Assessment Of Pharmacokinetic Parameters Research Articles

STUDYING THE PHARMACOKINETIC PARAMETERS OF NEW NORMOTHYMIC DRUG BASED ON THE COMPLEX OF LITHIUM CITRATE, ALUMINUM OXIDE AND POLYMETHYLSILOXANE

For the treatment of bipolar affective disorders, lithium preparations are the most famous and effective. But the main problem with the use of lithium preparations is the narrow «therapeutic corridor». An urgent task is the creation of dosage forms of lithium with a slow release and a wide therapeutic range. The study object was a new normotymic drug based on lithium, aluminum oxide and polymethylsiloxane. Due to the new carrier matrix lithium is released from its porous structure gradually providing a prolonged effect and maintaining an optimal concentration in the blood which also helps to minimize side effects. The purpose of the study was to explore the pharmacokinetic parameters of a normotymic drug based on a complex lithium citrate, aluminum oxide and polymethylsiloxane (LOAP). Material and methods: for the assessment of pharmacokinetic parameters the method of atomic emission spectrometry with inductively coupled plasma and two-chamber modeling were used. Results and discussion. The pharmacokinetic data showed a linear nature of pharmacokinetics of the drug based on LOAP as the foundation of data of the lithium’s amount in the blood plasma of rabbits after intragastric administration at doses of 200, 400 and 800 mg/kg. The drug with intragastric administration at a dose of 800 mg/kg is well absorbed from the gastrointestinal tract, with bioavailability (F) 74 %. This dose shows the maximum increase of the area under the pharmacokinetic curve (AUC - 32787.1 (ng x h)/ ml), and indicators of elimination constant (Kel - 0.062 h-1), clearance (Cl - 0.09 l/(kg x h)), elimination half-life (T1/2p - 11.436 h) in comparison with other doses remain unchanged.

Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4.

This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies. Three complementary studies were performed: 1) a dose-finding study in CKD stages 1-5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase; 2) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA1c concentrations monitored monthly; and 3) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4. First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning [qam] +1 g in the evening [qpm]) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA1c levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups. Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD.

Assessment of bioequivalence profile of locally produced flucloxacillin sodium capsules via urinary excretory rates

The assessment of pharmacokinetic parameters constitutes the basic approach to determining bioequivalence of pharmaceutical products in order to ensure safety, efficacy and potency of the administered drug. This study has examined a locally manufactured flucloxacillin (FLUXACIN 500) and the reference product (FLUCLOXACILLIN 500mg CAPSULES) for therapeutic equivalence in a cross–over non–replicate bioequivalence study using urinary excretion data. The study was conducted with twelve consenting healthy male volunteers in a fasting state using single–dose, randomized, two–period, two–treatment cross over study design. A seven-day washout period was allowed between treatments. Urine specimen collected were analysed by means of HPLC with UV detection while pharmacokinetic parameters were analysed using Microsoft Excel Spreadsheet 2013. fFluxacin 500 reached a maximum excretion rate at an average time of 1.42 hours while flucloxacillin 500 mg reached its maximum excretion rate at an average time of 1 hour. There was no statistical significant difference between the two times. The 90% Confidence Interval of the ratio of the Area under the Excretion Rate–time Curve of fluxacin 500 to flucloxacillin 500 mg was 96.20% to 101.24% while those of the Cumulative Amount of flucloxacillin excreted, and the Rate of Maximum Excretion were 102.92% to 116.85% and 72.59% to 94.61% respectively. Fluxacin 500 demonstrated bioequivalence relationship with flucloxacillin for all the four parameters: Maximal Rate of Excretion, Area under Excretion Rate–Time Curve, Cumulative Amount Excreted and the Time for Maximum Excretion. The test and reference drugs are therefore interchangeable.

Correction for photobleaching in dynamic fluorescence microscopy: application in the assessment of pharmacokinetic parameters in ultrasound-mediated drug delivery

We have previously demonstrated the feasibility of monitoring ultrasound-mediated uptake of a hydrophilic model drug in real time with dynamic confocal fluorescence microscopy. In this study, we evaluate and correct the impact of photobleaching to improve the accuracy of pharmacokinetic parameter estimates.To model photobleaching of the fluorescent model drug SYTOX Green, a photobleaching process was added to the current two-compartment model describing cell uptake. After collection of the uptake profile, a second acquisition was performed when SYTOX Green was equilibrated, to evaluate the photobleaching rate experimentally.Photobleaching rates up to 5.0 10−3 s−1 were measured when applying power densities up to 0.2 W.cm−2. By applying the three-compartment model, the model drug uptake rate of 6.0 10−3 s−1 was measured independent of the applied laser power.The impact of photobleaching on uptake rate estimates measured by dynamic fluorescence microscopy was evaluated. Subsequent compensation improved the accuracy of pharmacokinetic parameter estimates in the cell population subjected to sonopermeabilization.

