• East Asian mathematical journal
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• v.36 no.1
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• pp.81-90
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• 2020

Many compartment models assume a kinetically homogeneous amount of materials that have well-stirred compartments. However, based on observations from such processes, they have been heuristically fitted by exponential or gamma distributions even though biological media are inhomogeneous in real environments. Fractional differential equations using a specific kernel in Pharmacokinetic/Pharmacodynamic (PKPD) model are recently introduced to account for abnormal drug disposition. We discuss a tumor growth inhibition (TGI) model using fractional-order derivative from it. This represents a tumor growth delay by cytotoxic agents and additionally show variations in the equilibrium points by the change of fractional order. The result indicates that the equilibrium depends on the tumor size as well as a change of the fractional order. We find that the smaller the fractional order, the smaller the equilibrium value. However, a difference of them is the number of concavities and this indicates that TGI over time profile for fitting or prediction should be determined properly either fractional order or tumor sizes according to the number of concavities shown in experimental data.

• 제어로봇시스템학회:학술대회논문집
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• 2004.08a
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• pp.330-335
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• 2004

Phase specific models for cancer chemotherapy are described as optimal control problems. We review earlier results on scheduling optimal therapies when the controls represent the effectiveness of chemotherapeutic agents, or, equivalently, when the simplifying assumption is made that drugs act instantaneously. In this paper we discuss how to incorporate more realistic medical aspects which hitherto have been neglected in the models. They include pharmacokinetic equations (PK) which model the drug's plasma concentration and various pharmacodynamic models (PD) which describe the effect the concentrations have on cells. We also briefly discuss the important medical issue of drug resistance.

• 대한임상약리학회:학술대회논문집
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• 2001.12a
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• pp.26-26
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• 2001

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.212-213
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• 2002

Using the isolated perfused rat heart this study investigated 1) the cardiac uptake of idarubicin (IDA), 2) the role of P-glycoprotein (P-gp) in the uptake process, 3) the formation of IDOL from IDA in the heart, and 4) the effect of P-gp inhibitors (verapamil, amiodarone, PSC 833), doxorubicin, hypothermia, xanthine derivatives (caffeine, theophylline) and metabolism inhibitors (rutin, phenobarbital) on the pharmacokinetics and pharmacodynamics of IDA using a mathematical modeling approach. A minimal model was constructed; the differential equations were numerically solved and fitted to the data using the ADAPT II-software package using maximum likelihood estimation assuming that the measurement error has a standard deviation which is a linear function of the measured quantity［1］. (omitted)

• Journal of Pharmaceutical Investigation
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• v.17 no.4
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• pp.205-211
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• 1987

Renal dysfunction can have pronounced effects on the pharmacokinetic and pharmacodynamic characteristics of drugs. Because the exploration of these effects in patients may be limited by ethical and practical considerations, it often become necessary to perform studies on animals with experimental renal failure(ERF). ERF was produced in rats by the administration of uranyl nitrate, glycerol, salicylate, gentamicin and folate in this study. Changes in glomerular filtration rate(GFR) and renal secretion clearance of tetraethylammonium bromide$(CL^{scn}_{TEA})$, together with morphological changes of kidney cortex were evaluated and compared among ERF models. GFR(or glomeruli) and $CL^{scn}_{TEA}$(or renal tubules) were not damaged parallelly in some ERF model rats. Therefore, it seemed to be necessary to adjust dosage regimen of some basic drugs like TEA in renal dysfunction considering the functional changes of renal secretion in addition to glomerular filtration.

• Molecules and Cells
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• v.39 no.5
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• pp.389-394
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• 2016

Dovitinib (TKI258) is a small molecule multi-kinase inhibitor currently in clinical phase I/II/III development for the treatment of various types of cancers. This drug has a safe and effective pharmacokinetic/pharmacodynamic profile. Although dovitinib can bind several kinases at nanomolar concentrations, there are no reports relating to osteoporosis or osteoblast differentiation. Herein, we investigated the effect of dovitinib on human recombinant bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Dovitinib enhanced the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulated the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38. In addition, the mRNA expression of BMP-4, BMP-7, ALP, and OCN increased with dovitinib treatment. Our results suggest that dovitinib has a potent stimulating effect on BMP-2-induced osteoblast differentiation and this existing drug has potential for repositioning in the treatment of bone-related disorders.

