The accuracy of physiologically based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old, has not been systematically evaluated. The aim of this study was ...to characterize the pediatric predictive performance of the PBPK approach for 10 drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol), and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration–time profiles with observed clinical results for each drug and age group. PBPK models reasonably predicted the pharmacokinetics of desloratadine, diclofenac, itraconazole, lansoprazole, montelukast, ondansetron, sufentanil, theophylline, and tramadol across all age groups. Collectively, 58 out of 67 predictions were within 2‐fold and 43 out of 67 predictions within 1.5‐fold of observed values. Developed PBPK models can reasonably predict exposure in children age 1 month and older for an array of predominantly CYP metabolized drugs.
For the past five decades, there has been little progress in the development of oral anticoagulants, with the choices being limited to the vitamin K antagonists (VKAs). The situation is changing with ...the development of orally active small molecules that directly target thrombin or activated factor X (FXa). The two agents in the most advanced stages of development are dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively. Both are approved in the EU and Canada for venous thromboprophylaxis in patients undergoing elective hip- or knee-replacement surgery. Other agents in the early stages of development include several FXa inhibitors (apixaban, DU 176b, LY 517717, YM 150, betrixaban, eribaxaban PD 0348292 and TAK 442) and one thrombin inhibitor (AZD 0837). With a predictable anticoagulant response and low potential for drug-drug interactions, these new agents can be given in fixed doses without coagulation monitoring. This renders them more convenient than VKAs. While the anticoagulant effect of the new thrombin and FXa inhibitors is similar, differences in the pharmacokinetic and pharmacodynamic parameters may influence their use in clinical practice. Here, we compare the pharmacokinetic and pharmacodynamic features of these new oral agents.
Since 1972, Drug Metabolism Reviews has been recognized as one of the principal resources for researchers in pharmacological, pharmaceutical and toxicological fields to keep abreast of advances in ...drug metabolism science in academia and the pharmaceutical industry. With a distinguished list of authors and editors, the journal covers topics ranging from relatively mature fields, such as cytochrome P450 enzymes, to a variety of emerging fields. We hope to continue this tradition with the current compendium of mini-reviews that highlight novel biotransformation processes that were published during the past year. Each review begins with a summary of the article followed by our comments on novel aspects of the research and their biological implications. This collection of highlights is not intended to be exhaustive, but rather to be illustrative of recent research that provides new insights or approaches that advance the field of drug metabolism.
Abbreviations
NAPQI
N-acetyl-p-benzoquinoneimine
ALDH
aldehyde dehydrogenase
AO
aldehyde oxidase
AKR
aldo-keto reductase
CES
carboxylesterase
CSB
cystathionine β-synthase
CSE
cystathionine γ-lyase
P450
cytochrome P450
DHPO
2,3-dihydropyridin-4-one
ESI
electrospray
FMO
flavin monooxygenase
GSH
glutathione
GSSG
glutathione disulfide
ICPMS
inductively coupled plasma mass spectrometry
i.p.
intraperitoneal
MDR
multidrug-resistant
NNAL
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
NNK
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
oaTOF
orthogonal acceleration time-of-flight
PBK
physiologically based kinetic
PCP
pentachlorophenol
SDR
short-chain dehydrogenase/reductase
SULT
sulfotransferase
TB
tuberculosis
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•Phenolic acids, stilbenes, flavanol, anthocyanin, flavonol and flavanone were detected in all flowers.•The orange flower cosmos presented the highest content of phenolic ...compounds.•Bioaccessibility of phenolics varied among the compounds and within the flower source.•Before in vitro digestion mini rose displayed the highest activity in FRAP and DPPH assays.•The dialyzed fraction of cravine showed the highest activity in DDPH assay.•Cosmos and mini rose are source of bioaccessible phenolics with great antioxidant activity.
