Ixekizumab Citrate-Free Formulation : Results from Two Clinical Trials

Introduction: Subcutaneous (SC) injection is a common route of drug administration; however, injection site pain (ISP) might create a negative patient experience. We evaluated ISP, bioequivalence, and overall safety of the citrate-free (CF) formulation of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A. Methods: Two phase 1, single-blind studies were conducted in healthy participants. The crossover study A (NCT03848403) evaluated pain intensity on injection as measured by visual analog scale of pain (VAS) scores. Subjects (N = 70) were randomized 1:1:1 at the beginning to three possible treatment sequences and received a 1 mL SC injection of the three formulations sequentially in the abdomen on days 1, 8, and 15, respectively. A mixed-effects repeated measures analysis model was used to analyze VAS score by time post-injection. Study B (NCT04259346) evaluated the bioequivalence of a single 80 mg dose of CF formulation compared to the original commercial formulation. Subjects (N = 245) were randomized 1:1 to either commercial or CF formulation and received a single SC injection into the abdomen, arm, or thigh. Results: Primary endpoint was achieved in both studies. In study A, least-squares mean (LSM) difference of VAS scores immediately post injection between commercial (n = 61) and CF formulation (n = 63) was − 21.7 (p < 0.0001), indicating a lower degree of pain associated with CF formulation. In study B, bioequivalence of the CF formulation was established as 90% CIs for the ratio of geometric LSM AUC, AUC, and C between treatments were contained within the prespecified limits of 0.8 and 1.25. Except for less ISP in the CF formulation, overall safety profile was comparable. Conclusion: Ixekizumab CF formulation proved to be bioequivalent, was associated with less ISP, and had no other notable differences in the safety profile compared to the original commercial formulation. Trail Registration: ClinicalTrials.gov identifier NCT03848403, NCT04259346

Counting function fluctuations and extreme value threshold in multifractal patterns: the case study of an ideal 1/f1/f noise

To understand the sample-to-sample fluctuations in disorder-generated multifractal patterns we investigate analytically as well as numerically the statistics of high values of the simplest model - the ideal periodic $1/f$ Gaussian noise. By employing the thermodynamic formalism we predict the characteristic scale and the precise scaling form of the distribution of number of points above a given level. We demonstrate that the powerlaw forward tail of the probability density, with exponent controlled by the level, results in an important difference between the mean and the typical values of the counting function. This can be further used to determine the typical threshold $x_m$ of extreme values in the pattern which turns out to be given by $x_m^{(typ)}=2-c\ln{\ln{M}}/\ln{M}$ with $c=3/2$. Such observation provides a rather compelling explanation of the mechanism behind universality of $c$. Revealed mechanisms are conjectured to retain their qualitative validity for a broad class of disorder-generated multifractal fields. In particular, we predict that the typical value of the maximum $p_{max}$ of intensity is to be given by $-\ln{p_{max}} = \alpha_{-}\ln{M} + \frac{3}{2f'(\alpha_{-})}\ln{\ln{M}} + O(1)$, where $f(\alpha)$ is the corresponding singularity spectrum vanishing at $\alpha=\alpha_{-}>0$. For the $1/f$ noise we also derive exact as well as well-controlled approximate formulas for the mean and the variance of the counting function without recourse to the thermodynamic formalism.Comment: 28 pages; 7 figures, published version with a few misprints corrected, editing done and references adde

Ovine Fetal Thymus Response to Lipopolysaccharide-Induced Chorioamnionitis and Antenatal Corticosteroids

RATIONALE: Chorioamnionitis is associated with preterm delivery and involution of the fetal thymus. Women at risk of preterm delivery receive antenatal corticosteroids which accelerate fetal lung maturation and improve neonatal outcome. However, the effects of antenatal corticosteroids on the fetal thymus in the settings of chorioamnionitis are largely unknown. We hypothesized that intra-amniotic exposure to lipopolysaccharide (LPS) causes involution of the fetal thymus resulting in persistent effects on thymic structure and cell populations. We also hypothesized that antenatal corticosteroids may modulate the effects of LPS on thymic development. METHODS: Time-mated ewes with singleton fetuses received an intra-amniotic injection of LPS 7 or 14 days before preterm delivery at 120 days gestational age (term = 150 days). LPS and corticosteroid treatment groups received intra-amniotic LPS either preceding or following maternal intra-muscular betamethasone. Gestation matched controls received intra-amniotic and maternal intra-muscular saline. The fetal intra-thoracic thymus was evaluated. RESULTS: Intra-amniotic LPS decreased the cortico-medullary (C/M) ratio of the thymus and increased Toll-like receptor (TLR) 4 mRNA and CD3 expression indicating involution and activation of the fetal thymus. Increased TLR4 and CD3 expression persisted for 14 days but Foxp3 expression decreased suggesting a change in regulatory T-cells. Sonic hedgehog and bone morphogenetic protein 4 mRNA, which are negative regulators of T-cell development, decreased in response to intra-amniotic LPS. Betamethasone treatment before LPS exposure attenuated some of the LPS-induced thymic responses but increased cleaved caspase-3 expression and decreased the C/M ratio. Betamethasone treatment after LPS exposure did not prevent the LPS-induced thymic changes. CONCLUSION: Intra-amniotic exposure to LPS activated the fetal thymus which was accompanied by structural changes. Treatment with antenatal corticosteroids before LPS partially attenuated the LPS-induced effects but increased apoptosis in the fetal thymus. Corticosteroid administration after the inflammatory stimulus did not inhibit the LPS effects on the fetal thymus

