = 130) samples were collected during 30 interventions. The median unbound CFZ fraction was 0.25 (range 0.14-0.41). Correlations between the unbound CFZ fraction and total CFZ plasma concentration (0.46), time after administration (-0.38), albuminemia (-0.39) and gestational age (-0.19) were statistically significant. The median unbound CFZ fraction was higher during pregnancy when compared to observations in nonpregnant adults (0.25 vs. 0.19, P < 0.001). In a multiple-regression model, total plasma CFZ concentration and albuminemia were covariates of the unbound CFZ fraction (r(2) = 0.4). The concept of saturability of CFZ plasma protein binding has been confirmed during pregnancy, but the free CFZ fraction is higher, likely explained by the lower albuminemia during pregnancy.

Cefazolin pharmacokinetics in maternal plasma and amniotic fluid during pregnancy.

OBJECTIVE: To study cefazolin pharmacokinetics in maternal plasma and amniotic fluid during pregnancy. STUDY DESIGN: Newly collected time-concentrations profiles and reported studies investigating cefazolin disposition (plasma, amniotic fluid) were pooled. Nonlinear mixed effect modeling was applied. A 2-compartment linear disposition model was used to fit cefazolin plasma observations. A third compartment was used to model amniotic fluid concentration. RESULTS: One hundred eighty-seven plasma and 96 amniotic fluid samples were collected in 82 pregnancies (17-40 weeks gestational age). Cefazolin clearance and distribution estimates were 7.44 L/h and 12.04 L without gestational age-dependent trends in maternal plasma. The equilibration half-life (T(eq)) between plasma and amniotic fluid at term gestational age was 4.4 hours, increased with decreasing gestational age, and was 9.09 times longer in patients with polyhydramnios. CONCLUSION: Cefazolin clearance and distribution volume are increased during pregnancy. The cefazolin T(eq) depends on gestational age and polyhydramnios. On the basis of these observations, dosing regimes to attain higher amniotic fluid concentrations were formulated.

Calcitonin gene-related peptide: exploring its vasodilating mechanism of action in humans.

OBJECTIVE: In vitro studies suggest that the vasodilator mechanism of action of calcitonin gene-related peptide (CGRP) involves various endothelium-dependent and endothelium-independent mechanisms. An in vivo analysis of the contribution of nitric oxide, prostaglandins, calcium-sensitive potassium channels (K(+)(Ca) channels), and adenosine triphosphate (ATP)-sensitive potassium channels (K(+)(ATP) channels) to CGRP-induced vasodilation in humans was performed. METHODS: CGRP (3, 10, and 30 ng x min(-1) x dL(-1) forearm) was infused into the brachial artery of 40 healthy subjects. Forearm vascular responses were measured by venous occlusion plethysmography. First, dose-response curves were constructed during coinfusion of CGRP with placebo (sodium chloride, 0.9%). After washout, in 5 subgroups (n = 8 each), the infusions of CGRP were repeated with placebo (time-control experiments), N(G)-monomethyl-L-arginine (L-NMMA, a nitric oxide-synthase inhibitor), indomethacin (a cyclooxygenase inhibitor), tetraethylammonium chloride (TEAC) (a K(+)(Ca)-channel blocker), and glyburide (INN, glibenclamide) (a K(+)(ATP)-channel blocker), respectively. RESULTS: CGRP induced a dose-dependent and reproducible decrease in forearm vascular resistance (P < .001). Compared with placebo, L-NMMA reduced the decrease in forearm vascular resistance induced by CGRP (P < .001) (3 and 10 ng x min(-1) x dL(-1) forearm). The absence of an inhibitory effect of L-NMMA on CGRP-induced vasodilation at the highest dose of CGRP suggests that still other mechanisms are involved. The vasodilator response to CGRP was not affected by coinfusion of indomethacin, tetraethylammonium chloride, or glyburide. CONCLUSIONS: The intrabrachial infusion of CGRP results in a dose-dependent and reproducible forearm vasodilator response. CGRP-induced vasodilation is dependent at least in part on the release of nitric oxide and does not involve the release of prostaglandins or the activation of K(+)(Ca) channels or K(+)(ATP) channels in humans.