Frequency: Quarterly E- ISSN: 2250-0251 P- ISSN: 2249-3549 IBI Factor: 4.09 Abstracted/ Indexed in: Ulrich's International Periodical Directory, Google Scholar, SCIRUS, Genamics Journal Seek, PSOAR, getCITED, InfoBase Index, EBSCO Information Services
Quarterly published in print and online "Inventi Impact: Pharmacokinetics & Pharmacodynamics" publishes high quality unpublished as well as high impact pre-published research and reviews catering to the needs of researchers and professionals. This journal focuses on all areas of pharmacokinetics and pharmacodynamics of drug substances and products including drug absorption, distribution, metabolism and excretion, and application of pharmacokinetics principles for effective management of drugs. Articles from the areas such as drug action, clinical pharmacokinetics, drug metabolites, dosage form evaluation in animals and humans, bioavailabilty studies, scaling from animals to humans, and in vitro and in vivo correlations are also welcome.
Fexuprazan is a potassium-competitive acid blocker approved for treating gastric-acidrelated diseases. Although the effectiveness of the recent formulation fexuprazan 10 mg has been demonstrated in Phase 3 clinical trials, data on the pharmacokinetics (PKs) of administering fexuprazan 10 mg twice daily at a 12 h interval are lacking. Moreover, it is imperative to ensure the bioequivalence of the new formulation with the previously approved 40 mg formulation. This study evaluated the pharmacokinetics (PKs) of the single- and multiple-dose oral administration of fexuprazan 10 mg tablets in healthy participants (Part 1) and investigated their bioequivalence with 40 mg tablets (Part 2). Part 1 comprised a single- and multiple-dose, one-sequence, two-period design and eight participants, while Part 2 comprised a single-dose, 2 × 2 crossover design and 24 participants. In Part 1, in Periods 1 and 2, participants received single and multiple doses (twice daily) of fexuprazan 10 mg, respectively. The maximum plasma concentration (Cmax) area under the concentration–time curve from 0 to 12 h (AUC0–12h) of the multiple-dose participants was approximately double that of the single-dose participants. In Part 2, the geometric mean ratios (90% confidence intervals) for Cmax and AUC from zero to the time of the last quantifiable concentration (AUClast) of the use of four fexuprazan 10 mg tablets to those of one fexuprazan 40 mg tablet were 1.0290 (0.9352–1.1321) and 1.0290 (0.9476–1.1174), respectively, meeting the bioequivalence criteria. Favorable PKs were observed after single and multiple administrations of one fexuprazan 10 mg tablet, and four fexuprazan 10 mg tablets were pharmacokinetically equivalent to one fexuprazan 40 mg tablet....
KAF156 belongs to a new class of antimalarial, the imidazolopiperazines, and is currently in clinical development for the treatment\nof uncomplicated malaria. This first-in-human, single- and multiple-ascending-dose study in 70 healthy male volunteers\ndetermined the maximum oral dose of KAF156 tolerated by healthy adults and derived pharmacokinetic data (including preliminary\nfood effect) to enable dose calculations for malaria patients. KAF156 was studied in single-dose cohorts (10 to 1,200 mg,\nincluding one 400-mg food effect cohort (4 to 10 subjects/cohort), and in multiple-dose cohorts (60 to 600 mg once daily for 3\ndays; 8 subjects/cohort). The follow-up period was 6 to 14 days after the last dose. KAF156 was tolerated, with self-limited mild\nto moderate gastrointestinal and neurological adverse events. In treated subjects after single doses, headache (n4; 11.1%),\ndiarrhea (n3; 8.3%), dizziness (n3; 8.3%), and abdominal pain (n2; 5.6%) were the most common adverse events. Headache\n(n4; 16.7%), nausea (n3; 12.5%), upper respiratory tract infection (n3; 12.5%), and dizziness (n2; 8.3%) were the\nmost common adverse events following multiple doses. KAF156 time to maximum concentration (Tmax) was between 1.0 and 6.0\nh. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased more than dose-proportionally\nin both single- and multiple-ascending-dose cohorts (terminal half-life, 42.5 to 70.7 h). There was no significant accumulation\nover 3-day repeated administration. The extent of absorption was not significantly affected by food at a single dose\nof 400 mg, while mean Cmax decreased from 778 ng/ml to 627 ng/ml and Tmax was delayed from a median of 3.0 h under fasting\nconditions to 6.0 h under fed conditions. Renal elimination is a minor route....
