Outcome and Prognostic Factors of COVID-19 Infection in Swiss Cancer Patients: Final Results of SAKK 80/20 (CaSA).

Purpose: These are the final results of a national registry on cancer patients with COVID-19 in Switzerland. Methods: We collected data on symptomatic COVID-19-infected cancer patients from 23 Swiss sites over a one-year period starting on 1 March 2020. The main objective was to assess the outcome (i.e., mortality, rate of hospitalization, ICU admission) of COVID-19 infection in cancer patients; the main secondary objective was to define prognostic factors. Results: From 455 patients included, 205 patients (45%) had non-curative disease, 241 patients (53%) were hospitalized for COVID-19, 213 (47%) required oxygen, 43 (9%) invasive ventilation and 62 (14%) were admitted to the ICU. Death from COVID-19 infection occurred in 98 patients, resulting in a mortality rate of 21.5%. Age ≥65 years versus <65 years (OR 3.14, p = 0.003), non-curative versus curative disease (OR 2.42, p = 0.012), ICU admission (OR 4.45, p < 0.001) and oxygen requirement (OR 20.28, p < 0.001) were independently associated with increased mortality. Conclusions: We confirmed high COVID-19 severity and mortality in real-world cancer patients during the first and second wave of the pandemic in a country with a decentralized, high-quality, universal-access health care system. COVID-19-associated mortality was particularly high for those of older age in a non-curative disease setting, requiring oxygen or ICU care.

Pharmacokinetic modelling and simulation to optimize albendazole dosing in hookworm- or Trichuris trichiura-infected infants to adults.

BACKGROUND: Albendazole is the most commonly used drug in preventive chemotherapy programmes against soil-transmitted helminth (STH) infections, with the standard dose of 400 mg resulting in suboptimal clinical outcomes. Population pharmacokinetic (PK) models that could inform dosing strategies are not yet available. METHODS: A population pharmacokinetic model was developed based on micro-blood samples collected from 252 patients aged 2 to 65 years, infected with either hookworm or Trichuris trichiura and treated with albendazole doses ranging from of 200 to 800 mg. An exposure-response analysis was performed relating albendazole and its two metabolites to cure rates and egg reduction rates (ERR). Finally, model-based simulations were conducted to determine equivalent exposure coverage in infants to adults. RESULTS: A population PK model, with one distribution compartment for each compound and one peripheral compartment, following oral administration with a lag time, assuming first-order absorption and linear elimination, best described the concentration-time profiles. Clearance and volume parameters were scaled to body size (weight for albendazole and height for albendazole sulfoxide and sulfone). Dose proportionality was observed for the active metabolite, albendazole sulfoxide, but only in hookworm-infected individuals, with increasing exposure resulting in increased ERR. Exposure of sulfoxide was lowest in the tallest individuals. CONCLUSIONS: Pharmacometric simulations indicate that doses up to 800 mg could further increase albendazole efficacy in hookworm-infected adults, whereas the standard dose of 400 mg is sufficient in the youngest age cohorts. In the absence of evidence-based arguments for adjusting albendazole doses in T. trichiura-infected individuals, the search for new treatment options is further emphasized.

Pharmacometric Analysis of Tribendimidine Monotherapy and Combination Therapies To Achieve High Cure Rates in Patients with Hookworm Infections.