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Not AvailableThe study was conducted on 56 female camels for E2 and P4 profiles at different reproductive stages, viz. 35bred females (Group A) monitored after breeding once daily for 0-30 days were divided into 2 groups of pregnant (n=13) and nonpregnant (n=22) based on P4 profiles, another pregnant group (Group B) (n=8) was monitored at weekly intervals from 23rd weeks to the end of gestation; periparturient camels (Group C) were monitored at 6h intervals, while nonpregnant females (n=7) (Group D) with growing and mature follicles were monitored for E2 profiles before and after mating. The average P4 concentrations in pregnant and nonpregnant femals of group A were similar from days 0-10 after mating. They declined from day 11 onward in nonpregnant females, but continued to increase in pregnant animals (P<0.01). The average daily E2 profiles were found to be low or basal in both non-pregnant (1.32 to 8.74 pg/ml) and pregnant femals (0.69 to8.24 pg/ml). The average concentration of p4 in group B was relatively higher (5.87 to 12.07 ng/ml) between 23rd to 32nd weeks of gestation than at later stages (2.88 to 5.09 ng/ml). The average concentration of P4 trcorded in periparturient female camels og group c was around 4.0-4.5 ng/ml at 55-31 hrs prior to parturition and declined slightly to measure 3 ng/ml at parturition. It started to increase slowly and steadily after the 39th week and measured more than 50, 100, 250, 300 and 375 pg/ml at the 42nd, 45th, 47th, 49th, and 52nd weeks of gestation, respectively. It decline in periparturient females to 92.2-243 g/ml at 1-55 hrs before calving. It further declined sharply to 23.3, 5.6 and 6.6 pg/ml at 5, 11 and 17 hrs after calving. E2 profile of nonpregnent females of group D (n=7) with mature sized ovarian follicles monitored at 30 minute intervals for 2 hrs daily for 15-20 days (for E2 profiles only) revealed mostly basal levels with a few intermittent peaks, indicating the pulsatile nature its secretion. One grou of nonpregnant females, Group E (n=6) with mature follicles monitored for E2 profiles only, one day prior to and immediately after mating showed that E2 profiles are these times did not differNot Availabl

Not Available

Not AvailableThe study was conducted on 56 female camels for E2 and P4 profiles at different reproductive stages, viz. 35 bred females (Group A) monitored after breeding once daily for 0-30 days were divided into 2 groups of pregnant (n=13)and nonpregnant (n=22)based on P4 profiles, another pregnant group (Group B) (n=8)was monitored at weekly intervals from 23 rd weeks to the end of gestation; periparturient camels (Group C) were monitored at 6h intervals, while nonpregnant females (n=7) (Group D) with growing and mature follicles were monitored for E2 profiles only and the final group (Group E) (n=6)of nonpregnant females was monitored for E2 profiles before and after mating. The average P4 concentrations in pregnant and nonpregnant females of group A were similar from days 0 -10 after mating. They declined from day 11 onward in nonpregnant females, but continued to increase in pregnant animals (P<0.01). The average daily E2 profiles were found to be low or basal in both non-pregnant (1.32 to 8.74 pg/ml) and pregnant females (0.69 to 8.24 pg/ml). The average concentration of P4 in group B was relatively higher (5.87 to 12.07 ng/ml) between 23rd to 32nd weeks of gestation than at later stages (2.88 to 5.09 ng/ml). The average concentration of P4 recorded in periparturient female camels of Group C was around 4.0-4.5 ng/ml at 55-31 hrs prior to parturition and declined slightly to measure 3 ng/ml at parturition. A further decline in P4 concentration to 1.6 ng/ml occurred after expulsion of the fetus. The average concentration of E2 was low up to 38th weeks of gestation. It started to increase slowly and steadily after the 39th week and measured more than 50, 100, 250, 300 and 375 pg/ml at the 42nd, 45th, 47th, 49th and 52nd weeks of gestation, respectively. It declined in periparturient females to 92.2-243 g/ml at 1-55 hrs before calving. It further declined sharply to 23.3, 5.6 and 6.6 pg/ml at 5, 11 and 17 hrs after calving. E2 profiles of nonpregnant females of group D (n=7)with mature sized ovarian follicles monitored at 30 minute intervals for 2 hrs daily for 15-20 days (for E2 profiles only) revealed mostly basal levels with a few intermittent peaks, indicating the pulsatile nature its secretion. One group of nonpregnant females, Group E (n=6) with mature follicles monitored for E2 profiles only, one day prior to and immediately after mating showed that E2 profiles ar these times did not differNot Availabl