A new Visual BASIC (ver. 4.0) program “WinHARMONY”, which operates withWindows 95, has been developed for the pharmacokinetic analysis of drugs. This pro gram uses the noncompartmental analysis method, where the recognition of the terminal elimination phase has an important role in the total analysis of the data. Three statistical methods for the automatic identification of the terminal elimination phase have been implemented and evaluated using two kinds of plasma drug concentrationtime data: 1) Plasma cyclosporin A (CyA) concentration-time data in 13 healthy human subjects, and 2) as an example of drugs having short and long half-lives, triazolam was selected and its plasma concentration-time data in 9 healthy human subjects under the single adminis tration and the coadministration with either ketoconazole or itraconazole were analyzed with this program. Among the three methods, an algorithm which performs an automatic identification of the terminal elimination phase based on two factors of linear regression analysis, i. e., an error variance and a confidence interval, gave the estimated value of the terminal elimination rate constant, λz, of 0.064 (mean) ±0.031 (SD) hr. This estimated value was not significantly different from the estimated value, 0.067±0.027 hr, of Grevel et al. who used a nonlinear regression analysis by assuming a two-compartment open model to describe the plasma CyA concentration-time data. Moreover, this program was found to work well even in the case of a drug with a long half-life such as triazolam under the coadministration with either ketoconazole or itraconazole. Since analytical results are shown on the CRT display and can be printed out, visual inspection of the analytical results is possible. Basically, the pharmacokinetic data are manually input and are saved at once in a data file. Prior to the analysis, each data set is read out from the data file. To improve upon a shortcoming of Visual BASIC where “DATA” command cannot be accepted, two optional data input modes are included in the program, i. e., a data file made by the format type of text file and data input by means of a spread sheet program. As this program is written in Visual BASIC, it runs on almost all personal computers except Macintosh and is thought to be useful for the analysis of pharmacokinetic data both in preclinical and clinical pharmacokinetic studies.

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A population pharmacokinetic analysis of valproic acid in conventional and slow release formulations was carried out. Three hundred and forty-four points in two hundred and fifteen patients were analyzed. The pharmacokinetic model, which took into account the age of the patients and the absorption lag time of the slow release formula tions, and a pharmacostatistical model with individual and residual variability were evaluated. The influence of the age of the patients and the absorption lag time on the valproic acid pharmacokinetics was significant based on the results of the statistical test. The ka of slow release formulations was 0.230 (1/h), the ka of conventional formulations was 8.14 (1/h), the Vd of the conventional and slow release formulations was 0.212 (L/kg) and the ke of the conventional and slow release formulations was 0.0495 (1/h) in adults (≥12 years) and the lag time of the slow release formulations was 1.25 (h). The ka changed with the patient's age. The ka was different for conventional and slow release formulations. Though conventional formulations did not have a lag time, the slow release formulations had a lag time. The patient age and the lag time are thought to be included in the population pharmacokinetic model using a slow release formulation. The findings suggest that the values obtained for these population pharmacokinetic parameters will be useful in optimizing valproic acid therapy for individual patients.

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Objectives: The relationship between the two CYP2C19 genotype mutations, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4, and omeprazole hydroxylation phenotype in healthy Japanese volunteers was studied. A simplified method for phenotyp-ing of CYP2C19 with omeprazole was also investigated.
Methods: A total of 50 healthy Japanese volunteers were orally administered 20 mg omeprazole (OPZ) after overnight fasting. The area under the serum concentration-time curve (AUC) ratio of OPZ to 5-hydroxy OPZ (OPZ-OH) between 0 and 6 hr after dosing was calculated. After phenotyping, 28 subjects were analyzed for CYP2C19 genotype with the PCR-RFLP method.
Results: The ratio of AUC _(0-6hOPZ) to AUC _(0-6hOPZ-OH) was significantly correlated with the OPZ/OPZ-OH serum concentration ratios, termed hydroxylation index (HI), at 2 and 3 hr after dosing. Twelve out of 50 subjects showed HI values of more than 6 at 3 hr after drug intake and were judged as poor metabolizers (PMs: 24%). Six out of 28 subjects were homozygous for the wild-type (wt/wt) allele in both exon 5 and exon 4 ; 11, heterozygous for the CYP2C19m1 (wt/m1); 5, heterozygous for the CYP2C19m2 (wt/m2); 5, homozygous for the CYP2C19m1 (m1/m1); 1, heterozygous for both defects (m1/m2). The homozygous genotype was compatible with the phenotype of the extensive metabolizer (EMs: wt/wt) and PMs (m1/m1). The heterozygous genotype, however, was not clearly compatible with the phenotype: one out of 11 with wt/m1 genotype was judged as PM. Five subjects with wt/m2 were EMs. The phenotype of one subject with m1/m2 could not be identified due to extremely low serum concentrations of OPZ and OPZ-OH.Discussion: From our findings, genotype and phenotype correlated well among the subjects. Further studies are needed to clarify the relationship between the CYP2C19 genotype and phenotype in subjects with a heterozygous genotype. Care should be taken in phenotyping CYP2C19 with OPZ using a few sampling points since gastric emptying time affects the systemic absorption of OPZ, and hence serum concentrations of the drug especially in the clinical situation are affected by co-administered medicines.