In the treatment of hookworm infections, pharmacotherapy has been only moderately successful and drug resistance is a threat. Therefore, novel treatment options including combination therapies should be considered, in which tribendimidine could play a role. Our aims were to (i) characterize the pharmacokinetics of tribendimidine's metabolites in adolescents receiving tribendimidine monotherapy or in combination with ivermectin or oxantel pamoate, (ii) evaluate possible drug-drug interactions (DDI), (iii) link exposure to response, and (iv) identify a treatment strategy associated with high efficacy, i.e., >90% cure rates (CRs), utilizing model-based simulations. A population pharmacokinetic model was developed for tribendimidine's primary and secondary metabolites, dADT and adADT, in 54 hookworm-positive adolescents, with combination therapy evaluated as a possible covariate. Subsequently, an exposure-response analysis was performed utilizing CRs as response markers. Simulations were performed to identify a treatment strategy to achieve >90% CRs. A two-compartmental model best described metabolite disposition. No pharmacokinetic DDI was identified with ivermectin or oxantel pamoate. All participants receiving tribendimidine plus ivermectin were cured. For the monotherapy arm and the arm including the combination with oxantel pamoate, Emax models adequately described the correlation between dADT exposure and probability of being cured, with required exposures to achieve 50% of maximum effect of 39.6 and 15.6 nmol/ml·h, respectively. Based on our simulations, an unrealistically high monotherapy tribendimidine dose would be necessary to achieve CRs of >90%, while combination therapy with ivermectin would meet this desired target product profile. Further clinical studies should be launched to develop this combination for the treatment of hookworm and other helminth infections.

Efficacy and safety of ascending dosages of albendazole against Trichuris trichiura in preschool-aged children, school-aged children and adults: A multi-cohort randomized controlled trial.

BACKGROUND: The efficacy of the widely used albendazole against the soil-transmitted helminth Trichuris trichiura is limited; yet optimal doses, which may provide increased efficacy, have not been thoroughly investigated to date. METHODS: A randomized-controlled trial was conducted in Côte d'Ivoire with preschool-aged children (PSAC), school-aged children (SAC), and adults infected with T. trichiura. Participants were randomly assigned (1:1:1:1) using computer-generated randomization. PSAC were randomized to 200 mg, 400 mg, 600 mg of albendazole or placebo. SAC and adults were randomized to 400 mg, 600 mg, 800 mg of albendazole or placebo. The primary outcome was cure rates (CRs) against trichuriasis. Secondary outcomes were T. trichiura egg reduction rates (ERRs), safety, CRs and ERRs against other soil-transmitted helminths. Outcome assessors and the trial statistician were blinded. Trial registration at ClinicalTrial.gov: NCT03527745. FINDINGS: 111 PSAC, 180 SAC, and 42 adults were randomized and 86, 172, and 35 provided follow-up stool samples, respectively. The highest observed CR among PSAC was 27·8% (95% CI: 9·7%-53·5%) in the 600 mg albendazole treatment arm. The most efficacious arm for SAC was 600 mg of albendazole showing a CR of 25·6% (95% CI: 13·5%-41·2%), and for adults it was 400 mg of albendazole with a CR of 55·6% (95% CI: 21·2%-86·3%). CRs and ERRs did not differ significantly among treatment arms and flat dose-responses were observed. 17·9% and 0·4% of participants reported any adverse event at 3 and 24 h follow-up, respectively. INTERPRETATION: Albendazole shows low efficacy against T. trichiura in all populations and doses studied, though findings for PSAC and adults should be carefully interpreted as recruitment targets were not met. New drugs, treatment regimens, and combinations are needed in the management of T. trichiura infections. FUNDING: Bill and Melinda Gates Foundation.

Ivermectin Dosing Strategy to Achieve Equivalent Exposure Coverage in Children and Adults.

Ivermectin is a commonly used broad-spectrum antiparasitic drug, yet doses that produce consistent exposure coverage across age have not been characterized, and no data are available in children weighing < 15 kg. First, a population pharmacokinetic model is developed based on data from 200 children and 11 adults, treated with 100-600 µg/kg ivermectin. Second, model-based simulations are performed to identify a dosing strategy that achieves equivalent exposure coverage in children and adults. Median (90% confidence interval) clearance of 0.346 (0.12-0.73) L/hour/kg in pre-school-aged (2-5 years) children is similar to 0.352 (0.17-0.69) L/hour/kg in school-aged (6-12 years) children but higher than in adults (0.199 (0.10-0.31) L/hour/kg), resulting in significantly lower exposure in children following a 200 µg/kg dose. Simulations indicate that a dose increase to 300 and 250 µg/kg in children aged 2-5 and 6-12 years, respectively, will achieve equivalent ivermectin exposure coverage in children and adults.

