Pharmacokinetics and Safety of Eptinezumab in Healthy Chinese Participants: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVE: Most evidence suggests that the pharmacokinetics of monoclonal antibodies (mAbs) are not meaningfully altered by patient characteristics, including racial/ethnic differences. Nevertheless, the pharmacokinetic profile of eptinezumab has not been evaluated in a Chinese population. This study was designed to confirm the hypothesis that the pharmacokinetic profile of the anti-calcitonin gene-related peptide mAb, eptinezumab, is similar in healthy Chinese individuals to that of healthy non-Asian individuals and non-Asian patients with migraine. METHODS: Over a study period of 12 weeks, healthy adult Chinese participants (N = 20) were randomized (1:1) to receive a single intravenous dose of eptinezumab 100 mg (n = 10) or 300 mg (n = 10) in a prospective, single-site, open-label parallel-group trial. Blood samples for the evaluation of plasma eptinezumab concentrations were obtained over 84 days, and standard pharmacokinetic parameters were derived. RESULTS: Mean maximum plasma concentrations (Cmax) of eptinezumab occurred 1.0-1.5 h post start of infusion, were similar between the 100 mg and 300 mg dose groups, and slowly declined in a biphasic manner. Cmax and area under the drug concentration-time curve (AUC) increased in a dose-proportional manner. Volume of distribution and clearance were similar between the 100 mg and 300 mg dose groups, and half-life was 22.5-28.1 days. Eptinezumab was generally well tolerated with no new safety signals identified. Only one participant, randomized to the 100 mg dose group, was positive for eptinezumab anti-drug antibodies, but negative for neutralizing antibodies, with no impact on pharmacokinetics. CONCLUSION: The pharmacokinetic profile of eptinezumab in healthy Chinese individuals was generally similar to that reported for non-Asian populations with migraine, and eptinezumab was generally well tolerated. Evaluation of immunogenicity showed no evidence of an impact of anti-drug antibodies or neutralizing antibodies on safety profiles. This supports the globally approved doses of 100 mg and 300 mg as being appropriate for Chinese patients with episodic migraine or chronic migraine.

Loricate choanoflagellates (Acanthoecida) from warm water seas. IX. Coronoeca gen. nov., Polyfibula Manton and spiny forms of Parvicorbicula Deflandre.

The ambition to generate an overview of warm water loricate choanoflagellate biodiversity, based on a classic morphometric approach, is here completed by analyses of a range of tiny forms with anterior spines or projections and in most cases also a posterior pedicel. The warm water study complements previously obtained results from the more extensively studied temperate and polar regions of the world's oceans. It thus contributes to a significantly more balanced approach to global diversity patterns for these organisms. The current survey includes taxa such as Polyfibula elatensis, Parvicorbicula pedicellata, as well as a range of primarily undescribed and taxonomically challenging species, that are in an interim approach allocated to Coronoeca gen. nov. (C. kosmaniae sp. nov., C. conicella sp. nov., C. superpositus (Booth) comb. nov., C. marchantii sp. nov., C. tongiae sp. nov., and C. patongiensis sp. nov.). The analysis of warm water acanthoecid biodiversity has revealed in total 80 species from the six geographic regions sampled, corresponding to approximately 50% of all loricate species described. Nineteen species are previously undescribed forms. The Andaman Sea, Thailand, and West Australia are in a global context the most species-rich regions with 62 and 64 species respectively.

Loricate choanoflagellates (Acanthoecida) from warm water seas. VIII. Crinolina Thomsen and Diaphanoeca Ellis.

The loricate choanoflagellate genera Diaphanoeca Ellis and Crinolina Thomsen encompass a total of ten species. The majority of these are recorded from the warm water regions reported on here. A distinct morphological dichotomy characterizes the genus Diaphanoeca as currently circumscribed. The species distribute themselves within a 'D. grandis subgroup' and a 'D. pedicellata subgroup' distinguished on e.g., the position of the protoplast inside the lorica chamber and the elaboration of the anterior projections. We are, while awaiting in particular further molecular evidence, taking a conservative approach and abstain from dealing with the subgroup issue at the generic level. The examination of material from the warm water regions of the world's oceans has resulted in the description of D. sargassoensis sp.n., D. pseudoundulata sp.n., and D. throndsenii sp.n., and a thorough re-examination of D. undulata. Species of Crinolina share multiple features with in particular the D. grandis species subgroup. It is yet relevant, both in a morphological and molecular perspective, to retain the genus Crinolina which remains unambiguously defined based on the posteriorly open lorica. A high level of agreement is found when contrasting morphological and molecular based phylogenetic schemes.

Loricate choanoflagellates (Acanthoecida) from warm water seas. VII. Calotheca Thomsen and Moestrup, Stephanacantha Thomsen and Syndetophyllum Thomsen and Moestrup.

The tectiform loricate choanoflagellate genera Calotheca, Stephanacantha and Syndetophyllum have all been first described from warm water habitats and share the presence of flattened and often elaborate costal strips in the lorica. The current reinvestigation does confirm both the widespread occurrence of these taxa within the global warm water belt, and largely corroborates the established genus and species matrix. We describe here Stephanacantha oceanica sp. nov. which closely resembles S. campaniformis, and transfer Parvicorbicula zigzag to the genus Stephanacantha, despite differences in costal strip morphology, but based on a complete agreement in lorica constructional details.

Loricate choanoflagellates (Acanthoecida) from warm water seas. VI. Pleurasiga Schiller and Parvicorbicula Deflandre.

