Synthesis and self-assembly behaviors of α-galactosyl ceramide (1,2)-polysaccharide analogue.

α-Galactosyl ceramide (GalCer) as a glycolipid has been long used as a standard reference for positive control in natural killer T cell studies. The (1,2)-disaccharide analogue of GalCer attracts a special attention in the study of lysosomal glycolipid processing. This paper describes the synthesis and self-assembly behaviors of GalCer 1,2-polysaccharide analogue (PolyGalCer), having considered the 1,2-disaccharide analogue as a structural motif. The synthesis of PolyGalCer is performed via one-pot glycosidation technique of 1,2-linked oligogalactan exploiting chain polymerization of galactose-based cyclic sulfite as a monomer initiated with ceramide-based alcoholic aglycon. Through the concentration dependence of PolyGalCer solutions in water or in MeOH on the turbidity, it is found that PolyGalCer forms associates in both media. From the intersection points, the critical aggregation concentration (CAC) values of PolyGalCer in water and MeOH were estimated. To know the self-assembly and the thermal transition behaviors, we performed dynamic light scattering (DLS) analysis of the associates comprising PolyGalCer in water. The transmission electron microscopy observations of the aqueous sample solution indicate that the solution of PolyGalCer includes large spherical associates. The results clarify that the 1,2-galactan moiety of PolyGalCer skeleton contributes on the kinetic inhibition of large associate formation and the metamorphosis of associates.

Dynamic-to-Static Planar Chirality Conversion in Pillar[5]arenes Regulated by Guest Solvents or Amplified by Crystallization.

Controlling dynamic chirality and memorizing the controlled chirality are important. Chirality memory has mainly been achieved using noncovalent interactions. However, in many cases, the memorized chirality arising from noncovalent interactions is erased by changing the conditions such as the solvent and temperature. In this study, the dynamic planar chirality of pillar[5]arenes was successfully converted into static planar chirality by introducing bulky groups through covalent bonds. Before introducing the bulky groups, pillar[5]arene with stereogenic carbon atoms at both rims existed as a pair of diastereomers, and thus showed planar chiral inversion that was dependent on the chain length of the guest solvent. The pS and pR forms, regulated by guest solvents, were both diastereomerically memorized by introducing bulky groups. Furthermore, the diastereomeric excess was amplified by crystallization of the pillar[5]arene. The subsequent introduction of bulky groups yielded pillar[5]arene with an excellent diastereomeric excess (95 % de).

Holding of planar chirality of pillar[5]arene by kinetic trapping using host-guest interactions with achiral guest solvents.

We report a solvent-dependent switching and holding of planar chirality of pillar[5]arene with stereogenic carbons at both rims by host-guest complexation with achiral guest solvents. The planar chirality could be held for a given length of time at 25 °C in long linear guest solvents by kinetic trapping through host-guest complexation. The kinetic trapping worked at 25 °C, but not at 60 °C, thus a planar-chiral inversion using kinetic trapping based on host-guest complexation in the long linear solvents was demonstrated.

Model-Based Comparison of Dose-Response Profiles of Tofacitinib in Japanese Versus Western Rheumatoid Arthritis Patients.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this analysis was to characterize the relationship between tofacitinib dose and efficacy, as measured by American College of Rheumatology (ACR) response rates, and to compare this between Japanese and Western patients with RA. Efficacy data were pooled from 2 double-blind, dose-ranging phase 2 studies of tofacitinib monotherapy 1-15 mg twice daily in patients with RA with an inadequate response to disease-modifying antirheumatic drugs (DMARDs). NCT00550446 was carried out in mostly Western patients and NCT00687193 in Japanese patients. ACR20, ACR50, and ACR70 response rates in week 12 were analyzed using maximum drug effect (Emax ) models on the logit domain. Both studies showed a dose-response for each end point, supporting the efficacy of tofacitinib in patients with inadequate response to DMARDs. Study-specific differences in Emax were noted, whereas potency (dose providing half the maximum effect [ED50 ]) was similar across studies. After adjustment for study differences in Emax by calculating the fractions of the maximum placebo-adjusted proportion of ACR responses, the estimated locations for the 5- and 10-mg twice-daily doses on the dose-response curves were similar for the 2 patient populations: ACR20, ACR50, andACR70 mean fractional responses for 5 and 10 mg twice daily were 0.78, 0.43, 0.32 and 0.90, 0.69, and 0.56, respectively, for the Japanese study and 0.54, 0.41, and 0.22 and 0.73, 0.61, and 0.40, respectively, for the Western study. This analysis therefore supports the rationale for the same dosing regimen in Japanese patients as in Western patients from an efficacy perspective.