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Purpose: Giucagon is in wide clinical use (growth hormone secretion test, diagnosis of insulinoma, and pretreatment for radiography or endoscopic examination of the digestive tract etc.). The action time of glucagon in the pretreatment for endoscopy has been confirmed to be about 15 minutes by intravenous administration and about 25 minutes by intramuscular administration. Clinically, however, the examination may be prolonged for various reasons, and additional administration may become necessary. In this study, glucagon was administered twice at an interval of 15 minutes intravenously and 25 minutes intramuscularly, and the pharmacokinetics and changes in the blood glucose and insulin concentrations were investigated. The findings were also evaluated with previously obtained results after a single administration.
Methods: Recombinant glucagon (GL-G) was administered to the healthy volunteers at 1 mg twice at an interval of 15 minutes intravenously (n=6) and 25 minutes intramuscularly (n=6), and the changes in the blood glucagon, insulin, and glucose concentrations after administration were evaluated.
Results: C_max of the blood glucagon concentration did not increase on two serial administrations by the intravenous route, but that after the second administration was about twice the level after the first administration by the intramuscular route (mean±SD, 3645±743 pg/ml after the first administration and 7402±1770 pg/ml after the second administration). The glucagon concentration returned to the level of 15 minutes and 25 minutes after the first intravenous and intramuscular administrations, respectively, [estimated to be the minimum effective concentrations (MEC) for the digestive tract] at about 30 minutes and 70 minutes, after the first administrations.
C_max of the blood glucose concentration was about 1.4 times higher by two serialintravenous administrations and 1.3 times higher by two serial intramuscular administrations than the levels after a single administration, and the decreases in the blood glucoseconcentration 1.5-2 hours after the administration, which are considered to be rebounds, were similar to those observed after a single administration.
Conclusions: 1) The tolerability of two serial administrations of GL-G was satisfactory by both intravenous and intramuscular administrations. 2) From changes in theblood glucagon concentration, the times of suppression of peristalsis of the digestive tracton two serial intravenous and intramuscular administrations were estimated to be abouttwice and three times those on a single administration, respectively. 3) The rebounddecrease in the blood glucose concentration was similar between single and two serialadministrations.

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The purpose of this study was to clarify the effects of histamine H₁ receptor antagonists promethazine and homochlorcyclizine, which are reported to be cytochrome P450 2D6 (CYP2D6) inhibitors, on the steady-state plasma concentrations (C_ss) of haloperidol (HAL) and reduced haloperidol (RHAL). Twenty-one schizophrenic patients treated with HAL 12-36 mg/day received promethazine 150 mg/day (n=11) or homochlorcyclizine 60 mg/day (n=10) for at least one week. The changes in C_ss of HAL and RHAL were monitored before and during coadministration of promethazine or homochlorcyclizine and one week after the discontinuation. In 11 cases with promethazine coadministration, the C_ss of HAL was significantly higher during the coadministration period than that before the coadministration (p<0.01) or one week after the discontinuation (p<0.01) (before and during coadministration of promethazine and one week after its discontinuation: 13.3±11.0, 29.3±25.0, 16.6±15.1 ng/ml, respectively). The C_ss of reduced haloperidol was also significantly higher during the coadministration period than that before the coadministration (p<0.01) or one week after the discontinuation (p<0.05) (5.6±6.2, 9.5±13.7, 6.3±8.2 ng/ml). Likewise, in 10 cases with homochlorcyclizine coadministration, the C_ss of HAL was significantly higher during the coadministration period than before the coadministration (p<0.01) or one week after the discontinuation (p<0.05) (11.7±7.9, 16.5±8.4, 14.1±7.8 ng/ml), and the C_ss of RHAL was also significantly higher during the coadministration period than that before the coadministration (p<0.01) or one week after the discontinuation (p<0.05) (4.2±4.0, 7.4±5.8, 5.4±4.5 ng/ml). These results suggest that promethazine and homochlorcyclizine inhibit the metabolism of HAL and RHAL via inhibitory effects on CYP2D6 activity. Therefore, it is considered that the C_ss of HAL and RHAL are at least partly affected by the CYP2D6 activity.

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This paper describes a simple numerical method to calculate the measures of the mean prediction error and the mean squared prediction error for evaluating the perfor-mance of Bayesian pharmacokinetic estimation in population pharmacokinetics. The proposed method presupposes that an appropriate pharmacokinetic model and a popula-tion distribution of pharmacokinetic parameters are given from previous clinical investi-gations of the drug of interest. The two measures were suggested by Sheiner and Beal as the measures of bias and precision, and have been widely used in typical pharmacokinetic analysis. The proposed method enables us to easily calculate the two useful measures for the Bayesian pharmacokinetic estimation. The method needs no actual observations. An application is given to an actual population pharmacokinetic study of irinotecan (CPT-11), an anti-neoplastic drug, to show how the proposed method works in practice.

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This presentation will describe the practical activities of clinical research associates (CRA_s) and clinical research coordinators (CRC_s) during the conduction of a typical clinical investigation with a new drug in the United States. There are an estimated 12, 000-15, 000 CRC_s working at investigation sites in the US . Approximately 2, 000 CRC_s have become certified since 1993. Probably more than 25, 000 clinical research . associates work in the US pharmaceutical industry companies or CRO_s in the US; 500 of these CRA_s have become certified since 1995. Study activities will be reviewed and discussed from a chronological perspective, beginning with pre-study preparation activities and ending with preparation of a clinical study report. US GCP requirements supporting each of the activities will be described.

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