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Pharmacokinetic variability due to environmental differences.

Translational and Clinical Pharmacology.2017;25(2):59-62. doi:10.12793/tcp.2017.25.2.59

This tutorial describes sources of pharmacokinetic variability that are not obviously linked to genetic differences. The sources of variability are therefore described as environmental. The major quantitative sources of environmental variability are body size (including body composition), maturation and organ function. Size should be considered in all patients. Maturation is mainly relevant to neonates and infants less than 2 years of age. Renal function is the most important predictable source of variability due to differences in organ function.
Body Size ; Humans ; Infant ; Infant, Newborn ; Pharmacokinetics

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The stable isotope method for determining absolute bioavailability.

Arthur J ATKINSON

Translational and Clinical Pharmacology.2017;25(2):53-58. doi:10.12793/tcp.2017.25.2.53

The bioavailability of a drug is usually assessed in healthy subjects. However, it is reasonable to expect that significant alterations in bioavailability may occur in actual patients with different diseases or in individuals belonging to special populations. Relatively few studies have been conducted to examine this possibility. The stable isotope method is well suited to compare absolute bioavailability in patients and healthy subjects. Studies in which this method was used indicate that significant changes in the bioavailability of some drugs are particularly likely in patients with advanced liver disease and in those whose splanchnic blood flow is reduced. The expectation is that bioavailability in neonates, children, and pregnant women may also differ from that in non-pregnant adults.
Adult ; Biological Availability* ; Child ; Female ; Healthy Volunteers ; Humans ; Infant, Newborn ; Liver Diseases ; Methods* ; Pharmacokinetics ; Pregnant Women

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Intracerebroventricular drug administration.

Arthur J. ATKINSON

Translational and Clinical Pharmacology.2017;25(3):117-124. doi:10.12793/tcp.2017.25.3.117

Among the various routes of drug administration, perhaps the least studied is intracerebroventricular (ICV) administration. This route has been shown to be particularly useful in administering to the central nervous system (CNS) drugs that do not cross the blood-brain barrier readily. As such, the ICV route is a valuable option for providing therapeutic CNS drug concentrations to treat patients with CNS infectious and neoplastic diseases. This route of drug administration also has the advantage of minimizing systemic toxicity.
Blood-Brain Barrier ; Central Nervous System ; Humans ; Meningitis ; Pharmacokinetics

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Inhibition of indoxyl sulfate-induced intrarenal renin-angiotensin system activation: targeting the aryl hydrocarbon receptor.

Muhammad Firman AKBAR

Translational and Clinical Pharmacology.2017;25(3):114-116. doi:10.12793/tcp.2017.25.3.114

Indoxyl sulfate, a protein-bound uremic toxin, leads to CKD (chronic kidney disease) progression and its complications through the activation of AhR (aryl hydrocarbon receptor) and RAS (renin-angiotensin system). Inhibition of these pathways may slow the development of CKD and CKD-associated complications.
Indican ; Kidney ; Receptors, Aryl Hydrocarbon* ; Renal Insufficiency, Chronic ; Renin-Angiotensin System*

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Principles of transparency and clinical trial registration.

Dong Seok YIM

Translational and Clinical Pharmacology.2017;25(3):113-113. doi:10.12793/tcp.2017.25.3.113

No abstract available.

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Screening study for genetic polymorphisms affecting pharmacokinetics of pioglitazone.

Ji Young YUN ; Bo Hyung KIM ; Ji Hyun LEE ; Kidong LEE ; KyuBum KWACK ; Sung Vin YIM

Translational and Clinical Pharmacology.2016;24(4):194-202. doi:10.12793/tcp.2016.24.4.194

Pioglitazone is known to have antidiabetic effects through decreasing peripheral, hepatic and vascular insulin resistance by the stimulation of PPAR gamma. To address the possible genetic factors affecting the pharmacokinetics (PK) of pioglitazone, 27 male Korean volunteers were enrolled from two separate bioequivalence studies. Each subject was administered 15 mg pioglitazone and reference drug PK parameters were used. We used Illumina Human610 Quad v1.0 DNA Analysis BeadChip for whole genome SNPs analysis and whole genome genotyping data was processed by linear regression analysis for PK parameters. We found 35 significant SNPs (P < 0.0001) in C(max), 1,118 significant SNPs (P < 0.0001) in T(max) and 1,259 significant SNPs (P < 0.0001) in AUC(inf) from whole genome analysis. For clinical pharmacological purpose, we selected SNPs from several phase I and II drug metabolizing enzyme and analyzed PK parameters with genotypes. Four SNPs (rs7761731 and rs3799872 from CYP39A1; rs156697 from GSTO2; rs1558139 from CYP4F2) showed significant associations with pioglitazone C(max). In the T(max) group, seven SNPs from 3 genes (rs3766198 from CYP4B1; rs2270422 from GSTZ1; rs2054675, rs10500282, rs3745274, rs8192719, and rs11673270 from CYP2B6) had significant associations. In the AUC(inf) group, seven SNPs from 4 genes (rs11572204 from CYP2J2; rs4148280 from UGT2A1, rs4646422 from CYP1A1; rs3745274, rs8192719, rs11673270, and rs707265 from CYP2B6) showed significant associations with pioglitazone absorption. These results showed that genetic makeup could affect the PK parameters and these informations could be provide information for personalized pioglitazone therapy.
Absorption ; Cytochrome P-450 CYP1A1 ; DNA ; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination ; Genome ; Genotype ; Humans ; Insulin Resistance ; Linear Models ; Male ; Mass Screening* ; Pharmacogenetics ; Pharmacokinetics* ; Polymorphism, Genetic* ; Polymorphism, Single Nucleotide ; PPAR gamma ; Therapeutic Equivalency ; Volunteers