Application of Physiologically-Based Pharmacokinetic Modeling for the Prediction of Tofacitinib Exposure in Japanese.

Tofacitinib (3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3 -oxopropanenitrile) is an oral Janus kinase inhibitor that is approved in countries including Japan and the United States for the treatment of rheumatoid arthritis, and is being developed across the globe for the treatment of inflammatory diseases. In the present study, a physiologically-based pharmacokinetic model was applied to compare the pharmacokinetics of tofacitinib in Japanese and Caucasians to assess the potential impact of ethnicity on the dosing regimen in the two populations. Simulated plasma concentration profiles and pharmacokinetic parameters, i.e. maximum concentration and area under plasma concentration-time curve, in Japanese and Caucasian populations after single or multiple doses of 1 to 30 mg tofacitinib were in agreement with clinically observed data. The similarity in simulated exposure between Japanese and Caucasian populations supports the currently approved dosing regimen in Japan and the United States, where there is no recommendation for dose adjustment according to race. Simulated results for single (1 to 100 mg) or multiple doses (5 mg twice daily) of tofacitinib in extensive and poor metabolizers of CYP2C19, an enzyme which has been shown to contribute in part to tofacitinib elimination and is known to exhibit higher frequency in Japanese compared to Caucasians, were also in support of no recommendation for dose adjustment in CYP2C19 poor metabolizers. This study demonstrated a successful application of physiologically-based pharmacokinetic modeling in evaluating ethnic sensitivity in pharmacokinetics at early stages of development, presenting its potential value as an efficient and scientific method for optimal dose setting in the Japanese population.

Clinical impact of genetic variants of drug transporters in different ethnic groups within and across regions.

Drug transporters, together with drug metabolic enzymes, are major determinants of drug disposition and are known to alter the response to many commonly used drugs. Substantial frequency differences for known variants exist across geographic regions for certain drug transporters. To deliver efficacious medicine with the right dose for each patient, it is important to understand the contribution of genetic variants for drug transporters. Recently, mutual pharmacokinetic data usage among Asian regions, which are thought to be relatively similar in their own genetic background, is expected to accelerate new drug applications and reduce developmental costs. Polymorphisms of drug transporters could be key factors to be considered in implementing multiethnic global clinical trials. This review addresses the current knowledge on genetic variations of major drug transporters affecting drug disposition, efficacy and toxicity, focusing on the east Asian populations, and provides insights into future directions for precision medicine and drug development in east Asia.

Recrystallization and zone melting of charged colloids by thermally induced crystallization.

We examined the application of recrystallization and zone-melting crystallization methods, which have been used widely to fabricate large, high-purity crystals of atomic and molecular systems, to charged colloidal crystals. Our samples were aqueous dispersions of colloidal silica (with particle diameters of d = 108 or 121 nm and particle volume fractions of ϕ = 0.035-0.05) containing the weak base pyridine. The samples crystallized upon heating because of increases in the particle charge numbers, and they melted reversibly on cooling. During the recrystallization experiments, the polycrystalline colloids were partially melted in a Peltier cooling device and then were crystallized by stopping the cooling and allowing the system to return to ambient temperature. The zone-melting crystallization was carried out by melting a narrow zone (millimeter-sized in width) of the polycrystalline colloid samples and then moving the sample slowly over a cooling device to recrystallize the molten region. Using both methods, we fabricated a few centimeter-sized crystals, starting from millimeter-sized original polycrystals when the crystallization rates were sufficiently slow (33 µm/s). Furthermore, the optical quality of the colloidal crystals, such as the half-band widths of the diffraction peaks, was significantly improved. These methods were also useful for refining. Small amounts of impurity particles (fluorescent polystyrene particles, d = 333 nm, ϕ = 5 × 10(-5)), added to the colloidal crystals, were excluded from the crystals when the crystallization rates were sufficiently slow (∼0.1 µm/s). We expect that the present findings will be useful for fabricating large, high-purity colloidal crystals.

Impact of drug transporter pharmacogenomics on pharmacokinetic and pharmacodynamic variability - considerations for drug development.

