Hirohito Ikeda

Population pharmacokinetics of phenobarbital by mixed effect modelling using routine clinical pharmacokinetic data in Japanese neonates and infants: an update.

What is known and objective:  Optimal use of phenobarbital in the neonatal population requires information regarding the drug’s pharmacokinetics and the influence of various factors, such as different routes of administration, on the drug’s disposition. However, because of sampling restrictions, it is often difficult to perform traditional pharmacokinetic studies in neonates and infants. This study was conducted to establish the role of patient characteristics in estimating doses of phenobarbital for neonates and infants using routine therapeutic drug monitoring data.

Population Pharmacokinetic Investigation of Digoxin in Japanese Infants and Young Children

To establish the role of patient characteristics in estimating doses of digoxin for infants and young children using routine therapeutic drug monitoring data, the steady‐state blood‐level data (n = 245) after repetitive oral administration in 117 hospitalized infants and young children were analyzed using nonlinear mixed effects modeling (NONMEM), a computer program designed for analyzing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a 1‐compartment pharmacokinetic model. Estimates generated by NONMEM indicated that the clearance of digoxin (CL/F; L/h) was influenced by the following demographic variables: total body weight (TBW), presence of congestive heart failure (CHF), and infant‐young children clearance factor (trough serum concentration of digoxin; Conc). These influences could be modeled by the equation CL/F (L/h) = 0.302 · TBW (kg)1.17 · 0.905CHF · Conc (trough serum digoxin concentration >1.7 ng/mL)−0.540; F = 0.754, where CHF is 1 for presence of congestive heart failure, 0 otherwise; F is bioavailability, 1 for elixirs, 0.754 for powders; and Conc−0540 is 1 for digoxin concentration <1.7 ng/mL. Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of his or her clinical need for the drug.

Determination of Digoxin Clearance in Japanese Elderly Patients for Optimization of Drug Therapy

AbstractBackground: Optimal use of digoxin in the elderly population requires information about the drug’s pharmacokinetics and the influence of various factors on the drug’s disposition. However, because of sampling restrictions, it is often difficult to perform traditional pharmacokinetic studies in elderly patients. Objective: This study was conducted to determine the apparent total clearance of digoxin from serum after oral administration (CL/F) and to establish the role of patient characteristics in estimating doses of digoxin for elderly patients (age ≥65 years), using routine therapeutic drug monitoring data. Methods: Analyses of the pharmacokinetics of digoxin were conducted using the nonlinear mixed-effects modelling (NONMEM®) software, a computer program designed to analyse pharmacokinetics in study populations by allowing pooling of data. Steady-state data (140 observations) obtained by routine therapeutic drug monitoring following repeated oral administration of digoxin in 94 hospitalized elderly patients (age ≥65 years) were analysed to establish the role of patient characteristics in estimating doses of digoxin for elderly patients. Results: Estimates generated by NONMEM® indicated that digoxin CL/F was influenced by the demographic variables of total bodyweight (TBW), serum creatinine (SCr), age (AGE), presence of congestive heart failure (CHF), concomitant administration of the calcium channel antagonists (calcium channel blockers [CCBs]: verapamil, diltiazem or nifedipine), sex (SEX) and elderly clearance factor (trough serum concentration of digoxin; [Ctrough]^θ). The full version of the final NONMEM® model was CL/F[L/h]=(0.588 × TBW [kg])^(0.189) × SCr[mg/dL]^(−0.163) × (AGE [years]/65)^(−0.152) × 0.957^(CCB) × 0.941^(CHF) × 0.965^(SEX) × Ctrough [ng/mL]^ (−0.180), where CCB is 1 for concomitant administration of a CCB and is 0 otherwise; CHF is 1 for patients with CHF and is 0 otherwise; SEX is 0 for male and is 1 for female; and the elderly clearance factor Ctrough−0.180 is 1 for digoxin Ctrough <1.7ng/mL. Conclusions: We developed a new model for elderly patient dosing of digoxin with good predictive performance. Clinical application of the findings of the present study to patient care may permit selection of an appropriate initial digoxin maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect. However, the digoxin dosage regimen should be based on an appraisal of the individual patient’s clinical need for the drug.

