Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Co-administered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults

Despite repeated malaria infection, individuals living in malaria endemic areas remain vulnerable to re-infection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with anti-malarial therapy. This randomized, single-blind, placebo-controlled, single center phase 1 trial investigated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants aged 18–55 years were randomized to either ruxolitinib (20 mg) ( n = 6) or placebo ( n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for three days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether) and lumefantrine exposure were not affected by ruxolitinib co-administration. Ruxolitinib co-administration resulted in a 3-fold greater pSTAT3 inhibition compared to placebo (geometric mean ratio: 3.01 [90%CI 2.14, 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634).

Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial

Objective To evaluate whether extended release metformin could be used to prolong gestation in women being expectantly managed for preterm pre-eclampsia. Design Randomised, double blind, placebo controlled trial. Setting Referral hospital in Cape Town, South Africa. Participants 180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks’ gestation undergoing expectant management: 90 were randomised to extended release metformin and 90 to placebo. Intervention 3 g of oral extended release metformin or placebo daily, in divided doses, until delivery. Main outcome measure The primary outcome was prolongation of gestation. Results Of 180 participants, one woman delivered before taking any trial drug. The median time from randomisation to delivery was 17.7 days (interquartile range 5.4-29.4 days; n=89) in the metformin arm and 10.1 (3.7-24.1; n=90) days in the placebo arm, a median difference of 7.6 days (geometric mean ratio 1.39, 95% confidence interval 0.99 to 1.95; P=0.057). Among those who continued to take the trial drug at any dose, the median prolongation of gestation in the metformin arm was 17.5 (interquartile range 5.4-28.7; n=76) days compared with 7.9 (3.0-22.2; n=74) days in the placebo arm, a median difference of 9.6 days (geometric mean ratio 1.67, 95% confidence interval 1.16 to 2.42). Among those who took the full dosage, the median prolongation of gestation in the metformin arm was 16.3 (interquartile range 4.8-28.8; n=40) days compared with 4.8 (2.5-15.4; n=61) days in the placebo arm, a median difference of 11.5 days (geometric mean ratio 1.85, 95% confidence interval 1.14 to 2.88). Composite maternal, fetal, and neonatal outcomes and circulating concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin did not differ. In the metformin arm, birth weight increased non-significantly and length of stay decreased in the neonatal nursery. No serious adverse events related to trial drugs were observed, although diarrhoea was more common in the metformin arm. Conclusions This trial suggests that extended release metformin can prolong gestation in women with preterm pre-eclampsia, although further trials are needed. It provides proof of concept that treatment of preterm pre-eclampsia is possible. Trial registration Pan African Clinical Trial Registry PACTR201608001752102 https://pactr.samrc.ac.za/ .

Pharmacokinetics and Bioequivalence of Sitagliptin Phosphate/Metformin Hydrochloride Tablets in Healthy Chinese Subjects: A Randomized, Open, Crossover Study

Objective To evaluate the pharmacokinetics and bioequivalence between Sitagliptin Phosphate/metformin Hydrochloride Tablets (test formulation) at a single dose of 50mg/850mg and Sitagliptin Phosphate/metformin Hydrochloride Tablets (reference formulation, JANUMET®) at a single dose of 50mg/850mg in healthy Chinese subjects.Methods The study was designed as a randomized, open-lable, two-period double-crossover trial. A total of 24 volunteers under fasting condition and 24 subjects under fed condition were given a single oral dose of 50mg/850mg Sitagliptin Phosphate/metformin Hydrochloride Tablets of test and reference, respectively. Liquid chromatography Tandem mass spectrometry (LC-MS/MS) method was used to determine the concentrations of sitagliptin and metformin in the plasma of subjects. The pharmacokinetic parameters were calculated by WinNonlin 7.0 program and the bioequivalence was evaluated by SAS 9. 4program. Results The 90% confidential interval (CI) of geometric mean ratio under fasting condition for Cmax, AUC0-t and AUC0-∞ of sitagliptin between the test group and the reference group were 101.70%-120.62%, 99.81%-105.61%, 100.27%-106.12% and metformin were 90.39%-111.48%, 94.76%-109.12%, 95.76%-110.38%. The 90% CI of geometric mean ratio under fed condition for Cmax, AUC0-t and AUC0-∞ between the test group and the reference group were 102.12%-117.31%, 100.80%-107.81%, 100.82%-107.78% and metformin were 95.53%-105.22%, 92.76%-103.07%, 93.40%-104.14%. Both were generally well tolerated.Conclusion The two formulations of Sitagliptin Phosphate/metformin Hydrochloride Tablets were bioequivalent under fasting and fed condition in healthy Chinese subjects.Trial registration Clinical Trial Registry (trial ID: NCT04877106).