Pharmacokinetics of ascending doses of ivermectin in Trichuris trichiura-infected children aged 2-12 years.

BACKGROUND: Yearly, millions of children are treated globally with ivermectin mainly for neglected tropical diseases. Anatomical, physiological and biochemical differences between children and adults may result in changes in pharmacokinetics. However, paediatric pharmacokinetic data of ivermectin are lacking. METHODS: In the framework of a randomized controlled dose-finding trial in rural Côte d'Ivoire, Trichuris trichiura-infected pre-school-aged children (PSAC, 2-5 years) and school-aged children (SAC, 6-12 years) were assigned to 100 or 200 µg/kg and 200, 400 or 600 µg/kg ivermectin, respectively (ISRCTN registry no. ISRCTN15871729). Capillary blood was collected on dried blood spot cards until 72 h post-treatment. Ivermectin was quantified by LC-MS/MS, and pharmacokinetic parameters were evaluated by non-compartmental analysis. RESULTS: C max and AUC increased in PSAC and SAC with ascending doses and were similar in both age groups when the current standard dose (200 µg/kg) was administered (∼23 ng/mL and ∼350 ng×h/mL, respectively). PSAC with lower BMI were associated with significantly higher AUCs. AUC and Cmax were ∼2-fold lower in children compared with parameters previously studied in adults, whereas body weight-adjusted CL/F (∼0.35 L/h/kg) was significantly higher in children. Tmax (∼6 h), t1/2 (∼18 h), mean residence time (MRTINF) (∼28 h) and V/F (∼8 L/kg) were similar in all paediatric treatment arms. CONCLUSIONS: A positive association of AUC or Cmax with dose was observed in both age groups. Undernutrition might influence the AUC of ivermectin in PSAC. Ivermectin shows a lower exposure profile in children compared with adults, highlighting the need to establish dosing recommendations for different age groups.

Pharmacokinetics of Albendazole, Albendazole Sulfoxide, and Albendazole Sulfone Determined from Plasma, Blood, Dried-Blood Spots, and Mitra Samples of Hookworm-Infected Adolescents.

Albendazole is an effective anthelmintic intensively used for decades. However, profound pharmacokinetic (PK) characterization is missing in children, the population mostly affected by helminth infections. Blood microsampling would facilitate PK studies in pediatric populations but has not been applied to quantify albendazole's disposition. Quantification methods were developed and validated using liquid chromatography-tandem mass spectrometry to analyze albendazole and its metabolites albendazole sulfoxide and albendazole sulfone in wet samples (plasma and blood) and blood microsamples (dried-blood spots [DBS]; Mitra). The use of DBS was limited by a matrix effect and poor recovery, but the extraction efficiency was constant throughout the concentration range. Hookworm-infected adolescents were venous and capillary blood sampled posttreatment with 400 mg albendazole and 25 mg/kg oxantel pamoate. Similar half-life (t1/2 = ∼1.5 h), time to reach the maximum concentration (tmax = ∼2 h), and maximum concentration (Cmax = 12.5 to 26.5 ng/ml) of albendazole were observed in the four matrices. The metabolites reached Cmax after ∼4 h with a t1/2 of ca. 7 to 8 h. A statistically significant difference in albendazole sulfone's t1/2 as determined by using DBS and wet samples was detected. Cmax of albendazole sulfoxide (288 to 380 ng/ml) did not differ among the matrices, but higher Cmax of albendazole sulfone were obtained in the two microsampling devices (22 ng/ml) versus the wet matrices (14 ng/ml). In conclusion, time-concentration profiles and PK results of the four matrices were similar, and the direct comparison of the two microsampling devices indicates that Mitra extraction was more robust during validation and can be recommended for future albendazole PK studies.

In Vitro and In Vivo Drug-Drug Interaction Study of the Effects of Ivermectin and Oxantel Pamoate on Tribendimidine.