Difference in formation mechanism of inclusion complex between configuration isomers of gallate-type catechin and β-cyclodextrin

The formation mechanism of inclusion complex between (-)-epigallocatechin gallate (EGCg), which is the main catechin in tea leaves, or (-)-gallocatechin gallate (GCg), which is an isomer of EGCg, and β-cyclodextrin (βCD) was studied by isothermal titration microcalorimetry (ITC), NMR and molecular modeling calculation (MMC). ITC measurements revealed that EGCg or GCg interacted with βCD at 1:1 molar ratio driven by enthalpy. Comparing the values of binding constant (7.2 × 103 1/M for EGCg with βCD and 3.9 × 104 1/M for GCg with βCD), it was suggested that GCg interacted with βCD more strongly rather than EGCg. In their ROESY NMR spectra, the cross-peaks were observed between the protons of A, B and B′ ring of EGCg and the protons in the cavity of βCD, and between the protons of B and B′ ring of GCg and the protons in the cavity of βCD. MMC in water showed that EGCg had one kind and GCg had two kinds of most stable conformation (GCg(E) and GCg(A)) in energy. In the stable conformation of EGCg, B ring was coordinated equatorially to C ring, and B′ ring was axially coordinated to C ring. On the other hand, in GCg (E), the coordination of B ring and B′ ring to C ring was both equatorial, and in GCg (A), the coordination of B ring and B′ ring was both axial. MMC also revealed B or B′ ring of GCg(A) was easy to be included in the cavity of βCD more deeply than each ring of EGCg or GCg(E) since the steric hindrance of B ring or B′ ring was small. Therefore, it was found that the difference of B ring’s configuration of gallate-type catechin greatly affected the formation of inclusion complex with βCD.

Effect of solution pH on complex formation between epi-type catechin and β-cyclodextrin

The effect of solution pH on the formation of an inclusion complex between (−)-epigallocatechin gallate (EGCg: pKa = 7.5) and β-cyclodextrin (β-CD) was investigated by isothermal titration calorimetry and 1H-NMR spectroscopy. The formation of an inclusion complex (EGCg-β-CD) depended on the solution pH; two different types of inclusion complexes were formed at 1:1 molar ratio in acid/neutral solutions, and only one type of complex was formed in the basic solution. The first type of EGCg-β-CD with larger association constant was formed independently of pH, with the AC-ring of EGCg being deeply inserted into the cavity of β-CD and the B-ring existing near the secondary hydroxyl group of β-CD. On the other hand, the formation of the second type depended on the solution pH. The B′-ring of EGCg was included in the case of acid and neutral solutions, but the formation of an inclusion complex in the basic solution was difficult due to the ionization of the 4″-OH on the B′-ring. 1H-NMR spectroscopy supported these results. These results suggested that when determining the structures of EGCg-β-CD in an aqueous solution, it is necessary to consider unionized and ionized forms of EGCg.

Interaction Energy Analysis for Drug-Cyclodextrin Inclusion Complexes in Aqueous Solutions

It is vital to elucidate the role of asymmetric intermolecular interactions resulting from the stereospecific structures of molecules in order to understand the mechanisms of chemical and biochemical reactions such as enzyme-substrate reactions, antigen-antibody reactions, etc. In order to reveal the mechanism of the inclusion phenomenon for b-cyclodextrin (CD)-ampicillin complexes and b-CD-ibuprofen complexes, binding free energies were determined using molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) analysis. To clarify the details of the interaction energies of these complexes, pair interaction energy decomposition analysis (PIEDA) was carried out. The direction of inclusion of drugs into b-CD cavities was clarified on the basis of results obtained using the above-mentioned methods.