Application of physiologically‐based pharmacokinetic modeling in hepatic impairment populations (1064.9)

Diagnosis of hepatic impairment (HI) is associated with a reduction in hepatocyte expression, a decrease in albumin and α‐1‐acid glycoprotein and a reduction in renal function, the combination of which can result in alteration of the pharmacokinetic (PK) properties of a drug. Therefore, regulatory agencies such as the U.S. Food and Drug Administration often require the assessment of PK parameters in HI populations. These studies can entail single or multiple‐dose approaches and must be of sufficient duration to capture the terminal half‐life of the drug, a parameter which may be extended in HI populations. The use of physiologically‐based pharmacokinetic (PBPK) modeling, a technique combining demographic and genetic factors, anatomical and physiological parameters and drug‐specific properties, can aid in the prediction of PK parameters and the design of clinical trials in HI populations. To that end, the utility of PBPK modeling in predicting unique clinical scenarios in HI populations was evaluated for a number of compounds including sensitive P450 substrates and drugs cleared by multiple P450s. Drug interactions, enantioselective PK changes and effects on hepatic versus intestinal CYP3A4 metabolism due to HI were predicted. Results suggest that PBPK modeling is a useful tool for predicting changes in PK parameters under multiple conditions and for contributing to the design of HI clinical trials.

An Immunodeficient Mouse Model With Circulating Human Platelets To Evaluate The Platelet Clearance and Pharmacokinetics Of Platelet-Targeted Coagulation Factor VIIa

Treatment of bleeding episodes in hemophilia patients with inhibitory antibodies to factor VIII or factor IX by recombinant activated factor VII (rFVIIa, NovoSeven) has been sub-optimal partly due to its low affinity to activated platelets and its short half-life in circulation. To develop a rFVIIa variant with enhanced coagulant activity, we have targeted rFVIIa to platelets by monoclonal antibodies that recognize the human platelet receptor αIIbβ3. However, the assessment of pharmacokinetic parameters in mice is limited by the lack of recognition of mouse αIIbβ3 by antibodies to human αIIbβ3. The present study addresses the need to develop appropriate in vivo models to study this new class of bypass therapeutics.First, we evaluated the survival of human platelets in hemophilia A, NOD/SCID, and NOD/SCID/gamma (NSG) mice. Platelet concentrates were prepared from normal human donors and transfused retro-orbitally into mice. The whole blood from dosed mice was then collected via tail vein laceration at various times and the human platelet counts in blood was determined by flow cytometry after staining with fluorescently labeled antibodies against human CD42b, mouse CD61, human FVII to visualize the human platelets, mouse platelets, and the FVIIa candidate that bound to human platelets, respectively. The half-life of human platelets in NOD/scid/gamma (NSG) mice was approximately 4 hours, which is considerably longer than the 0.8 hour half-life observed in hemophilia A mice.The effect of platelet-targeted FVIIa variants on the clearance of human platelets was then investigated in NSG mice. The FVIIa candidates were pre-selected for their inactivity toward human platelet activation and aggregation, as determined in a battery of in vitro assays. In agreement with the in vitro results, all of these selected candidates did not affect the clearance of the transfused human platelets when dosed in NSG mice at 5 nmol/kg. In contrast, a control antibody fusion protein that is known to activate platelets and cause thrombocytopenia in vivo led to rapid platelet clearance in NSG mice. Similar results were observed for these proteins in cynomolgous monkeys when dosed at 2 nmol/kg.The NSG mice with circulating human platelets were also explored to evaluate the clearance of FVIIa candidates that remain platelet-associated in vivo. To improve the pharmacokinetics, we have fused XTEN, a hydrophilic peptide that increases the dynamic radius of payload proteins, to the platelet-targeted FVIIa candidates. When tested in NSG mice model for the clearance of platelet-associated protein, addition of XTEN markedly reduced the clearance rate, resulting in several fold increase in exposure.Together these data indicate that NSG mice with circulating human platelets can be used to assess the safety and pharmacokinetics of the platelet-targeted FVIIa variants, and the method can be adapted to evaluate other agents designed to utilize platelet-targeting approaches. Disclosures:Tan:Biogen Idec: Employment, Equity Ownership. Chen:Biogen Idec: Employment, Equity Ownership. Salas:Biogen Idec: Employment, Equity Ownership. Peters:Biogen Idec: Employment, Equity Ownership. Light:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership.

