Yasuo Kodama

The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N‐acetyltransferase activities in humans

Our objective was to evaluate the activity of cytochrome P4501A2 (CYP1A2), xanthine oxidase (XO), and N ‐acetyltransferase 2 (NAT2) from early to late pregnancy and after delivery.

The quality of conduct in Japanese clinical trials: deficiencies found in GCP inspections

The quality of commercially sponsored clinical studies in Japan was examined with reference to deficiencies in the audit reports issued by the Organization for Pharmaceutical Safety and Research (OPSR). The OPSR is responsible for domestic good clinical practice auditing in Japan. Routine audits from 1997 to 2000 for 331 hospitals revealed various types of deficiencies such as errors in case report form (CRF) entries, institutional review board problems, and protocol deviations. The high prevalence of CRF-related deficiencies seemed to stem from peculiarities of the Japanese study environment such as the historical lack of on-site monitoring by the sponsor and the absence of research nurses. Characteristics in usual medical practices such as multiple drug use and loose informed consent also seemed to be associated with prevalence of similar deficiencies in clinical trials.

Clinical trials and the new good clinical practice guideline in Japan. An economic perspective.

AbstractJapanese clinical trials have been drastically changing in response to the implementation of the International Conference on Harmonisation — Good Clinical Practice (ICH-GCP) guideline in 1997. The most important aim of the new guideline is to standardise the quality of clinical trials in the US, European Union and Japan, but it inevitably imposes substantial costs on investigators, sponsors and even patients in Japan.The study environment in Japan differs from that in the US in several ways: (i) historical lack of a formal requirement for informed consent; (ii) patients’ attitudes to clinical trials in terms of expectation of positive outcomes; (iii) the implications of universal health insurance for trial participation; (iv) the historical absence of on-site monitoring by the sponsor, with the attendant effects on study quality; and (v) the lack of adequate financial and personnel support for the conduct of trials. Implementation of the new GCP guideline will improve the ethical and scientific quality of trials conducted in Japan. It may also lead to an improved relationship between medical professionals and patients if the requirement for explicit informed consent in clinical trials leads to the provision of a similar level of patient information in routine care and changes the traditional paternalistic attitude of physicians to patients.The initial response of the Japanese ‘market’ for clinical trials to the implementation of the ICH-GCP guideline has been clinical trial price increases and a decrease in the number of study contracts. These changes can be explained by applying a simple demand-supply scheme. Whether clinical trials undertaken in Japan become more or less attractive to the industry in the long term will depend on other factors such as international regulations on the acceptability of foreign clinical trials and the reform of domestic healthcare policies.

Effect of temperature on serum protein binding characteristics of phenytoin in monotherapy paediatric patients with epilepsy

Objectives: To determine the effects of temperature on binding characteristics of phenytoin to serum proteins in paediatric patients with epilepsy.

Binding parameters of valproic acid to serum protein in healthy adults at steady state.

Two hundred milligrams of valproic acid (VPA) was administered orally to seven healthy adults at 9:00 and 21:00 h for 5 consecutive days, including the morning dose on day 6. On the sixth day, blood samples were drawn at 0, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 3, and 6 h after the morning dose. Binding of VPA to serum protein was evaluated by ultrafiltration, and total and unbound VPA concentrations were determined by fluorescence polarization immunoassay. Binding parameters of VPA to serum protein were calculated for each subject by the Scatchard analysis. The binding parameters obtained from seven subjects showed that the mean association constant (K) was 2.72 x 104 L/mol while the total number of binding sites (nPt) was 789 μmol/L. There were marked interindividual variations and the coefficient of variation was 42% for K and 28% for nPt. These results show that endogenous free fatty acids (FFAs) significantly reduce the binding affinity of VPA to serum albumin (p < 0.05). In addition, they suggest the possibility that the primary binding sites for VPA can be strongly reduced by FFAs. Therefore, we consider that interindividual differences in binding parameters may be clinically important.

Gender- or age-related binding characteristics of valproic acid to serum proteins in adult patients with epilepsy.

The aim of the present study was to determine the gender- or age-related binding characteristics of valproic acid (VPA) to serum proteins in the adult population. Serum samples examined in the study were obtained from 70 adult patients (36 males, 34 females) with epilepsy on VPA monotherapy. Their age ranged from 16 to 68 years (mean age with (SD), 37.7 (15.7) years; <45 years, n=44; >/=45 years, n=26). The in vivo population binding parameters of VPA to serum proteins and theoretical minimal unbound serum VPA fraction (Fu) were determined using an equation derived from the Scatchard equation in: (1), all; (2), male and female subgroups; and (3), younger (<45 years) and older (>/=45 years) subgroups. There was a significant difference in serum concentration of unbound VPA between male and female patients. The mean association constant (K) was 0.010 microM(-1) in all, male, and female patients. The mean total concentration of binding sites (n(Pt)) was 1453 microM for all patients, and 1561 and 1394 microM for male and female patients, respectively. The Fu was 0.064 for all patients, and 0.060 and 0.067 for male and female patients, respectively. There were no significant differences in the binding characteristics of VPA to serum proteins between the male and female groups. On the other hand, there were significant differences in the serum albumin concentration and molar concentration ratio of free fatty acids to albumin in serum between the younger and older patients. The mean value of K was 0.016 microM(-1) for the younger patients and 0.007 microM (-1) for the older patients. The mean n(Pt) was 1157 microM for the younger patients and 1703 microM for the older patients. The Fu was 0.051 for the younger patients and 0.077 for the older patients. Thus, significant differences were observed in the binding characteristics of VPA to serum proteins between the younger and older groups. Our results show that age, but not gender, has significant influences on the binding characteristics of VPA to serum proteins in our patient population.

