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Mechanistic model‐based simulations can be deployed to project the persistence of humoral immune response following vaccination. We used this approach to project the antibody persistence through 24 months from the data pooled across five clinical trials in severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2)‐seronegative participants following vaccination with Ad26.COV2.S (5 × 1010 viral particles), given either as a single‐dose or a homologous booster regimen at an interval of 2, 3, or 6 months. Antibody persistence was quantified as the percentage of participants with detectable anti‐spike binding and wild‐type virus neutralizing antibodies. The projected overall 24‐month persistence after single‐dose Ad26.COV2.S was 70.5% for binding antibodies and 55.2% for neutralizing antibodies, and increased after any homologous booster regimen to greater than or equal to 89.9% for binding and greater than or equal to 80.0% for neutralizing antibodies. The estimated model parameters quantifying the rates of antibody production attributed to short‐lived and long‐lived plasma cells decreased with increasing age, whereas the rate of antibody production mediated by long‐lived plasma cells was higher in women relative to men. Accordingly, a more pronounced waning of antibody responses was predicted in men aged greater than or equal to 60 years and was markedly attenuated following any homologous boosting regimen. The findings suggest that homologous boosting might be a viable strategy for maintaining protective effects of Ad26.COV2.S for up to 24 months following prime vaccination. The estimation of mechanistic modeling parameters identified the long‐lived plasma cell pathway as a key contributor mediating antibody persistence following single‐dose and homologous booster vaccination with Ad26.COV2.S in different subgroups of recipients stratified by age and sex. [ABSTRACT FROM AUTHOR]

The population pharmacokinetic (PK) and exposure–response (E–R) analyses for the safety of ibrutinib for the treatment of chronic graft‐versus‐host disease (cGVHD) is presented. This work aims to develop a population PK model for ibrutinib based on data from clinical studies in subjects with cGVHD, to evaluate the impact of intrinsic and extrinsic factors on PK parameters as well as systemic exposure levels, and to assess an E–R relationship for selected safety end points. Pooled data from 162 subjects with cGVHD enrolled in 4 clinical studies were included in the population PK analysis. In the studies, an ibrutinib dose of 420 mg once daily was administered orally. With the exception of 1 study, the study protocols instructed for a reduction of the ibrutinib dose to 140 or 280 mg once daily, depending on concomitant CYP3A inhibitor use. Concomitant CYP3A inhibitor use was found to be a primary covariate for relative bioavailability (F1): the F1 value increased 2.22‐fold with concomitant moderate CYP3A inhibitors and 3.09‐fold with concomitant strong CYP3A inhibitors, compared with the F1 value in the absence of CYP3A inhibitors. In addition, Japanese ethnicity led to an F1 value that was 1.70‐fold higher than that in the non‐Japanese population. Simulations using the final PK model suggest that ibrutinib exposure was appropriately controlled within the therapeutic range in the entire cGVHD population by applying dose reductions depending on the use of CYP3A inhibitors, and that additional dose modification for the Japanese population would not be required. The subsequent E–R analysis suggests no apparent association between the systemic exposure to ibrutinib and the selected safety end points. [ABSTRACT FROM AUTHOR]

Guselkumab is a human IgG1λ monoclonal antibody that has been approved for treatment of multiple immunologic diseases including palmoplantar pustulosis in Japan. The efficacy of guselkumab in reducing disease severity as compared with placebo has been demonstrated in phase 2 and 3 clinical studies. In some patients assigned to the placebo treatment, worsening of Palmoplantar Pustulosis Area and Severity Index (PPPASI) score was noted. Most of these patients were smokers, raising a possibility of an association of smoking with the disease progression. To understand the clinical implications of guselkumab dose, baseline disease severity, and smoking on the treatment effect and describe the longitudinal relationship between guselkumab exposure and the PPPASI score, a pharmacokinetic/pharmacodynamic modeling analysis was conducted using the pooled data from 1 phase 2 and 1 phase 3 study. Data from 207 Japanese patients (77% women and 60% smokers) with a median PPPASI score of 24.6 were included in the analysis. The observed treatment efficacy (the PPPASI score reduction) appeared to be similar at the current approved dose (100 mg) and the higher dose (200 mg). A greater PPPASI score reduction (in absolute points) is expected in patients with higher baseline PPPASI score (severe disease). However, the higher baseline did not translate to larger magnitude of the change from baseline (in percentage) in the PPPASI score. Incorporating a linear disease progression effect in the model significantly decreased the Nonlinear Mixed Effects Modeling objective function value (P <.001). Smoking status appeared to be related to disease worsening in some patients, but the covariate did not reach statistical significance in the model. [ABSTRACT FROM AUTHOR]