Extracellular vesicles and citrullinated histone H 3 in coronavirus disease 2019 (COVID-19) patients

Objectives Pulmonary thrombus formation is a hallmark of coronavirus disease 2019 (COVID-19). A dysregulated immune response culminating in thromboinflammation has been described, but the pathomechanisms remain unclear. Methods We studied 41 adult COVID-19 patients with positive results on reverse-transcriptase polymerase-chain-reaction assays and 37 sex-and age-matched healthy controls. Number and surface characteristics of extracellular vesicles (EV) and citrullinated histone H 3 levels were determined in plasma upon inclusion by flowcytometry and immunoassay. Results 20 patients had severe and 21 non-severe disease. The number of EV [median, (25th, 75th percentile)] was significantly higher in patients compared with controls [658.8 (353.2, 876.6) vs 435.5 (332.5, 585.3), geometric mean ratio (95% confidence intervals): 2.6 (1.9, 3.6); p<0.001]. Patients exhibited significantly higher numbers of EV derived from platelets, endothelial cells, leukocytes, or neutrophils than controls. EV from alveolar-macrophages and alveolar-epithelial-cells were detectable in plasma and were significantly higher in patients. Intercellular Adhesion Molecule 1-positive EV levels were higher in patients, while no difference between tissue factor-positive and angiotensin converting enzyme-positive EV was seen between both groups. Levels of EV did not differ between patients with severe and non-severe COVID-19. Citrullinated histone H 3 levels [ng/ml, median (25th, 75th percentile)] were higher in patients than in controls [1.42 (0.6, 3.4) vs 0.31 (0.1, 0.6), geometric mean ratio: 4.44 (2.6, 7.7); p<0.001], and were significantly lower in patients with non-severe disease compared to those with severe disease. Conclusion EV and citrullinated histone H 3 are associated with COVID-19 and could provide information regarding pathophysiology of the disease.

Effect of Dihydroartemisinin-Piperaquine on the Pharmacokinetics of Praziquantel for Treatment of Schistosoma mansoni Infection

Praziquantel (PZQ) and dihydroartemisinin-piperaquine (DHP) combination recently showed superior effectiveness than PZQ alone to treat intestinal schistosomiasis. In this follow-up study, we investigated the effect of DHP co-administration on the pharmacokinetics of PZQ and its enantiomers among 64 Schistosoma mansoni infected children treated with PZQ alone (n = 32) or PZQ + DHP combination (n = 32). Plasma samples collected at 0, 1, 2, 4, 6, and 8 h post-dose were quantified using UPLCMS/MS. The geometric mean (GM) of AUCs for total PZQ, R-PZQ and S-PZQ were significantly higher among children who received PZQ + DHP than PZQ alone. The geometric mean ratio (GMR) and (90% CI) of AUC0–∞ for PZQ + DHP to PZQ for total PZQ, R-PZQ, and S-PZQ were 2.18 (1.27, 3.76), 3.98 (2.27, 7.0) and 1.86 (1.06, 3.28), respectively. The GMR and (90% CI) of AUC0–8 for total PZQ, R-PZQ, and S-PZQ were 1.73 (1.12, 2.69), 2.94 (1.75, 4.92), and 1.50 (0.97, 2.31), respectively. The GM of Cmax for total PZQ, R-PZQ and S-PZQ were significantly higher among those who received PZQ + DHP than PZQ alone. The GMR (90% CI) of Cmax of PZQ + DHP to PZQ for total PZQ, R-PZQ, and S-PZQ were 1.75 (1.15, 2.65), 3.08 (1.91, 4.96), and 1.50 (1.0, 2.25%), respectively. The 90% CI of the GMRs for both AUCs and Cmax for total PZQ, R-PZQ, and S-PZQ were outside the acceptable 0.80–1.25 range, indicating that the two treatment arms were not bioequivalent. DHP co-administration significantly increases systemic PZQ exposure, and this may contribute to increased effectiveness of PZQ + DHP combination therapy than PZQ alone to treat schistosomiasis.