Microdialysis, a sampling method for pharmacokineticsââ?¬â??pharmacodynamics (PKââ?¬â??PD)\nmodeling in preclinical and clinical studies, is a convenient in vivo sampling technique. Geniposide\n(GE), an iridoid glycoside compound, is the major active ingredient of Gardenia jasminoides Ellis fruit\nwhich has an anti-inflammatory effect. In this study, an articular cavity microdialysis sampling system\nfor adjuvant arthritic (AA) rats was established to study the effect of GE on the release of prostaglandin\nE2 (PGE2) in AA rats induced by Freundââ?¬â?¢s complete adjuvant (FCA). An UHPLC-MS/MS method\nwas developed to determine the concentrations of GE and PGE2 in the dialysate. Through the\ndetermination of drug concentrations and PGE2 efficacy levels in the dialysate, the developed\nmethods were successfully applied to set up concentrationââ?¬â??time and effectââ?¬â??time profiles followed\nby PKââ?¬â??PD modeling of GEââ?¬â?¢s effect on decreasing PGE2 release after oral administration of GE.\nThe effect was well described by the developed PKââ?¬â??PD modeling, indicating that GE may play an\nanti-inflammatory role via decreasing AA-induced elevated PGE2 levels. In the selection of suitable\nendogenous small molecules as effect markers, the establishment of AA rat joint-cavity microdialysis\nis an attractive technique for rational PKââ?¬â??PD studies....
Combining amoxicillin with the immunostimulatory toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) represents an innovative approach for enhancing antibacterial treatment success. Exploiting pharmacokinetic and pharmacodynamic data from an infection model of Streptococcus pneumoniae infected mice, we aimed to evaluate the preclinical exposure-response relationship of amoxicillin with MPLA coadministration and establish a link to survival.....................
Pharmacodynamic modeling has been increasingly used as a decision support tool to guide dosing regimen selection, both in the drug development and clinical settings. Killing by antimicrobial agents has been traditionally classified categorically as concentration-dependent (which would favor less fractionating regimens) or time-dependent (for which more frequent dosing is preferred). While intuitive and useful to explain empiric data, a more informative approach is necessary to provide a robust assessment of pharmacodynamic profiles in situations other than the extremes of the spectrum (e.g., agents which exhibit partial concentration-dependent killing). A quantitative approach to describe the interaction of an antimicrobial agent and a pathogen is proposed to fill this unmet need. A hypothetic antimicrobial agent with linear pharmacokinetics is used for illustrative purposes. A non-linear functional form (sigmoid Emax) of killing consisted of 3 parameters is used. Using different parameter values in conjunction with the relative growth rate of the pathogen and antimicrobial agent concentration ranges, various conventional pharmacodynamic surrogate indices (e.g., AUC/MIC, Cmax/MIC, %T>MIC) could be satisfactorily linked to outcomes. In addition, the dosing intensity represented by the average kill rate of a dosing regimen can be derived, which could be used for quantitative comparison. The relevance of our approach is further supported by experimental data from our previous investigations using a variety of gram-negative bacteria and antimicrobial agents (moxifloxacin, levofloxacin, gentamicin, amikacin and meropenem). The pharmacodynamic profiles of a wide range of antimicrobial agents can be assessed by a more flexible computational tool to support dosing selection....
The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of puerarin loaded carboxymethyl chitosan\nmicrospheres (Pue-CCMs). The differences in pharmacokinetics parameters of rats after intragastric administration of Pue-CCMs\nand puerarin were investigated using HPLC. To assess the protective effect of Pue-CCMs on myocardial injury in rats, serum\nlevels of creatine kinase (CK), lactate dehydrogenase (LDH), total superoxide dismutase (T-SOD), and malondialdehyde (MDA)\nwere measured, in addition to pathological examinations and immunohistochemical staining. Our present study has shown that\nthe AUC0ââ?¬â??...
Malaria caused by Plasmodium falciparum is responsible for approximately 80% of the incidence and 90% of deaths which occur\nin the World Health Organization (WHO) African region, with children and pregnant women having the highest incidence. P.\nfalciparumhas developed resistance, and therefore neweffective candidate antimalarial drugs need to be developed. Previous studies\nidentified 3,5-diaryl-2-aminopyridines as potential antimalarial drug candidates; therefore, derivatives of these compounds were\nsynthesized in order to improve their desired properties and pharmacokinetic (PK) properties of the derivatives were investigated\nin a mouse model which was dosed orally and intravenously. Collected blood samples were analyzed using liquid chromatography\ncoupled to mass spectrometer (LC-MS/MS). The mean peak plasma level of 1.9 ????M was obtained at 1 hour for compound 1 and\n3.3 ????Mat 0.5 hours for compound 2. A decline in concentration was observed with a half-life of 2.53 and 0.87 hours for compound\n1 in mice dosed orally and intravenously, respectively. For compound 2 a half-life of 2.96 and 0.68 hours was recorded. The\nbioavailability was 69% and 59.7% for compound 1 and compound 2, respectively....