Abstract: This single‐center, double‐blind, placebo‐controlled, sequential‐group phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of mavatrep (JNJ‐39439335), a transient receptor potential vanilloid 1 antagonist, in healthy Japanese and caucasian subjects. In part 1, a single‐ascending‐dose study, 50 subjects (25 each healthy Japanese and caucasians) were enrolled and received a single oral dose of 10, 25, or 50 mg mavatrep. Caucasian subjects were matched to Japanese subjects with respect to age (±5 years) and body mass index (±5 kg/m2). In part 2, a multiple‐ascending‐dose study, 36 Japanese subjects were enrolled and received once‐daily oral doses of 10, 25, or 50 mg of mavatrep for 21 days. The single‐dose PK of mavatrep and its metabolites was similar in the Japanese and caucasian subjects after adjustment of body weight. Following multiple dosing in Japanese subjects, a steady‐state condition was reached in approximately 14 days. M2 and M3 are major circulating metabolites with mean exposure > 10% of mavatrep. Nonrenal clearance was the major route of elimination for mavatrep, M2, and M3. Mavatrep exhibited a long half‐life, ranging from 68 to 101 and 82–130 hours for Japanese and caucasian subjects, respectively. After single and multiple dosing, mavatrep was well tolerated. The most common adverse events observed were thermohypoesthesia, feeling cold, chills, and feeling hot. Mavatrep and its metabolites exhibited similar PK profiles after single ascending doses in healthy Japanese and caucasian men. [ABSTRACT FROM AUTHOR]

The dimensional accuracy of optical bite registration in the CEREC system was compared to that of the conventional physical method in vitro using a bite registration material. Maxillary and mandibular full-arch dentate epoxy models mounted on an articulator were used to measure the interarch distance and the angles created by the occlusal planes. The preparations for a single restoration on the maxillary first molar or for multiple restorations on the maxillary posterior quadrant were made on the model. Optical impression and bite registration data were collected to construct virtual models using computer-aided design software. A silicone material was used for the physical method, and the dimensional accuracy was measured by means of the coordinate measuring machine. The discrepancy relative to the baseline before preparation was analyzed in each registration record. For the single restoration, the optical method created a mean discrepancy of 243.2 µm relative to baseline at the prepared tooth, which was insignificantly but slightly lower than the mean discrepancy of 311.1 µm obtained with the physical method. The mean rotational deviation in the horizontal plane was significantly lower for the optical method. For the multiple preparations, the optical method showed significantly larger discrepancy on the right molar and on the left premolar and molar sites. In the frontal view, the optical method created significantly larger rotational deviation than the physical method. The result indicates that the optical bite registration was effective in terms of dimensional accuracy for single posterior restorations. [ABSTRACT FROM AUTHOR]

Abstract: First convergent synthesis of (+)-myxothiazol A (1) was achieved based on modified (one-pot) Julia olefination between (3,5R)-dimethoxy-(4R)-methyl 6-oxo-(2E)-hexenamide (2), corresponding to left-side of the final molecule, and E-4-2′-(1S,6-dimethylheptadiene)-(2,4′-bis-thiazole)-4-methybenzothiazole sulfone (4) corresponding to right-side. [Copyright &y& Elsevier]

Abstract: We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K+ channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain. [Copyright &y& Elsevier]

Abstract: We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine. [Copyright &y& Elsevier]