Soil-transmitted helminth (STH) infections still remain a major health problem in poor rural settings. The lack of efficacious drugs against all STH species raises interest in drug combinations. Drug-drug interactions (DDIs) are, however, of major concern, so careful in vitro and in vivo characterization is needed. The combination of tribendimidine with either ivermectin or oxantel pamoate targets a broad range of STHs and thus represents a promising treatment alternative. Drug-drug interactions, however, have not yet been investigated. Therefore, the effects of combinations of ivermectin, oxantel pamoate, and tribendimidine's active metabolite deacylated amidantel (dADT) on cytochrome P450 (CYP450) metabolism were evaluated, followed by a pharmacokinetic analysis of tribendimidine and ivermectin alone and in combination in healthy rats. Oxantel pamoate is only poorly absorbed and was therefore excluded from pharmacokinetic analysis. No evident effect was observed for tribendimidine-oxantel pamoate at the CYP450 metabolism level, whereas a combination of tribendimidine and ivermectin led to moderately increased CYP2D6 inhibition compared to ivermectin or tribendimidine alone. Coadministration of tribendimidine with ivermectin altered neither the time to maximum concentration of drug in plasma (Tmax) nor the elimination half-lives of dADT, the acetylated derivative of amidantel (adADT), and ivermectin. While the area under the concentration-versus-time curve (AUC) and maximum concentration of drug in plasma (Cmax) values of dADT, adADT, and ivermectin are reduced by coadministration, the change is insufficient to declare that a DDI has been detected. Further studies are necessary to understand the observed interaction of tribendimidine and ivermectin, which is not related to P450 metabolism, and its significance for the situation in humans.

Preventive Chemotherapy in the Fight against Soil-Transmitted Helminthiasis: Achievements and Limitations.

Soil-transmitted helminths (STHs) are endemic in more than half of the world's countries. The World Health Organization has advocated targeted preventive chemotherapy (PC) to control STH infections by distributing albendazole or mebendazole to at-risk populations. While the overall impact and sustainability of this strategy is disputed, a decrease in moderate and heavy STH infections can be largely attributed to a scale-up of drug distribution. Two factors might jeopardise the success of PC programs. First, the benzimidazoles possess unsatisfactory efficacy against Trichuris trichiura infections. Second, increased drug distributions might trigger anthelmintic resistance. This review presents an overview of the burden of STH infections, the evolution of PC along with its success and challenges, recent estimates of the efficacy of recommended drugs, and alternative treatment options.

Efficacy and Safety of Ivermectin Against Trichuris trichiura in Preschool-aged and School-aged Children: A Randomized Controlled Dose-finding Trial.

Background: Although trichuriasis affects millions of children worldwide, recommended drugs lack efficacy and new treatment options are urgently needed. Ivermectin has promising potential to complement the anthelminthic armamentarium. Methods: A randomized placebo-controlled trial was conducted in rural Côte d'Ivoire to provide evidence on the efficacy and safety of ascending oral ivermectin dosages in preschool-aged children (PSAC) and school-aged children (SAC) infected with Trichuris trichiura. The primary outcome was the cure rate (CR) for T. trichiura infection, and the secondary outcomes were safety, egg-reduction rates (ERRs) against T. trichiura infection, and CRs and ERRs against other soil-transmitted helminth species. Results: A total of 126 PSAC and 166 SAC were included in an available case analysis. In PSAC, efficacy against T. trichiura did not differ between 200 µg/kg ivermectin and placebo treatment arm, as expressed in CRs (20.9% [95% confidence interval {CI}, 11.9%-52.8%] vs 19.5% [10.4%-49.9%]) and geometric mean ERRs (78.6% [60.1%-89.5%] vs 68.2% [40.5%-84.8%]). In SAC, the highest administered ivermectin dose of 600 µg/kg had a low CRs (12.2% [95% CI, 4.8%-32.3%]) and moderate ERRs (66.3% [43.8%-80.2%]). Only mild adverse events and no organ toxicity, based on serum biomarkers, was observed. Conclusion: Ivermectin can be administered safely to PSAC with trichuriasis. Given the low efficacy of ivermectin monotherapy against T. trichiura infection, further research should investigate the optimal drug combinations and dosages with ivermectin against soil-transmitted helminthiasis. Clinical Trials Registration: ISRCTN15871729 (www.isrctn.com).