This study assessed the phenolics and their bioaccessibility through an in vitro digestion system coupled to a simulated intestinal barrier in eight edible flowers of distinct colors, namely mini rose, torenia, mini daisy, clitoria, cosmos, cravine, begonia and tagete. The antioxidant activity of the flowers before in vitro digestion, in their derived dialyzed and non-dialyzed fractions was evaluated using distinct approaches. All flowers presented in their composition phenolic acids, stilbenes, flavanol, anthocyanin, flavonol and flavanone, however distinct compounds and contents were found in each flower. The bioaccessibility varied among the phenolics and within the flower source (p < 0.05). Cosmos presented the highest (p < 0.05) content of phenolics and activity in ORAC assay before in vitro digestion and in dialyzed and non-dialyzed fraction; the observed activity was correlated (r = 0.9) to its major compounds, hesperidin and rutin, as well as to caftaric acid and procyanidin B2. Mini rose displayed the highest antioxidant activity in FRAP and DPPH assays before in vitro digestion; its dialyzed and non-dialyzed fraction showed the highest activity in FRAP, correlated to pelargonidin 3,5-diglucoside, catechin, epicatechin galate, epicagocatechin galate, procyanidin A2, quercitin 3-glucoside and trans-resveratrol (r = 0.9). In DPPH assay, mini rose showed the highest activity in the non-dialyzed fraction, while cravine showed the highest activity in the dialyzed fraction, which was mainly correlated to syringic acid (r = 1.0), pelargonidin 3,5-diglucoside and epicatechin (r = 0.9). Results show great variability in the phenolic composition and their bioaccessibility among the edible flowers studied. Our findings indicate cosmos and mini rose as sources of bioaccessible phenolics with great antioxidant activity.
The aims of this work were to study pharmacokinetics of randomly selected drugs in plasma and saliva samples in healthy human volunteers, and to introduce a Salivary Excretion Classification System. ...Saliva and plasma samples were collected for 3-5 half-life values of sitagliptin, cinacalcet, metformin, montelukast, tolterodine, hydrochlorothiazide (HCT), lornoxicam, azithromycin, diacerhein, rosuvastatin, cloxacillin, losartan and tamsulosin after oral dosing. Saliva and plasma pharmacokinetic parameters were calculated by noncompartmental analysis using the Kinetica program. Effective intestinal permeability (Peff) values were estimated by the Nelder-Mead algorithm of the Parameter Estimation module using the SimCYP program. Peff values were optimized to predict the actual average plasma profile of each drug. All other physicochemical factors were kept constant during the minimization processes. Sitagliptin, cinacalcet, metformin, tolterodine, HCT, azithromycin, rosuvastatin and cloxacillin had salivary excretion with correlation coefficients of 0.59-0.99 between saliva and plasma concentrations. On the other hand, montelukast, lornoxicam, diacerhein, losartan and tamsulosin showed no salivary excretion. Estimated Peff ranged 0.16-44.16 × 10(-4) cm/s, while reported fraction unbound to plasma proteins (fu) ranged 0.01-0.99 for the drugs under investigation. Saliva/plasma concentrations ratios ranged 0.11-13.4, in agreement with drug protein binding and permeability. A Salivary Excretion Classification System (SECS) was suggested based on drug high (H)/low (L) permeability and high (H)/low (L) fraction unbound to plasma proteins, which classifies drugs into 4 classes. Drugs that fall into class I (H/H), II (L/H) or III (H/L) are subjected to salivary excretion, while those falling into class IV (L/L) are not. Additional data from literature was also analyzed, and all results were in agreement with the suggested SECS. Moreover, a polynomial relationship with correlation coefficient of 0.99 is obtained between S* and C*, where S* and C* are saliva and concentration dimensionless numbers respectively. The proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion. Future work is planned to test these initial findings, and demonstrate SECS robustness across a range of carefully selected (based on physicochemical properties) drugs that fall into classes I, II or III.