Phase 1 study of the investigational, oral angiogenesis inhibitor motesanib in Japanese patients with advanced solid tumors

The aim of this study was to investigate the safety and pharmacokinetics of motesanib (AMG 706), a small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and c-Kit in Japanese patients with advanced solid tumors. Patients were administered motesanib orally once daily (QD) at doses of 50, 100, and 125 mg QD. The total study duration for each patient consisted of three cycles of 28 days per cycle. The primary endpoints were the incidence of dose-limiting toxicities (DLTs), estimation of the maximum tolerated dose (MTD), and assessment of pharmacokinetic parameters of motesanib. Fifteen patients were enrolled and received motesanib. No DLTs were observed and, therefore, the MTD was not reached. Motesanib had acceptable toxicity at doses up to 125 mg QD. The pharmacokinetics of motesanib appears to be dose proportional. No objective responses per RECIST were observed. However, all 15 patients achieved stable disease, and five patients had durable (>24 weeks) stable disease. The results of this study demonstrate that motesanib is tolerable in Japanese patients at doses up to 125 mg QD.

Serum elimination profiles of methyllycaconitine and deltaline in cattle following oral administration of larkspur (Delphinium barbeyi)

To describe the simple elimination kinetics of methyllycaconitine (MLA) and deltaline and evaluate the heart rate response in cattle following oral administration of larkspur. 5 healthy Angus steers that were habituated to metabolism crates. Tall larkspur (Delphinium barbeyi) in the early flowering stage was collected, dried, and ground. Each steer received a single dose of larkspur that was equivalent to 10.4 mg of MLA/kg and 11.0 mg of deltaline/kg via oral administration. Steers were housed in metabolism crates during a 96-hour period following larkspur administration; heart rate was monitored continuously, and blood samples were collected periodically for analysis of serum MLA and deltaline concentrations as well as assessment of pharmacokinetic parameters. No overt clinical signs of poisoning developed in any steer during the experiment. Mean +/- SE heart rate reached a maximum of 79.0 +/- 5.0 beats/min at 17 hours after larkspur administration. Serum MLA concentration was correlated directly with heart rate. Mean times to maximal serum concentration of MLA and deltaline were 8.8 +/- 1.2 hours and 5.0 +/- 0.6 hours, respectively. Mean elimination half-life values for MLA and deltaline were 20.5 +/- 4.1 hours and 8.2 +/- 0.6 hours, respectively. Following larkspur administration in 5 healthy steers, maximum serum concentrations of MLA and deltaline were detected within 10 hours, and changes in serum MLA concentration and heart rate were correlated. Results indicated that cattle that have consumed larkspur will eliminate 99% of MLA and deltaline from serum within 144 hours.

A Bayesian approach for the estimation of pharmacokinetic parameters in children.

A Bayesian method is proposed for the first-time assessment of pharmacokinetic parameters (area under the curve [AUC], maximum concentration [C(max)], half-life [T(1/2)]) in children after a single oral dose. Pharmacokinetic parameters were compared using sparse sampling (three blood samples) with extensive sampling (nine blood samples). Two different therapeutic classes of drugs were evaluated in this study. The population pharmacokinetic parameters and the blood sampling time points were obtained from adult data. The results indicate that the Bayesian approach can be used to estimate pharmacokinetic parameters in children with fair degree of accuracy. The Bayesian method described here can be used to assess pharmacokinetic parameters in children, provided there is a prior knowledge of the pharmacokinetics of a drug in adult population.

The assessment of pharmacokinetic parameters of teicoplanin in burns comparing the methods of nonlinear curve fitting and quantified maximum entropy

The pharmacokinetics of teicoplanin in patients with severe burns has been assessed using two different numerical methods: a nonlinear curve fitting procedure and quantified maximum entropy. On the whole nonlinear curve fitting and quantified maximum entropy provided different pharmacokinetic parameter estimates for the same sets of data. With respect to correctness and reliability of the values, quantified maximum entropy appears to be the better approach. However, its full success depends on the data available. The data material need to be comprehensive to assure a maximum information content to be extracted. The nonlinear curve fitting approach requires less sophisticated mathematical modelling which is possible on common hardware, and produces results faster than quantified maximum entropy. Thus, nonlinear curve fitting is the method of choice if a rapid assessment of the data is required, whereas quantified maximum entropy should be the method of choice in research and development, where the required accuracy of the estimates is more important than time.