The loricate choanoflagellate genera Pleurasiga and Parvicorbicula are taxonomically ambiguous. Pleurasiga because of the uncertainty that relates to the true identity of the type species, and Parvicorbicula because too many newly described species over time have been dumped here in lack of better options. While all species currently allocated to the genus Pleurasiga (with the exception of the type species) are observed in our samples from the global warm water belt, the genus Parvicorbicula is represented by just a few and mostly infrequently recorded taxa. Two new species, viz. Pl. quadrangiella sp. nov. and Pl. minutissima sp. nov., are described here. While the former is closely related to Pl. echinocostata, the latter is reminiscent of Pl. minima. Core species of Pleurasiga and Parvicorbicula deviate from the vast majority of loricate choanoflagellates in having both the anterior and the mid-lorica transverse costae located exterior to the longitudinal costae. In Pl. quadrangiella there is no mid-lorica transverse costa but rather a small posterior transverse costa located inside the longitudinal costae. In Pl. minutissima the mid-lorica transverse costa has extensive costal strip overlaps which reveal patterns of costal strip junctions that deviate from the norm.

Loricate choanoflagellates (Acanthoecida) from warm water seas. V. Thomsenella Özdikmen (= Platypleura Thomsen).

Loricate choanoflagellate genera that incorporate flattened costal strips in the lorica (i.e. Calotheca, Stephanacantha, Thomsenella (= Platypleura) and Syndetophyllum) are prevalent in warm water habitats. The genus Thomsenella (=Platypleura) thus comprises four species and three of these have an Andaman Sea type locality. Our ongoing examination of loricate choanoflagellate material from all major warm water oceans has provided us with the opportunity of revisiting species of Thomsenella in order to test and fortunately verify, in a morpho-specific context, the robustness of the species matrix initially defined.

Loricate choanoflagellates (Acanthoecida) from warm water seas. IV. Cosmoeca Thomsen.

Aided by an extensive collection of specimens from warm water seas, it has been possible to revisit the loricate choanoflagellate genus Cosmoeca. While the type species C. norvegica and also C. ventricosa sensu stricto have been described from temperate North Atlantic realms and share a cosmopolitan distribution, the remaining species and morphotypes of Cosmoeca are largely confined to warmer waters. The new data broadly validates the initial circumscription of species of Cosmoeca. The persisting taxonomic puzzle with respect to C. ventricosa, which in addition to the core type accommodates no less than five different morphotypes (form A-E), has been further elucidated. The Cosmoeca paper is part of a 'monographic' series of warm water loricate choanoflagellate contributions in progress, where the aim is to provide the best possible account of warm water species diversity, based on traditional light and electron microscopical techniques, as a tool for future identification work based on microscopy, and in support of the work in progress with establishing a quality assured molecular tool for future recognition of diversity.

Loricate choanoflagellates (Acanthoecida) from warm water seas. III. Acanthocorbis Hara and Takahashi and Stephanoeca Ellis.

A large-scale investigation of warm water loricate choanoflagellate communities has revealed the presence of close to 80 species, which is approximately half of all loricate choanoflagellate taxa described when including also hitherto undescribed forms known to us. We are in the process of stepwise providing a monographic treatment of these communities. The overall aim is to contribute the best possible account of species diversity, based on traditional light and electron microscopical techniques, as a tool for future identification work based on microscopy, and in support of the work in progress with establishing a quality assured molecular tool for future recognition of diversity. In this paper we summarize our findings of species of Acanthocorbis and Stephanoeca, which include the description of several new taxa: A. conicella sp. nov., A. gladiella sp. nov., S. broomia sp. nov., S. naja sp. nov., and S. andemanica sp. nov.

Acanthoecid choanoflagellates from the Atlantic Arctic Region - a baseline study.

The examination and statistical analysis of loricate choanoflagellate material collected from Greenland waters during the period 1988-1998 represents a de facto baseline study of heterotrophic nanoflagellates from the Atlantic Arctic Region. The geographic sites sampled are Disko Bay (West Greenland) and the high-arctic North-East Water (NEW) and North Water (NOW) polynya. The analyses encompass close to 50 taxa. Some of these are described as new species, i.e. Acanthocorbis glacialis, A. reticulata and Diaphanoeca dilatanda. Two distinct clusters of species that are separated in time and space occur at all three sampling sites. A PCA analysis of NEW and NOW data points to that one community is linked to e.g. an early season high nutrient and low phytoplankton biomass scenario, whereas the other is predominant when nutrient levels are exhausted and the phytoplankton biomass high or declining. The material additionally allows for a comprehensive examination of e.g. the Cosmoeca ventricosa morphological variability encountered, as well as puts on record bimodal size variability within a number of species.

Circumstantial evidence of life history events in loricate choanoflagellates.

Sex is found in all major eukaryotic groups of organisms. It has been known for some time that the choanoflagellates also possess the genes involved in meiosis and a full sexual cycle was also recently accounted for in Salpingoeca rosetta. With reference to the loricate choanoflagellates the current status is that only circumstantial evidence, from wild material of Bicosta spinifera, exists in favour of documenting division patterns that go beyond plain asexual division, and that has the potential to represent stages in a sexual life cycle. Here we present further evidence from wild material documenting possible morphotype changes that might similarly indicate the existence of complex life cycles. In this particular case, it revolves around the existence of so-called 'combination loricas' (i.e. two loricas that occur physically united), representing consistent species combinations from the genera Acanthocorbis and Stephanoeca.