Risa Takayanagi

Assessment of systemic adverse reactions induced by ophthalmic β-adrenergic receptor antagonists

To assess quantitatively the risks of ophthalmic beta-blocking agents for cardiovascular and respiratory adverse reactions, we analyzed the binding kinetics of beta-blocking agents to the beta-1 and beta-2 adrenoceptors. The relationship between the occupancies for beta-1 and beta-2 adrenoceptors and the effects on the exercise pulse rate or the forced expiratory volume in one second (FEV1) after topical administration of carteolol, befunolol, timolol and betaxolol was analyzed using a ternary complex model. The beta-1 and beta-2 receptor occupancies after ophthalmic administration were calculated to be quite high as well as those after oral administration. The maximum occupancies for beta-1 and beta-2 receptors after ordinary ophthalmic administration were 52% and 88% for carteolol, 52% and 61% for befunolol, 62% and 82% for timolol, and 44% and 3% for betaxolol, respectively. Concave relationships were obtained between a decrease in exercise pulse rate and the beta-1 receptor occupancy and between a decrease in FEV1 and beta-2 receptor occupancy, respectively. Nasolacrimal occlusion was estimated to decrease the exercise pulse rate and FEV1 by 65% and 50%, respectively. The beta-1 and beta-2 adrenoceptor occupancies were proved to be the most appropriate indicators for cardiac and pulmonary adverse reactions evoked by ophthalmic beta-blocking agents.

Population Pharmacokinetics of Transdermal Fentanyl in Patients With Cancer-Related Pain

ABSTRACT Determining the appropriate dose of transdermal fentanyl (TDF) for the alleviation of cancer pain requires determining the factors causing variations in serum fentanyl concentration after TDF treatment. The objective of this study was to identify these factors and incorporate them into a formula that can be used to predict serum fentanyl concentration after application of a TDF patch. Blood samples of cancer patients treated with a TDF patch for the alleviation of pain were collected at 24, 48, and 72 hours after application to evaluate population pharmacokinetics using the nonlinear mixed-effect model (NONMEM). Based upon this evaluation, Child-Pugh Score and use of a cytochrome P450 3A4 (CYP3A4) inducer were identified as the most significant factors in variations in serum fentanyl concentration and incorporated into the following Final Model formula: CLfenta (L/h) = 3.53 × (15 − Child-Pugh Score) × (1 + 1.38 × use or no use of CYP3A4 inducer). Bootstrap evaluation of the Final Model revealed a high convergence rate, suggesting that the model formula is a reliable and useful tool for determining TDF dose for the alleviation of cancer pain.

Receptor occupancy theory-based analysis of interindividual differences in antiemetic effects of 5-HT3 receptor antagonists

BackgroundThe aim of this study was to estimate interindividual differences in the antiemetic effects of 5-HT3 receptor antagonists by evaluating the influence of pharmacokinetics on 5-HT3 receptor occupancies, based on receptor occupancy theory.MethodsWe analyzed interindividual differences of 5-HT3 receptor occupancies and antiemetic effects after the oral and/or intravenous administration of standard doses of the following 5-HT3 receptor antagonists: azasetron, granisetron, indisetron, ondansetron, ramosetron, and tropisetron.ResultsThe interindividual difference between maximum and minimum 5-HT3 receptor occupancies after oral administration ranged from 0.6% to 64.0%, and that difference after intravenous administration ranged from 0.6% to 29.6%. Following oral administration, the interindividual difference between maximum and minimum complete vomiting inhibition rates ranged from 0.2% to 16.1%. After intravenous administration, that difference ranged from 0.8% to 52.5%.ConclusionInterindividual differences in the clinical effects of 5-HT3 receptor antagonists could be evaluated based on receptor occupancy theory, and the differences varied among drugs. Drug selection considering these individual variations might be useful for the patients who experienced vomiting associated with chemotherapy.

Population Pharmacokinetics of Oxycodone in Patients With Cancer-Related Pain

ABSTRACT Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 − Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); Vd (L) = 193; ka (h−1) = 0.336; Tlag (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, Vd: 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

Pharmacokinetic and Pharmacodynamic Analysis of Systemic Effect of Topically Applied Timolol Maleate Ophthalmic Gelling Vehicle (Rysmon® TG)

Purpose: The objective of this study was to evaluate the degree of systemic absorption and the systemic side effect after instillation of timolol maleate ophthalmic gelling vehicle in human. Methods: A volunteer study was employed, and a randomized crossover design with the two phases was used. In one phase, the volunteers instilled a single drop of the 0.5% timolol maleate ophthalmic gelling vehicle; in the other phase, the volunteers instilled a single drop of the 0.5% timolol maleate ophthalmic solution. The plasma concentration of timolol and the heart rates were studied during the following 120 min and 60 min, respectively. Results: The area under the blood concentration time curve (AUC) in timolol maleate ophthalmic gelling vehicle was lower than that in timolol maleate ophthalmic solution (p < 0.05). No differences were observed in heart rates between ophthalmic gelling vehicle and ophthalmic solution. The correlation between the calculated occupancy of beta-adrenergic receptors and the systemic side effects after instillation could be successfully analyzed with a pharmacokinetic and pharmacodynamic model, showing the predictability of the model for the systemic side effects of timolol. Conclusions: The result of our analysis clearly shows that timolol maleate ophthalmic gelling vehicle reduced the systemic absorption below that of ophthalmic solution, but the degree in difference of systemic effects was negligible.