This study was performed to evaluate and compare the pharmacokinetic parameters between two dosage formulations of hesperidin and naringenin: mixture and tablet. Our objective was to determine that the flavonoid tablet does not significantly modify the pharmacokinetic parameters compared with the mixture. For this study, we administered 161 mg/kg of either mixture (Mix-160) or tablet composed of hesperidin and by intragastric administration. Blood microsamples were collected from tail vein up to 24 h. Serum flavonoid extraction was performed by solid phase extraction and analyzed by LC-MS/MS of triple quadrupole (QqQ). Serum concentration vs. time plot showed that data fitted for a first-order model. The pharmacokinetic parameters were calculated by a noncompartmental model. The results showed that the absorption constant is higher than the elimination constant. The first concentration was found at five minutes, and minimal concentration at 24 h after administration, suggesting a enterohepatic recirculation phenomena and regulation of liver cytochromes’ activity. We did not find meaningful differences between the pharmacokinetic parameters of both samples. We concluded that tablet form did not interfere with the bioavailability of hesperidin and naringenin, and it could be a suitable candidate for developing a drug product....
Background: In clinical practice, the prevalent problem of polypharmacy could result in increased risks of drug–drug interactions. Regorafenib (REG) is commonly co-administered with paracetamol (PA) as a treatment protocol in cancer patients with pain therapy. Purpose: This study aimed to demonstrate the effect of paracetamol on the pharmacokinetic parameters of regorafenib and its metabolites following a single administration of both substances in rats. Additionally, the influence of REG and its metabolites on the pharmacokinetics of paracetamol was also determined. Methods: Twenty-four rats were divided randomly into three groups: REG group (IIREG, regorafenib 20 mg/kg, n = 8), PA group (IIIPA, paracetamol 100 mg/kg, n = 8), and REG+PA co-administration group (IREG+PA, REG 20 mg/kg and PA 100 mg/kg, n = 8). The concentrations of regorafenib, regorafenib-N-oxide (M-2), and N-desmethyl-regorafenib-N-oxide (M-5) were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The plasma concentrations of PA and its glucuronide (GPA) and sulfate (SPA) metabolites were measured using the validated high-performance liquid chromatography method with ultraviolet detection (HPLC– UV). The pharmacokinetic parameters were calculated using a non-compartmental model. The statistical evaluation was performed in the SAS program. Results: After the administration of PA, the Cmax and AUC0–∞ of REG increased by 890% and 1140%, respectively; for M-2, they increased by 220% and 170%, and for M-5, by 2130% and 1730% (Cmax and AUC0–∞, respectively). A difference in the ratio of M-2/REG for AUC0–∞ and Cmax between the groups was observed, but not for M- 5/REG. The AUC0–∞ for PA and GPA decreased by 20.7% and 51.1%, respectively, when PA was co-administered with REG. But the AUC0–∞ for SPA increased by 91.35% in the IREG+PA group. A difference in the ratio of GPA/PA for Cmax and for SPA/PA for AUC0–t and AUC0–∞ between the groups was observed. Conclusions: Paracetamol increased the plasma exposure of regorafenib, M-2, and M-5, which may exacerbate the drug’s side effects. In contrast, REG reduced paracetamol exposure and contributed to its faster elimination, which may reduce the analgesic and antipyretic effects of paracetamol. These findings suggest clinical relevance for oncology patients requiring analgesic treatment....
Biancaea decapetala (Roth) O. Deg. (Fabaceae), traditionally used by the Hmong people to treat rheumatoid arthritis (RA), has not been extensively studied for the correlation between its anti-inflammatory activity and its active components. Protosappanoside D (PTD), a new component, has been isolated for the first time from the extract of Biancaea decapetala. This study focused on the anti-arthritic and anti-inflammatory effects of Biancaea decapetala extracts (BDE) and PTD, along with their pharmacokinetic–pharmacodynamic (PK-PD) analysis. In the adjuvant-induced arthritis (AA) rat model, HE staining and cytokine assays showed that BDE alleviated joint damage and reduced inflammatory cytokines, similar to the positive control. In the LPS-induced inflammatory cell model, both BDE and PTD demonstrated anti-inflammatory effects by inhibiting the secretion of inflammatory factors. A PK-PD analysis of BDE in AA rats and inflammatory cells, as well as an analysis of PTD as a monomer, was conducted. The results indicated that PTD had different regulatory effects on cytokines like TNF-α, with a certain lag and sustained effects. These findings suggest the potential of BDE and PTD as treatments for rheumatoid arthritis, though further in vivo studies and clinical trials are needed....
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