Prediction of human pharmacokinetics is important in the preclinical stage. Values for total clearance of compounds from plasma should be one of the most important pharmacokinetic parameters for ...predictions. Although several physiological and empirical methods including single-species allometry for prediction of values for human clearance of compounds using humanized-liver mice have been reported, further improvement of prediction accuracies would be still expected. To optimize these approaches, we proposed methods for unbound intrinsic clearance in virtually 100% humanized-liver mouse by incorporating unbound plasma fractions of compounds in differently humanized-liver mice. Comparisons of prediction accuracies of values for human clearance of 15 model compounds were performed among our current physiological and previously reported models and single-species allometry using humanized-liver mice. Incorporation of the actual unbound plasma fractions of compounds and correction of residual mice hepatocyte in humanized-liver mice showed comparable prediction accuracy to that by single-species allometry. After exclusion of 3 compounds with large species differences in values of clearance and unbound plasma fractions between mice and humans out of 15 compounds, prediction accuracies were improved in the methods investigated. The previously and present reported physiological methods could show the good prediction accuracy of values for clearance of drugs from plasma.
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Purpose
To date, the interchangeability of generic drugs has only been investigated for a limited number of medicines. The objective of this study was to investigate generic-generic drug ...interchangeability in a large subset of generic formulations in order to cover a broad spectrum of drugs.
Methods
Orally administered drugs for investigation in this study were selected using strict, predefined criteria, with the purpose to avoid bias. This selection procedure yielded atorvastatin, bicalutamide, naratriptan, olanzapine, perindopril, and venlafaxine. Further, ciclosporin, tacrolimus, and mycophenolate mofetil were investigated as test immunosuppressants. Adjusted indirect comparisons were conducted between generic drugs containing the same active substance, and the 90 % confidence interval (CI) for AUC and C
max
was calculated.
Results
In total, 120 bioequivalence studies were identified in the Dutch medicine regulatory agency’s database, allowing 292 indirect comparisons between generic drugs. The indirect comparison results indicated that in the vast majority of cases, i.e., 80.5 %, the 90 % CIs for both AUC
t
and C
max
fell within the bioequivalence criteria (in 90.1 and 87.0 % for AUC
t
and C
max
, respectively). In 1 % of the 292 indirect comparison for AUC
t
and 3 % for C
max
, a wider range of 75–133 % (or 80–125 %) was exceeded.
Conclusions
Overall, our study suggests that exposure-related risks associated with the exchange of different generic drugs in clinical practice are not increased to a relevant extent compared to the situation in which a generic is exchanged with the innovator.
Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of ...pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis
. Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF
) that can enter cells desilylates and 'cleaves' a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody-drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF
could release a client protein-including an active gasdermin-from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF
sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF
desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade.
Introduction SUVN-G3031, potent and selective H3 receptor inverse agonist is being developed for the treatment of sleep related disorders. SUVN-G3031 modulates neurotransmitters involved in the ...maintenance of wakefulness and treatment of cataplexy. EEG in rodents produced wake promoting effects. Preclinical results provide a strong support for the potential therapeutic utility of SUVN-G3031 in sleep related disorders. Methods SUVN-G3031 was studied in a single-center, multifaceted phase 1 clinical studies (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single and multiple ascending doses in healthy subjects. For single ascending dose evaluation, healthy subjects were dosed with 0.1, 1, 6, 12, and 20 mg of SUVN-G3031. In multiple dose evaluation, once daily dose of 1, 3, and 6 mg were administered for 14 days in healthy adult male subjects. Effect of food, gender and age on pharmacokinetics was evaluated in healthy subjects at the dose of 6 mg. SUVN-G3031 was quantified in plasma using a validated LC-MS/MS method. Safety and tolerability was evaluated based on assessments of adverse events, physical examinations, laboratory tests, vital signs, 12-lead ECGs and continuous telemetry. Results Absorption of SUVN-G3031 was rapid and exposures were dose proportional at tested doses between 0.1 to 20 mg. SUVN-G3031 achieved the projected efficacy concentrations and attained steady state on day five in tested population on multiple administration. Food, gender and age had no effect on the pharmacokinetics of SUVN-G3031. SUVN-G3031 was well tolerated up to the highest tested dose of 20 mg/day single dose or 6 mg repeated dose in healthy subjects. Conclusion SUVN-G3031 has favorable safety and pharmacokinetic profile in healthy subjects. SUVN-G3031 is well tolerated in humans with adequate plasma exposure for efficacy and favorable pharmacokinetics suitable for once a day oral administration. Phase 2 POC study for the treatment of narcolepsy is being planned in USA. Support (If Any) None
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