Evaluation of a novel micro-sampling device, Mitra™, in comparison to dried blood spots, for analysis of praziquantel in Schistosoma haematobium-infected children in rural Côte d'Ivoire.

Pharmacokinetic (PK) studies with paediatric populations are increasing in importance for drug development. However, conventional PK sampling methods are characterised by invasiveness and low patient adherence, unsuitable for use with sensitive population, such as children. Mitra™ is a novel volumetric absorptive micro-sampling device, which offers an alternative to the dried blood spotting (DBS) technique, a current popular sampling technique within PK studies. We tested Mitra™ for the first time in the framework of a randomised controlled trial in rural Côte d'Ivoire. Thirty-five school-aged children, infected with Schistosoma haematobium, were sampled with both DBS and Mitra™, at 10 time points after treatment with praziquantel (PZQ). An extraction method for PZQ from Mitra™ was developed, optimised and validated. Analytes, namely R- and S-praziquantel (R-/SPZQ) and the main human metabolite, R-trans-4-OH-praziquantel, were measured using liquid chromatography-tandem mass spectrometry and the results were compared with Bland-Altman analysis to determine agreement between matrices. PK parameters, such as maximal plasma concentration and area under the concentration-time curve, were estimated using non-compartmental analysis. While we observed strong positive correlation (R2 > 0.98) and agreement between both matrices within the calibration line and quality control samples, Mitra™ revealed higher concentrations of all the analytes in the majority of patients' samples compared to DBS sampling, namely 63% samples for RPZQ, 49% for SPZQ and 78% for the metabolite were overestimated. While T1/2 and Tmax were in agreement between both matrices, area under the curve and maximal blood concentration were up to 2× higher for Mitra™ samples, with P < 0.005 for all parameters except Cmax of SPZQ, which was not significantly different between the two matrices. The reasons for the higher PZQ concentrations, more pronounced in incurred Mitra™ samples compared to spiked samples, are yet to be fully explored. Mitra™ appears superior to DBS in terms of simplicity and practicality however labelling issues and the high price of Mitra™ are difficult to overlook.

Site-Specific Polymer Conjugation Stabilizes Therapeutic Enzymes in the Gastrointestinal Tract.

The site-specific conjugation of polymers to multiple engineered cysteine residues of a prolyl endopeptidase leads to its stabilization in the gastrointestinal tract of rats, without compromising the activity relative to the native enzyme. The importance of polymer attachment sites is investigated, as well as the significance of polymer structure.

Improving oral drug bioavailability with polycations?

The administration of drugs via the oral route is challenging due to the (bio)chemical aggressivity of the digestive system and to the presence of barriers that hinder cell uptake and access to the bloodstream. Indeed, the gastrointestinal tract is characterized by large variations of pH, the presence of enzymes and surfactants, and by absorption barriers such as mucus and the epithelium. Thus, many compounds such as proteins and nucleic acids do not reach the systemic circulation due to their premature degradation and/or large size. Among the different strategies that have been investigated to address these challenges, polycations have been explored to improve the oral absorption of many types of drugs. Because of their multiple positive charges and repetitive structure, polycations can protect sensitive drugs against rapid degradation and interact with the gastrointestinal mucosa. Moreover, cationic polymers promote drug transfer across intestinal barriers through various mechanisms, including the opening of the tight junctions, and change in uptake pathway. This contribution provides an overview of the most common polycations currently investigated as absorption enhancers for the oral route, and discusses the manner in which they are employed (co-administration, micro- and nanoparticles, conjugation) to improve the oral drug delivery of different classes of therapeutics.

Impact of scaffold rigidity on the design and evolution of an artificial Diels-Alderase.