INTRODUCTION: Drug transporter proteins are expressed on the cell membrane, regulating substrate exposure in systemic circulation and/or peripheral tissues. Genetic polymorphism of drug transporter genes encoding these proteins could alter the functional activity and/or protein expression, having effects on absorption, distribution, metabolism and excretion (ADME), efficacy and adverse effects. AREAS COVERED: The authors provide the reader with an overview of the pharmacogenetics (PGx) of 12 membrane transporters. The clinical literature is summarized as to the quantitative significance on pharmacokinetics (PK) and implications on pharmacodynamics (PD) and adverse effects, due to transporter influence on intracellular drug concentrations. EXPERT OPINION: Unlike polymorphisms for cytochrome P450s (CYPs) resulting in large magnitude of PK variation, genetic mutations for membrane transporters are typically less than threefold alteration in systemic PK for drugs with a few exceptions. However, substantially greater changes in intracellular drug levels may result. We are aware of 1880 exome variants in 12 of the best-studied transporters to date, and nearly 40% of these change the amino acid. However, the functional consequences of most of these variants remain to be determined, and have only been empirically evaluated for a handful. To the extent that genetic polymorphisms impact ADME, it is a variable that will contribute to ethnic differences due to substantial frequency differences for the known variants.

Population pharmacokinetics of pregabalin in healthy subjects and patients with post-herpetic neuralgia or diabetic peripheral neuropathy.

AIM: Pregabalin, a chemical analogue of the mammalian neurotransmitter γ-aminobutyric acid, has been approved in many countries for partial-onset seizures, generalized anxiety disorder and various other pain disorders, including neuropathic pain associated with post-herpetic neuralgia and diabetic peripheral neuropathy and fibromyalgia. The aim of this study was to develop a population pharmacokinetic model and quantify the influence of covariates on the parameters. METHODS: This pregabalin population pharmacokinetic analysis was conducted on data from 14 clinical trials involving healthy subjects, subjects with impaired renal function and patients with post-herpetic neuralgia or diabetic peripheral neuropathy (n= 616). The data analysis was performed using nonlinear mixed effects modelling methodology as implemented by NONMEM. RESULTS: A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. The model indicated that pregabalin apparent clearance (CL/F) was proportional to estimated creatinine clearance (CL(cr) ). The pregabalin systemic exposure in patients with lower renal function who received pregabalin 150 mg twice daily was almost equal to that of patients with normal renal function administered pregabalin 300 mg twice daily. The systemic exposure stratified by lower or normal renal function was similar between patients with post-herpetic neuralgia and diabetic peripheral neuropathy. CONCLUSION: The developed model identified CL(cr) and ideal body weight as clinically influential covariates on CL/F and volume of distribution, respectively. This study indicates that renal function accounts for variability in the apparent clearance of pregabalin which is consistent with what is known about the elimination of this drug.

[Long-term efficacy and safety of pregabalin in patients with postherpetic neuralgia: results of a 52-week, open-label, flexible-dose study].

BACKGROUND: The efficacy of pregabalin was demonstrated in a randomized double-blind placebo-controlled 13-week trial in 371 Japanese patients with postherpetic neuralgia (PHN). In this study, we evaluated the long-term efficacy and safety of pregabalin for relief of PHN. METHODS: 126 patients were enrolled from the preceding double-blind study into the 52-week open-label study. Patients were given pregabalin 150 to 600 mg x day(-1). Pain intensity was measured using the Short-Form McGill Pain Questionnaire (SF-MPQ: total score, visual analogue scale and present pain intensity). RESULTS: The efficacy parameter SF-MPQ showed a decrease over the treatment-term. The changes of visual analogue scale and present pain intensity at the endpoint were -28.3 mm and -1.1 score, respectively. The commonly reported adverse events were dizziness, somnolence, peripheral edema and weight gain, and most of them were mild to moderate in intensity. No new adverse events were observed due to long-term pregabalin administration. CONCLUSIONS: These results suggest that long-term treatment of pregabalin may be beneficial in patients with PHN.

Predicting human liver microsomal stability with machine learning techniques.

To ensure a continuing pipeline in pharmaceutical research, lead candidates must possess appropriate metabolic stability in the drug discovery process. In vitro ADMET (absorption, distribution, metabolism, elimination, and toxicity) screening provides us with useful information regarding the metabolic stability of compounds. However, before the synthesis stage, an efficient process is required in order to deal with the vast quantity of data from large compound libraries and high-throughput screening. Here we have derived a relationship between the chemical structure and its metabolic stability for a data set of in-house compounds by means of various in silico machine learning such as random forest, support vector machine (SVM), logistic regression, and recursive partitioning. For model building, 1952 proprietary compounds comprising two classes (stable/unstable) were used with 193 descriptors calculated by Molecular Operating Environment. The results using test compounds have demonstrated that all classifiers yielded satisfactory results (accuracy > 0.8, sensitivity > 0.9, specificity > 0.6, and precision > 0.8). Above all, classification by random forest as well as SVM yielded kappa values of approximately 0.7 in an independent validation set, slightly higher than other classification tools. These results suggest that nonlinear/ensemble-based classification methods might prove useful in the area of in silico ADME modeling.