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Quarterly published in print and online "Inventi Impact: Pharmacokinetics & Pharmacodynamics" publishes high quality unpublished as well as high impact pre-published research and reviews catering to the needs of researchers and professionals.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.
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 pharmacokineticsÃ¢â?¬â??pharmacodynamics (PKÃ¢â?¬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 FreundÃ¢â?¬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 concentrationÃ¢â?¬â??time and effectÃ¢â?¬â??time profiles followed\nby PKÃ¢â?¬â??PD modeling of GEÃ¢â?¬â?¢s effect on decreasing PGE2 release after oral administration of GE.\nThe effect was well described by the developed PKÃ¢â?¬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 PKÃ¢â?¬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 AUC0Ã¢â?¬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: Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. Methods: Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. Results: The mean age of participants was 23.9 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (Cmax) was 160-200 nM and after 6 hours, the effective concentration (Ceff) was <150 nM. Conclusion: Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable Ceff of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent....
The antihypertensive felodipine is a calcium channel blocker of the dihydropyridine type,
and its pharmacodynamic effect directly correlates with its plasma concentration. As a sensitive
substrate of cytochrome P450 (CYP) 3A4 with high first-pass metabolism, felodipine shows low oral
bioavailability and is susceptible to drug–drug interactions (DDIs) with CYP3A4 perpetrators. This
study aimed to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD)
parent–metabolite model of felodipine and its metabolite dehydrofelodipine for DDI predictions. The
model was developed in PK-Sim® and MoBi® using 49 clinical studies (94 plasma concentration–time
profiles in total) that investigated different doses (1–40 mg) of the intravenous and oral administration
of felodipine. The final model describes the metabolism of felodipine to dehydrofelodipine
by CYP3A4, sufficiently capturing the first-pass metabolism and the subsequent metabolism of
dehydrofelodipine by CYP3A4. Diastolic blood pressure and heart rate PD models were included,
using an Emax function to describe the felodipine concentration–effect relationship. The model was
tested in DDI predictions with itraconazole, erythromycin, carbamazepine, and phenytoin as CYP3A4
perpetrators, with all predicted DDI AUClast and Cmax ratios within two-fold of the observed values.
The model will be freely available in the Open Systems Pharmacology model repository and can be
applied in DDI predictions as a CYP3A4 victim drug....
CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor that\nis being developed for dyslipidemia. Even though CKD-519 has shown potent CETP inhibition,\nthe exposure of CKD-519 was highly varied, depending on food and dose. For highly variable\nexposure drugs, it is crucial to use modeling and simulation to plan proper dose selection. This study\naimed to develop population pharmacokinetic (PK) and pharmacodynamics (PD) models of CKD-519\nand to predict the proper dose of CKD-519 to achieve target levels for HDL-C and LDL-C using results\nfrom multiple dosing study of CKD-519 with a standard meal for two weeks in healthy subjects.\nThe results showed that a 3-compartment with Erlangâ??s distribution, followed by the first-order\nabsorption, adequately described CKD-519 PK, and the bioavailability, which decreased by dose and\ntime was incorporated into the model (NONMEM version 7.3). After the PK model development,\nthe CETP activity and cholesterol (HDL-C and LDL-C) levels were sequentially modeled using the\nturnover model, including the placebo eect. According to PK-PD simulation results, 200 to 400 mg\nof CKD-519 showing a 40% change in HDL-C and LDL-C from baselines was recommended for proof\nof concept studies in patients with dyslipidemia....
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