By combining targeted mutagenesis, computational refinement, and directed evolution, a modestly active, computationally designed Diels-Alderase was converted into the most proficient biocatalyst for [4+2] cycloadditions known. The high stereoselectivity and minimal product inhibition of the evolved enzyme enabled preparative scale synthesis of a single product diastereomer. X-ray crystallography of the enzyme-product complex shows that the molecular changes introduced over the course of optimization, including addition of a lid structure, gradually reshaped the pocket for more effective substrate preorganization and transition state stabilization. The good overall agreement between the experimental structure and the original design model with respect to the orientations of both the bound product and the catalytic side chains contrasts with other computationally designed enzymes. Because design accuracy appears to correlate with scaffold rigidity, improved control over backbone conformation will likely be the key to future efforts to design more efficient enzymes for diverse chemical reactions.

Novel role of the serine protease inhibitor elafin in gluten-related disorders.

OBJECTIVES: Elafin, an endogenous serine protease inhibitor, modulates colonic inflammation. We investigated the role of elafin in celiac disease (CD) using human small intestinal tissues and in vitro assays of gliadin deamidation. We also investigated the potential beneficial effects of elafin in a mouse model of gluten sensitivity. METHODS: Epithelial elafin expression in the small intestine of patients with active CD, treated CD, and controls without CD was determined by immunofluorescence. Interaction of elafin with human tissue transglutaminase-2 (TG-2) was investigated in vitro. The 33-mer peptide, a highly immunogenic gliadin peptide, was incubated with TG-2 and elafin at different concentrations. The degree of deamidation of the 33-mer peptide was analyzed by liquid chromatography-mass spectrometry. Elafin was delivered to the intestine of gluten-sensitive mice using a recombinant Lactococcus lactis vector. Small intestinal barrier function, inflammation, proteolytic activity, and zonula occludens-1 (ZO-1) expression were assessed. RESULTS: Elafin expression in the small intestinal epithelium was lower in patients with active CD compared with control patients. In vitro, elafin significantly slowed the kinetics of the deamidation of the 33-mer peptide to its more immunogenic form. Treatment of gluten-sensitive mice with elafin delivered by the L. lactis vector normalized inflammation, improved permeability, and maintained ZO-1 expression. CONCLUSIONS: The decreased elafin expression in the small intestine of patients with active CD, the reduction of 33-mer peptide deamidation by elafin, coupled to the barrier enhancing and anti-inflammatory effects observed in gluten-sensitive mice, suggest that this molecule may have pathophysiological and therapeutic importance in gluten-related disorders.

PEG nanocages as non-sheddable stabilizers for drug nanocrystals.

Many potent drugs are difficult to administer intravenously due to poor aqueous solubility. One validated approach for addressing this issue is to process them into colloidal dispersions known as "nanocrystals" (NCs). However, NCs possess high-energy surfaces that must be stabilized with surfactants to prevent aggregation. In addition, the stabilizer provides a means of anchoring targeting moieties to the NCs for achieving deposition or uptake at specified locations. Nevertheless, a critical challenge is that the surfactant (and consequently the targeting agents) can be shed upon high dilution. This work demonstrates successful cross-linking by click chemistry of stabilizers around paclitaxel NCs to form polymeric "nanocages". Cross-linking does not cause aggregation, as evidenced by transmission electron microscopy, and the nanocages retained the particulate drug through a combination of physical entrapment and physisorption. Size measurements by dynamic light scattering showed that nanocages act as sterically stabilizing barriers to particle-particle interactions and aggregation. The nanocages were shown to be less shed from the NCs than comparable non-cross-linked stabilizers. This contribution provides crucial general tools for preparing poorly sheddable stabilizing coatings to NCs and potentially other classes of nanoparticles for which covalent attachment of the stabilizer to the particle is undesirable (e.g., a drug) or impossible (chemically inert). The presented approach also offers the possibility of more stably attaching targeting moieties to the latter by use of heterotelechelic PEG derivatives, which may favor active targeting and internalization by cells.