• Translational and Clinical Pharmacology
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• v.26 no.4
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• pp.160-165
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• 2018

Indobufen ($Ibustrin^{(R)}$), a reversible inhibitor of platelet aggregation, exists in two enantiomeric forms in 1:1 ratio. Here, we characterized the anti-platelet effect of S- and R-indobufen using response surface modeling using $NONMEM^{(R)}$ and predicted the therapeutic doses exerting the maximal efficacy of each enantioselective S- and R-indobufen formulation. S- and R-indobufen were added individually or together to 24 plasma samples from drug-naïve healthy subjects, generating 892 samples containing randomly selected concentrations of the drugs of 0-128 mg/L. Collagen-induced platelet aggregation in platelet-rich plasma was determined using a Chrono-log Lumi-Aggregometer. Inhibitory sigmoid $I_{max}$ model adequately described the anti-platelet effect. The S-form was more potent, whereas the R-form showed less inter-individual variation. No significant interaction was observed between the two enantiomers. The anti-platelet effect of multiple treatments with 200 mg indobufen twice daily doses was predicted in the simulation study, and the effect of S- or R-indobufen alone at various doses was predicted to define optimal dosing regimen for each enantiomer. Simulation study predicted that 200 mg twice daily administration of S-indobufen alone will produce more treatment effect than S-and R-mixture formulation. S-indobufen produced treatment effect at lower concentration than R-indobufen. However, inter-individual variation of the pharmacodynamic response was smaller in R-indobufen. The present study suggests the optimal doses of R-and S-enantioselective indobufen formulations in terms of treatment efficacy for patients with thromboembolic problems. The proposed methodology in this study can be applied to the develop novel enantio-selective drugs more efficiently.

• Korean Journal of Veterinary Research
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• v.51 no.4
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• pp.253-257
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• 2011

Amikacin is a semisynthetic derivative of kanamycin and primarily active against aerobic Gram-negative-pathogens with limited activity against Gram-positive bacteria. Meager study was reported on pharmacokinetic data on multi-days administration of amikacin. Hence, pharmacokinetics study was done in five clinically healthy goats (n = 5), after intravenous bolus injection of amikacin sulfate at the dose rate of 10 mg/kg body weight daily for three consecutive days. The amikacin concentrations in plasma and pharmacokinetics-parameters were analyzed by using microbiological assay technique and noncompartmental open-model, respectively. The mean peak plasma concentrations (Mean ${\pm}$ SD) of amikacin at time zero ($Cp^{0}$) was $114.19{\pm}20.78$ and $128.67{\pm}14.37{\mu}g/mL$, on day 1st and 3rd, respectively. The mean elimination half-life ($t_{1/2}ke$) was $1.00{\pm}0.28h$ on day 1st and $1.22{\pm}0.29h$ on day 3rd. Mean of area under concentration-time curve ($AUC_{0{\rightarrow}{\infty}}$) was $158.26{\pm}60.10$ and $159.70{\pm}22.74{\mu}g.h/mL$, on day 1st and 3rd respectively. The total body clearance ($Cl_{B}$) and volume of distribution at steady state (Vdss) on day 1st and 3rd were $Cl_{B}=0.07{\pm}0.02$ and $0.06{\pm}0.01L/h.kg$ and $Vdss=0.10{\pm}0.03$ and $0.11{\pm}0.05L/kg$, respectively. No-significant difference was noted in both drug-plasma concentration and pharmacokinetics-parameters, respectively. Amikacin concentration in plasma was found higher up-to 4 h and 6 h onward on down-ward trends favour to reduce toxicity. Which also support the pharmacokinetic-pharmacodynamic way of dosing of aminoglycosides and hence, amikacin may be administered 10 mg/kg intravenously daily to treat principally Gram-negative pathogens and limitedly Gram-positive-pathogens.