Effects of tumor necrosis factor α-857C/T polymorphism on the expression of tumor necrosis factor α

It was reported that homozygosity for a lymphotoxin α (LTA) 1‐1‐1‐1 haplotype (LTA NcoI‐TNFc‐aa13L‐aa26) may identify subgroups with a poor response to infliximab in Crohns disease patients. Previously, we found a genetic polymorphism that linked with the LTA 1‐1‐1‐1 haplotype and noted that it was a tumor necrosis factor (TNF) α‐857 T allele. To investigate the effects of the ‐857C/T (rs1799724) polymorphism on the expression of TNFα, we compared levels of transcriptional activity of the gene, mRNA, and protein of the TNFα. The change in transcriptional activity of the ‐857T allele was higher than that of the ‐857C allele. Furthermore, the accumulated transcriptional activity of the ‐857T allele was 1.3‐fold higher than that of the ‐857C allele up to 48 h. The levels of mRNA and protein of the TNFα after stimulation were also shown to be significantly higher in ‐857C/T as compared to the ‐857C/C genotype. Our results suggested that TNFα promoter ‐857T is higher than ‐857C in the levels of transcriptional activity of the gene, mRNA, and protein of the TNFα. The differences in therapeutic effect of TNF inhibitors among individuals can be explained in part by the induction ability of TNFα via the ‐857C/T polymorphism.

Theoretical method for evaluation of therapeutic effects and adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors in clinical treatment

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for non-small cell lung cancer patients with an EGFR gene mutation. However, skin disorders are known as adverse events. In the present study, we investigated whether EGFR-TK occupancy is useful as an index for assessing clinical efficacy and adverse events for the proper use and development of EGFR-TKIs. Average binding occupancies (Φss) of EGFR-TKIs, gefitinib and erlotinib, for the EGFR-TK of cancer or skin cells were calculated. The relationships of Φss with response rate (RR) or frequency of rash were analyzed using the ternary complex model. Then, the relationships between the dose of EGFR-TKIs and RR or frequency of rash were examined. Gefitinib showed a greater difference for Φss value for both wild-type and mutant EGFR as compared to erlotinib at usual dose. The RR increased in a nonlinear manner rapidly rising when Φss exceeded 95%. It was thought that a very high Φss value might be needed to obtain the therapeutic effect of EGFR-TKIs. Meanwhile, the frequency of rash increased in a linear manner along with elevation of Φss. It was shown that the Kd ratio (Kd for mutant/Kd for wild type) was less than 0.001, when the high RR and low frequency of rash were obtained simultaneously. The results showed that the therapeutic effects and skin disorder can be assessed by using Φss. Furthermore, it is likely that a proper choice of drug and dose can be made by using Φss in EGFR-TKI therapy.

Evaluation of drug efficacy of DPP-4 inhibitors based on theoretical analysis with pharmacokinetics and pharmacodynamics.

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are used clinically as therapeutic agents for the treatment of diabetes. To determine the rate of DPP‐4 inhibition induced by these inhibitors, pharmacokinetic and pharmacodynamic parameters were used to theoretically examine the relationship between the rate of DPP‐4 inhibition and clinical efficacy following the administration of four different DPP‐4 inhibitors (sitagliptin, vildagliptin, alogliptin, linagliptin) by focusing on the increase in the level of glucagon‐like peptide‐1 (GLP‐1) induced by their administration. On the basis of the relationship shown, changes in clinical efficacy in association with dose change were examined in order to discuss clinical dosage from the standpoint of proper usage. The results indicate that a high rate of DPP‐4 inhibition is necessary for the onset of the effect of an administered the DPP‐4 inhibitor and that the average value for the DPP‐4 inhibition rate can be utilized as a common parameter of clinical efficacy. Furthermore, the efficacy profiles of the present DPP‐4 inhibitors could be demonstrated on the basis of an increase in the GLP‐1 level. It is considered that the present findings provide useful information for promoting the proper clinical use of DPP‐4 inhibitors. Copyright

Theory-based analysis of clinical efficacy of triptans using receptor occupancy

BackgroundTriptans, serotonin 5-HT1B/1D receptor agonists, exert their action by targeting serotonin 5-HT1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans.MethodsTo evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUCcp) and the areas under the time curves for Ф1B and Ф1D (AUCФ1B and AUCФ1D). Moreover, parameters expressing drug transfer and binding rates (Acp, AФ1B, AФ1D) were calculated.ResultsOur calculations showed that Фmax1B and Фmax1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUCcp, AUCΦ1B, AUCΦ1D, and Acp · AUCcp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and AΦ1B · AUCΦ1B or AΦ1D · AUCΦ1D that was not affected by the drug and the form of administration.ConclusionsThese results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.

Single nucleotide polymorphisms of 17β‐hydroxysteroid dehydrogenase type 7 gene: Mechanism of estramustine‐related adverse reactions?

Objectives:  To investigate the influence of single nucleotide polymorphisms (SNP) on transcription of the 17β‐hydroxysteroid dehydrogenase (HSD17B7) gene.