No effect of gender or age on binding characteristics of valproic acid to serum proteins in pediatric patients with epilepsy

The gender‐ and age‐related binding characteristics of valproic acid to serum proteins were determined in the pediatric population. Serum samples examined in the study were obtained from 61 pediatric patients (28 males, 33 females) with epilepsy on valproic acid monotherapy. Their ages ranged from 1to 15 years (mean age with [SD]: 7.8 [3.9] years; < 10 years, n = 41; /10 years, n = 20). The in vivo population binding parameters of valproic acid to serum proteins and theoretical minimal unbound serum fraction (fu) of valproic acid were determined in (1) all, (2) male and female subgroups, and (3) prepubescent (< 10 years) and pubescent (/10 years) subgroups. The association constant (K) was approximately 1.4 times higher in male (0.018 L/μmol) than in female (0.013 L/μmol) patients, while the total concentration of binding sites (n(Pt)) was 1.2 times greater in female (1235 μmol/L) than in male (997 mmol/L) patients. The fu was 0.053 and 0.059 for male and female patients, respectively. The value of K was approximately 1.6 times higher in the pubescent (0.019 L/μmol) than in the prepubescent (0.012 L/μmol) patients, while the n(Pt) was 1.2 times higher in the prepubescent (1244 μmol/L) than in the pubescent (1057 μmol/L) patients. The fu was 0.063 for the prepubescent and 0.047 for the pubescent patients. No significant differences were observed in binding characteristics of valproic acid to serum proteins between male and female or younger and older patients. However, the differences in valproic acid binding to serum proteins appear to be relatively larger in binding affinity than in binding capacity between the two groups. Because no significant differences were observed in serum concentrations of total and unbound valproic acid, albumin, or free fatty acids between any subgroups (male and female, younger and older), the results suggest that gender or age may not be factors for the determination of the binding characteristics of valproic acid to serum proteins in pediatric patients.

In Vivo Determinations of Carbamazepine and Carbamazepine‐10, 11‐epoxide Binding Parameters to Serum Proteins in Monotherapy Patients

The in vivo serum protein binding parameters of carbamazepine (CBZ) and carbamazepine‐10, 11‐epoxide (CBZ‐E), which was the main metabolite of CBZ in plasma, were determined in sera from 27 patients on CBZ monotherapy. Based on the results by recent studies, the authors assumed that CBZ and CBZ‐E binding to serum proteins were composed of specific binding sites on α1‐acid glycoprotein (AAG) and albumin. Therefore, the authors determined the binding parameters of each compound by specific binding equation for two proteins. Association constants for drug‐AAG binding were .071 L/μmol for CBZ and .016L/μmol for CBZ‐E. Conversely, those for drug‐albumin binding were .00052 L/μmol for CBZ and .00072 L/μmol for CBZ‐E. Within the investigated total concentration ranges in each compound, the AAG binding contributes largely to the drug‐serum protein interactions. Furthermore, our results indicate that the albumin binding contributes to the nonsaturable serum protein binding of these compounds in the therapeutic range.

Effect of Unbound Clearance on Binding Parameters of Valproic Acid to Serum Proteins

Nine healthy subjects received 400 mg sodium valproate orally in the fasting state. Binding parameters of valproic acid to serum proteins were determined by Scatchard analysis for individual series of valproic acid data. Total and unbound (intrinsic) clearances (Cht and CLu) were calculated by dividing the dose by the appropriate area under the serum drug concentration‐time curve. Unbound clearance correlated positively with the product of association constant (Ka) and concentration of free protein ((UP)) (P < .05). Conversely, no significant correlation was found between CLt and binding parameters. The average unbound concentration correlated negatively with both CLu and ka(P) values. The result indicates an effect of CLu on Ka(P) value of valproic acid.

Quality of Japanese Clinical Trials Estimated from Good Clinical Practice Audit Findings

To describe qualitatively recent changes in the Japanese clinical trial environments, we compared the results of the Good Clinical Practice (GCP) audits conducted from April 1997 to March 2000 (FY1997 to FY1999) with those from April 2002 to March 2003 (FY2002). In addition, the audit results were compared between the United States and Japan. The audit findings in the former period were based on the official audits by the Organization for Pharmaceutical Safety and Research (OPSR) that covered 331 hospitals and 775 trials. The audits by the OPSR in the latter period targeted 136 hospitals and 226 trials. The total number of deficiencies detected in the Good Clinical Practice audits in the former 3-year period (FY1997 to FY1999) was 1529, and the number in the single year (FY2002) was 1627. The total number of deficiencies detected and reported was about 3-fold on an annual basis between the periods. By category of deficiencies, there were 2 remarkable changes in the OPSRs audit findings between FY1997-FY1999 and FY2002. One was an increase in the proportion of protocol deviations from 14.7% (225/1529) in FY1997-FY1999 to 48.2% (785/1627) in FY2002, and the other was a decrease in the proportion of case report form-related deficiencies from 43.6% (666/1529) to 16.0% (260/1627). The high prevalence of protocol nonadherence and the relatively few findings of informed consent errors were important characteristics of Japanese trials inferred from the audit result reported by the OPSR in FY2002. In the United States, relatively high proportions of protocol nonadherence and informed consent errors were observed in the audit finding reported in 1997. Although the audit results for clinical trials between the United States and Japan are not strictly comparable, our results suggest that protocol deviations are a compelling issue for quality improvement in the conduct of clinical trials for the 2 regions.