Oral paclitaxel with encequidar compared to intravenous paclitaxel in patients with advanced cancer: a randomised crossover pharmacokinetic study.

Background and purpose: Paclitaxel is a widely used anti-neoplastic agent but has low oral bioavailability due to gut extrusion by P-glycoprotein (P-gp). Oral paclitaxel could be more convenient, less resource intensive, and more tolerable than intravenous administration. Encequidar (HM30181A) is a novel, minimally absorbed gut specific P-gp inhibitor. We tested whether administration of oral paclitaxel with encequidar (oPac+E) achieved comparable AUC to intravenous paclitaxel (IVP) 80mg/m2. Experimental approach: We conducted a multi-centre randomised crossover study with two treatment periods. Patients (pts) with advanced cancer received either oral paclitaxel 615mg/m2 divided over three days and encequidar 15mg orally one-hour prior, followed by IVP 80mg/m2, or the reverse sequence. PK blood samples were taken up to day 9 for oPac+E and day 5 for IVP. Key Results: 42 pts were enrolled; 35 completed both treatment periods. AUC0-∞was 5033.5 +/- 1401.1 ng.h/mL for oPac+E and 5595.9 +/- 1264.1 ng.h/mL with IVP. The geometric mean ratio (GMR) for AUC was 89.5% (90% CI 83.9-95.5). Mean absolute bioavailability of oPac+E was 12%. PK parameters did not change meaningfully after 4 weeks administration of oPac+E in an extension study. G3 treatment emergent adverse events occurred in 7 (18%) pts with oPac+E and 2 (5%) with IVP. 75% of pts preferred oPac+E over IVP. Conclusion and Implications: GMR for AUC was within the predefined acceptable range of 80%-125% for demonstrating equivalence. oPac+E is tolerable and there is no evidence of P-gp induction with repeat administration. With further study, oPac+E is a candidate to replace IVP.

Nevirapine pharmacokinetics in HIV-infected persons receiving rifapentine and isoniazid for TB prevention

Background The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug–drug interactions with concomitantly used ART. Objectives To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and isoniazid for TB prevention in people living with HIV. Methods Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/isoniazid was calculated. Results Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13–66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266–9302) ng/mL; week 2, 5537 (3552–8462) ng/mL; and week 4, 5388 (3516–8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/isoniazid, 2.03 (1.58–2.58) L/h; and during rifapentine/isoniazid, 2.62 (1.81–3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26–1.33). Conclusions The CL/F of nevirapine significantly increased with concomitant rifapentine/isoniazid. The decrease in nevirapine trough concentrations during rifapentine/isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug–drug interaction suggests daily rifapentine/isoniazid for TB prevention should not be co-administered with nevirapine-containing ART.

ALT Trends through Childhood and Adolescence Associated with Hepatic Steatosis at 24 Years: A Population-Based UK Cohort Study

(1) Background: Alanine aminotransferase (ALT) is used to screen for non-alcoholic fatty liver disease (NAFLD) in children; however, the optimal age to commence screening is not determined. Our objective was to describe whether ALT trends from 9–24 years were associated with hepatic steatosis at 24 years in a population-based UK cohort. (2) Methods: The sample included 1156 participants who were assessed for hepatic steatosis at 24 years and had at least two ALT measurements at 9, 15, 17, and/or 24 years. Controlled attenuation parameter scores were used to assess steatosis (low (<248 dB/m), mild/moderate (248–279 dB/m), severe (>279 dB/m)). Sex-stratified mixed-effects models were constructed to assess the liver enzyme trends by steatosis level. (3) Results: The final sample was 41.4% male and 10.4% had severe steatosis. In both sexes, ALT trends from 9 to 24 years differed in those with low vs. severe steatosis at 24 years (p < 0.001). There was no evidence of differences prior to puberty. At 17 years, the low vs. severe geometric mean ratio (GMR) was 0.69, 95% CI: 0.57–0.85 in males and (0.81, 0.65–1.01) females. At 24 years, the GMR was (0.53, 0.42–0.66) in males and (0.67, 0.54–0.84) females. (4) Conclusions: Higher ALT concentration in adolescence was associated with hepatic steatosis at 24 years. The increased screening of adolescents could strengthen NAFLD prevention and treatment efforts.