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An imputation-based method to reduce bias in model parameter estimates due to non-random censoring in oncology trials.

Dongwoo CHAE ; Kyungsoo PARK

Translational and Clinical Pharmacology.2016;24(4):189-193. doi:10.12793/tcp.2016.24.4.189

In oncology trials, patients are withdrawn from study at the time when progressive disease (PD) is diagnosed, which is defined as 20% increase of tumor size from the minimum. Such informative censoring can lead to biased parameter estimates when nonlinear mixed effects models are fitted using NONMEM. In this work, we investigated how empirical Bayes estimates (EBE) could be exploited to impute missing tumor size observations and partially correct biases in the parameter estimates. 50 simulated datasets, each consisting of 100 patients, were generated based on the published model. From the simulated dataset, censoring due to PD diagnosis has been implemented. Using the post-hoc EBEs acquired from fitting the censored datasets using NONMEM, imputed values were generated from the tumor size model. Model fitting was carried out using censored and imputed datasets. Parameter estimates using both datasets were compared with true values. Tumor growth rate and cell kill rate were approximately 28% and 16% underestimated when fitted using the censored dataset, respectively. With the imputed datasets, relative biases of tumor growth rate and cell kill rate decreased to about 6% and 0%, respectively. Our work demonstrates that using EBEs acquired from fitting the model to the censored dataset and imputing the unknown tumor size observations with individual predictions beyond the PD time point is a viable option to solve the bias associated with structural parameter estimates. This approach, however, would not be helpful in getting better estimates of variance parameters.
Bays ; Bias (Epidemiology)* ; Dataset ; Diagnosis ; Humans ; Methods*

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Pharmacokinetic characteristics of cilostazol 200 mg controlled-release tablet compared with two cilostazol 100 mg immediate-release tablets (Pletal) after single oral dose in healthy Korean male volunteers.

Jin Dong SON ; Sang Min CHO ; Youn Woong CHOI ; Soo Hwan KIM ; In Sun KWON ; Eun Heui JIN ; Jae Woo KIM ; Jang Hee HONG

Translational and Clinical Pharmacology.2016;24(4):183-188. doi:10.12793/tcp.2016.24.4.183

Cilostazol controlled-release (CR) tablets have recently been developed by Korea United Pharm (Seoul, Korea). The tablets use a patented double CR system, which improves drug compliance by allowing "once daily" administration and reduces adverse events by sustaining a more even plasma concentration for 24 h. We conducted an open, randomized, two-period, two-treatment, crossover study to compare the pharmacokinetic (PK) characteristics and tolerability of cilostazol when administered to healthy Korean male volunteers as CR or immediate release (IR) tablets (Pletal, Korea Otsuka Pharmaceutical Co., Gyeonggi-do, Korea). Each volunteer was randomly allocated to receive a single tablet of cilostazol CR (200 mg) or two tablets of cilostazol IR (100 mg) with a 7-day washout period between treatments. Plasma cilostazol, OPC-13015 (3,4-dehydrocilostazol), and OPC-13213 (4'-trans-hydroxycilostazol) were assayed using liquid chromatography-tandem mass spectrometry for PK analysis. Thirty participants completed the study with no clinically relevant safety issues. The peak concentrations (C(max), mean ± SD) of cilostazol CR and cilostazol IR were 1414.6 ± 49.3 and 1413.1 ± 35.2 ng/mL, respectively, and the areas under the plasma concentration-time curve from 0 to the last concentration (AUC(last)) were 23928.7 ± 65.9 and 25312.0 ± 62.6 ng·h/mL, respectively. The geometric mean ratios (cilostazol CR/cilostazol IR, GMR) of the C(max) and AUC(last) values were 1.001 (90% CI: 0.822, 1.220) and 0.945 (90% CI: 0.814, 1.098), respectively. The frequencies of adverse events were similar. The present study showed that cilostazol PK and tolerability were comparable when administered to healthy Korean men, regardless of whether administered as cilostazol CR or IR.
Compliance ; Cross-Over Studies ; Gyeonggi-do ; Humans ; Korea ; Male* ; Mass Spectrometry ; Pharmacokinetics ; Plasma ; Tablets* ; Therapeutic Equivalency ; Volunteers*

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Pharmacokinetics and safety profiles of tadalafil/tamsulosin HCl fixed-dose combination capsule under fasted and fed condition in healthy volunteers.

