Yoshitaka Yano

Two-compartment dispersion model for analysis of organ perfusion system of drugs by fast inverse laplace transform (FILT)

A dispersion model developed in Chromatographic theory is applied to the analysis of the elution profile in the liver perfusion system of experimental animals. The equation for the dispersion model with the linear nonequilibrium partition between the perfusate and an organ tissue is derived in the Laplace-transformed form, and the fast inverse Laplace transform (FILT) is introduced to the pharmacokinetic field for the manipulation of the transformed equation. By the analysis of the nonlinear least squares method associated with FILT, this model (two-compartment dispersion model) is compared to the model with equilibrium partition between the perfusate and the liver tissue (one-compartment dispersion model) for the outflow curves of ampicillin and oxacillin from the rat liver. The model estimation by Akaikes information criterion (AIC) suggests that the two-compartment dispersion model is more proper than the one-compartment dispersion model to mathematically describe the local disposition of these drugs in the perfusion system. The blood space in the liver, VB, and the dispersion number DN are estimated at 1.30 ml (±0.23 SD) and 0.051 (±0.023 SD), respectively, both of which are independent of the drugs. The efficiency number, RN, of ampicillin is 0.044 (±0.049 SD) which is significantly smaller than 0.704 (±0.101 SD) of oxacillin. The parameters in the two-compartment dispersion model are correlated to the recovery ratio, FH, mean transit time, ¯tH, and the relative variance, σ2/¯tH2, of the elution profile of drugs from the rat liver.

Pharmacokinetic–Pharmacodynamic Modeling and Simulation for Bactericidal Effect in an In Vitro Dynamic Model

A pharmacokinetic (PK)/pharmacodynamic (PD) modeling strategy to explain the data from an in vitro dynamic model is proposed. Two carbapenem antibiotics, doripenem and meropenem, and three Pseudomonas aeruginosa strains were used as example drugs and strains. The PD model we originally developed to explain the in vitro time-kill data was modified by incorporating bactericidal activities and simulated in vivo PK profiles of the drugs. By employing only one parameter regarding the bactericidal activity from the data at a certain dosage regimen, the bacterial profiles at various dosage regimens could be well simulated for both antibiotics by the PK/PD model. Moreover, simulated bacterial counts for various dosage regimens correlated with time above minimum inhibitory concentration derived from free drug concentrations (fT > MIC) for doripenem. The predicted fT > MIC values to achieve PK/PD endpoints for three strains (static effect: 25.0%, 23.9%, and 39.8%, 2-log killing effect: 28.1%, 29.5%, and 49.6%, 90% maximum killing effect: 36.5%, 46.8%, and 80.7%) were similar to those estimated from free drug concentrations in animal infection models. The proposed in vitro PK/PD model would be useful for simulating bactericidal kinetics in the dynamic model and predicting the human therapeutic target for PK/PD indices estimated from animal infection models.

Analysis of enterohepatic circulation of cefixime in rat by fast inverse Laplace transform (FILT)

The enterohepatic circulation of cefixime in rat was evaluated by a nonlinear least square analysis program, MULTI(FILT), into which the fast inverse Laplace transform (FILT) was incorporated. The plasma time course in the bile duct-cannulated rat exhibited a biexponential curve after the rapid iv administration of cefixime. Several pharmacokinetic models for the enterohepatic circulation were constructed based on the recirculatory concept and the Laplace-transformed equations corresponding to these models were derived by means of the method of transfer function. The transformed equations were simultaneously fitted to the time courses of plasma concentration in rats with laparotomy and with bile duct cannula. The optimum model was selected based on the Akaikes information criterion (AIC). The local moment characteristics for a single pass through enterohepatic circulation were further calculated from the time courses of both the plasma concentration and the amount excreted into the bile. The recovery ratio (Fcand the mean circulatory time (¯tcthrough a single pass of enterohepatic circulation were estimated 27.9% and 1.07 hr, respectively. The recovery ratio (Faand the mean absorption time (¯tafor the absorption process from the intestinal tract into the systemic circulation were 68.3% and 0.0234 hr, respectively. The recovery ratio (Fband the mean transit time (¯tb)for the disposition process through the systemic circulation into the bile were 40.8% and 1.05hr, respectively.

Analysis of arterial–venous blood concentration difference of drugs based on recirculatory theory with fast inverse laplace transform (FILT)

An arterial and venous blood (or plasma) concentration difference of drugs across the lung of rats was evaluated based on the recirculatory concept. The recirculatory system is given by the combination of the transfer functions for the pulmonary and the systemic circulations and is described by a Laplace-transformed equation, i.e., an image equation. For the manipulation of the image equations, the fast inverse Laplace transform (FILT) was adopted and MULTI(FILT) was used for the simultaneous curve fitting to estimate the pharmacokinetic parameters in the recirculatory model. Metoprolol as a test drug and cephalexin as a control drag were infused, respectively into the femoral vein for 30 min, and arterial and venous blood samples were collected simultaneously through the cannula at the femoral artery and at right atrium during and after the infusion. Exponential functions were assumed for the weight functions through both the pulmonary and systemic circulations. Results of the curve fitting showed that the single-pass extraction ratio through the pulmonary circulation (Ep)of meloprolol was about 0.2, whereas that of cephalexin was negligible. The mean transit times through the pulmonary circulation (¯tpof metoprolol and cephalexin were both about 0.5 min, which is small. The singlepass extraction ratios through the systemic circulation (Es)of metoprolol and cephalexin were both about 0.1. and the mean transit times through the systemic circulation (¯tswere 11.5 min and 8.2 min, respectively.

Population analysis of myelosuppression profiles using routine clinical data after the ICE (ifosfamide/carboplatin/etoposide) regimen for malignant gliomas

We propose a simple and practical modeling approach for analysis of the data for myelosuppression after cancer chemotherapy, which can be applied when pharmacokinetic data are not available and several anticancer drugs were simultaneously administered. The model equation is based on the probability density function for the Erlang distribution. The data for cell counts of leukocytes (white blood cell, WBC), platelets (PLT), and reticulocytes (RET) obtained in routine clinical laboratory tests after the ICE (ifosfamide/carboplatin/etoposide) regimen for cancer chemotherapy were retrospectively collected from 28 patients, and a population analysis was applied. The time course profiles could be well explained by the proposed model. The individual values of the time to reach the nadir were obtained by the Bayesian method, and their medians (days) were 16.8 for WBC, 12.8 for PLT, and 8.2 for RET. Such information would be useful to determine the day of visit for outpatients especially for additional treatment to prevent side effects such as infections. The model is simple and applicable to explain the time course profiles for myelosuppression irrespective of cell types, and also practical because it requires only the data from routine clinical laboratory tests without any additional burden to patients.