THE EFFECTS OF PERIOPERATIVE DEXAMETHASONE ON GLYCEMIC CONTROL AND POSTOPERATIVE OUTCOMES

Objective: Perioperative glucocorticoids are commonly given to reduce pain and nausea in patients undergoing surgery. However, the glycemic effects of steroids and the potential effects on morbidity and mortality have not been systematically evaluated. This study investigated the association between perioperative dexamethasone and postoperative blood glucose, hospital length of stay (LOS), readmission rates, and 90-day survival. Methods: Data from 4,800 consecutive orthopedic surgery patients who underwent surgery between 2000 and 2016 within a single health system were analyzed retrospectively. Results: Patients with and without diabetes mellitus (DM) who were given a single dose of dexamethasone had higher rates of hyperglycemia during the first 24 hours after surgery as compared to those who did not receive dexamethasone (hazard ratio [HR] was 1.81, and 95% confidence interval [CI] was [1.46, 2.24] for the DM cohort; HR 2.34, 95% CI [1.66, 3.29] for the nonDM cohort). LOS was nearly 1 day shorter in patients who received dexamethasone (geometric mean ratio [GMR] 0.79, 95% CI [0.75, 0.83] for patients with DM; GMR 0.75, 95% CI [0.72, 0.79] for patients without DM), and there was no difference in 90-day readmission rates. In patients without DM, dexamethasone was associated with a higher 90-day overall survival (99.07% versus 96.90%; P = .004). Conclusion: In patients with and without DM who undergo orthopedic surgery, perioperative dexamethasone was associated with a transiently higher risk of hyperglycemia. However, dexamethasone treatment was associated with a shorter LOS in patients with and without DM, and a higher overall 90-day survival rate in patients without DM, compared to patients who did not receive dexamethasone. Abbreviations: BMI = body mass index; CAD = coronary artery disease; CI = confidence interval; DM = diabetes mellitus; GMR = geometric mean ratio; HR = hazard ratio; IV = intravenous; LOS = length of stay; POD = postoperative day

Interaction between Fexofenadine and CYP Phenotyping Probe Drugs in Geneva Cocktail

Drug metabolic enzymes and transporters are responsible for an important variability in drug disposition. The cocktail approach is a sound strategy for the simultaneous evaluation of several enzyme and transporter activities for a personalized dosage of medications. Recently, we have demonstrated the reliability of the Geneva cocktail, combining the use of dried blood spots (DBS) and reduced dose of phenotyping drugs for the evaluation of the activity of six cytochromes and P-glycoprotein (P-gp). As part of a study evaluating potential drug–drug interactions between probe drugs of the Geneva cocktail, the present paper focuses on the impact of cytochromes (CYP) probe drugs on the disposition of fexofenadine, a P-gp test drug. In a randomized four-way Latin-square crossover study, 30 healthy volunteers (15 men and 15 women) received caffeine 50 mg, bupropion 20 mg, flurbiprofen 10 mg, omeprazole 10 mg, dextromethorphan 10 mg, midazolam 1 mg, and fexofenadine 25 mg alone (or as part of a previously validated combination) and all together (Geneva cocktail). The determination of drug concentrations was performed in DBS samples and pharmacokinetic parameters were calculated. Fexofenadine AUC0–8 h and Cmax decreased by 43% (geometric mean ratio: 0.57; CI 90: 0.50–0.65; p < 0.001) and 49% (geometric mean ratio: 0.51; CI 90: 0.44–0.59; p < 0.001), respectively, when fexofenadine was administered as part of the Geneva cocktail in comparison to fexofenadine alone. Consequently, the apparent oral clearance (Cl/F) increased 1.7-fold (CI 90: 1.49–1.93; p < 0.001). There was no interaction between the remaining probes. In conclusion, an unexpected interaction occurred between fexofenadine and one or several of the following substances: caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, and midazolam. Further studies are necessary to elucidate the mechanism of this interaction.