Byung Hak JIN ; Byung Won YOO ; Eun Sil OH ; Seungwon YANG ; Jina JUNG ; Min Soo PARK

Translational and Clinical Pharmacology.2016;24(4):175-182. doi:10.12793/tcp.2016.24.4.175

Co-administration of tadalafil and tamsulosin HCl in patients with benign prostate hyperplasia and erectile dysfunction is increasing in clinical settings. Development of fixed-dose combination (FDC) of tadalafil and tamsulosin HCl could contribute to improving patients' adherence and treatment efficacy. We evaluated the pharmacokinetics and safety profiles of a newly developed fixed-dose combination capsule of tadalafil 5 mg/tamsulosin HCl 0.4 mg in comparison with co-administration of each formulation in healthy volunteers under fasted and fed conditions. Two randomized, open-label, single-dose, two-way, crossover studies were completed in 29 subjects under fasted condition, and 33 subjects under fed condition. Serial blood sample collection for PK analysis was conducted up to 72 hours after dosing, and PK parameters were calculated using non-compartmental analysis. Geometric mean ratios and 90% confidence intervals of the C(max) and AUC(last) were used to evaluate comparative bioavailability. In both fasted and fed condition studies, the bioequivalence was established. The most common adverse drug reactions were orthostatic hypotension and headache with no statistical difference between treatment groups. All subjects with orthostatic hypotension recovered at follow-up test. Although changes in vital signs from baseline were statistically significant, there were no subjects with systolic blood pressure < 90 mmHg and there were no clinically meaningful signs or symptoms associated. FDC of tadalafil and tamsulosin HCl can be an alternative to co-administration of individual drugs for providing better compliance. Changes in blood pressure should be kept in mind when tadalafil and tamsulosin HCl are co-administered in clinical settings.
Biological Availability ; Blood Pressure ; Compliance ; Cross-Over Studies ; Drug-Related Side Effects and Adverse Reactions ; Erectile Dysfunction ; Follow-Up Studies ; Headache ; Healthy Volunteers* ; Humans ; Hyperplasia ; Hypotension, Orthostatic ; Male ; Pharmacokinetics* ; Prostate ; Tadalafil ; Therapeutic Equivalency ; Treatment Outcome ; Vital Signs

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Effects of JOINS® on the pharmacokinetic profiles of aceclofenac in healthy Korean volunteers: an open-label, multiple-dose, one sequence, two-period study.

Dasohm KIM ; Eun Sil OH ; Choon Ok KIM ; Chungam CHOI ; Min Jung CHANG ; Min Soo PARK

Translational and Clinical Pharmacology.2016;24(4):169-174. doi:10.12793/tcp.2016.24.4.169

JOINS, an herbal anti-arthritic drug, was developed for the treatment and pain relief of knee osteoarthritis. It was approved for use in Korea by the Ministry of Food and Drug Safety in 2001. The aim of this study was to investigate the effect of JOINS on the pharmacokinetic (PK) profiles of aceclofenac in healthy adults. A PK drug-drug interaction study was conducted in 61 healthy subjects by using an open-label, multiple-dose, one sequence, two-period design. Blood samples were collected for plasma concentrations of aceclofenac during the reference period (aceclofenac 100 mg alone) and interaction period (aceclofenac 100 mg + JOINS 300 mg). The area under the curve within a dosing interval (τ) at steady state (AUC(τ,ss)) and the C(max) at steady state (C(max,ss)) of aceclofenac were analyzed by a non-compartment model using the Phoenix® WinNonlin® software version 6.3 (Pharsight, Mountain View, CA, USA). The 90% CIs of the geometric mean ratios (GMRs) of the AUC(τ,ss) of aceclofenac with JOINS to without JOINS (D4/D3 and D11/D3) were 0.9593–1.0130 and 0.9745–1.0291, respectively, and the corresponding values for the C(max,ss) of aceclofenac with JOINS to without JOINS (D4/D3 and D11/D3) were 0.8578–0.9795 and 0.8510–0.9717. Aceclofenac alone or co-administered with JOINS was safe and well tolerated with no serious adverse drug reactions or significant differences in the severity of adverse events (AEs) between the two treatment groups. We conclude that co-administration of aceclofenac with JOINS does not influence the PK and safety profiles of aceclofenac.
Adult ; Drug Interactions ; Drug-Related Side Effects and Adverse Reactions ; Healthy Volunteers ; Humans ; Korea ; Osteoarthritis, Knee ; Pharmacokinetics ; Plasma ; Volunteers*

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