Volume 38, No. 2/2000(February)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Congress report
Cultural differences: implications on drug therapy and global drug development
L.P. Balant and E.A. Balant-Gorgia
Abstract
L.P. Balant1 and E.A. Balant-Gorgia2
1Clinical Research Unit, and 2Therapeutic Drug Monitoring Unit, Department of Psychiatry, University of Geneva, Switzerland
Introductory remarks: Discussing the “inter-ethnicity” of kinetics and actions of drugs is fraught with terminology problems. It is, however, generally accepted that “ethnicity” covers the influences of factors genetically and culturally transmitted. The study of inter-ethnic variability in drug response addresses the problem of distinguishing variability factors that are common to one particular group of individuals from those which are not specifically shared. Differences in daily doses between different geographic regions: It is well known that for a number of drugs, the daily dose prescribed in Japan is lower than in the US and Europe. Presently, independent surveys strongly indicate that for a majority of drugs dose differences are not the result of pharmacokinetic differences. In addition, they indicate that inter-ethnic differences do not seem to be larger than intra-ethnic variations. The differences observed for daily doses must thus be found elsewhere than in pharmacogenetic traits. Differences in diagnoses: The most important impediments encountered in the evaluation of minority patients include differences with respect to language, communication style, cultural belief. The same problems arise if studies performed in different geographic areas are compared, socio-economic aspects play then an even greater role. Language problems arise differently if minorities are evaluated and compared to a majority of patients living in the same country or if clinical studies are performed in different regions. Communication styles also differ markedly between cultures. As an example, certain gestures may be considered as disrespectful or insulting by some ethnic groups and constitute normal behavior in others. Rating scales: Ethnicity clearly plays a role on the cross-cultural use of rating scales. Sophisticated rating scales established and validated in Western culture must undergo culturally sensitive revision and rigorous evaluation before their use in non-Western culture. Efficacy – safety assessment: As an example, the assessment of risk and benefit is different in Japan, Europe and the United States. In Japan, safety is given a greater weighting relative to efficacy than in the two other regions. Placebo/nocebo effects: Placebo and nocebo effects are difficult to study, even in the absence of any cultural difference. They are even more so if ethnicity is concerned. Patient compliance: Clinicians treating cross-cultural patients must carefully explore the beliefs held by their patient regarding illness causality and treatment expectations. Concluding remarks: There are many unanswered questions in the field of inter-ethnic variability in drug response. The present overview will not pretend to have given specific answers, but it is hoped that it will point to some areas where more research is needed, in particular in the area of methodologies to take inter-ethnicity into account during drug development.Correspondence to:
Prof. Dr. L. Balant; Department of Psychiatry, Belle-Idée, 2, Ch. du Petit-Bel-Air, CH-1225 Chêne-Bourg, Switzerland
Congress report
Predictability of the effects of race or ethnicity on pharmacokinetics of drugs
J.A. Johnson
Abstract
J.A. Johnson
Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville, FL, USA
The International Conference on Harmonization has put forth a tripartite guideline addressing mechanisms by which regulatory agencies might be able to accept foreign clinical data. A major issue is the effect of ethnicity on the drug’s pharmacokinetics, pharmacodynamics and/or safety. The purpose of this review was to determine whether the effects of ethnicity on pharmacokinetics are predictable. We also evaluated whether the premise that only pharmacokinetic processes which are biologically or biochemically mediated are likely to exhibit ethnic differences was supported by the literature. Bioavailability is determined by absorption, gut metabolism/transport and hepatic first pass metabolism. Absorption is usually a passive process and, as would be expected, no examples of ethnic differences in passive absorption were found in the literature. Direct evaluation of ethnic differences in gut metabolism/transport or hepatic first pass metabolism is largely lacking, although some studies suggest such differences exist. These differences would also be expected based on known ethnic differences in hepatic clearance of drugs. Ethnic differences in plasma protein-binding to the two major drug-binding proteins, a1-acid glycoprotein (AGP) and albumin, have been studied in several populations. Based on these studies, ethnic differences in plasma protein-binding for drugs which bind exclusively to albumin (e.g. acids) are uncommon. Conversely, ethnic differences in plasma protein-binding of drugs to AGP appear to be very common, with the studies consistently showing Caucasians have higher binding (lower plasma free fractions) than other ethnic groups. This difference appears, in all cases, to be explained by racial differences in plasma AGP concentration. Hepatic metabolism is the most common pharmacokinetic parameter for which there are ethnic differences. Differences have been documented in both oxidative and conjugative metabolism. Ethnic differences in hepatic metabolism are unpredictable by race (e.g. one racial group is not consistently higher or lower than another group) and specific enzyme (e.g. studies with different CYP3A4 substrates have yielded different results). Ethnic differences in renal tubular secretion have been documented, but also appear to be unpredictable, while differences in the passive processes of renal elimination, filtration and reabsorption, have not been observed. The literature supports the premise that pharmacokinetic processes which are active (e.g. involve a protein) are the ones with the potential for differences between ethnic groups while passive pharmacokinetic processes do not exhibit such differences. Based on the available literature, the drugs most likely to exhibit ethnic differences in their pharmacokinetics are those that undergo significant gut metabolism/transport and/or hepatic first pass metabolism; are highly bound to plasma proteins (especially AGP); or have hepatic metabolism as a major route of elimination.Correspondence to:
Dr. J.A. Johnson; Department of Pharmacy Practice, University of Florida, Box 100486, Gainesville, FL 32610, USA
Congress report
Interethnic differences of drug-metabolizing enzymes
A. Gaedigk
Abstract
A. Gaedigk
Section on Pediatric Clinical Pharmacology and Experimental Therapeutics, Children’s Mercy Hospital Kansas City, Missouri, and Departments of Pediatrics and Pharmacology, University of Missouri-Kansas City, Kansas City, Missouri, USA
Polymorphisms exhibited by drug-metabolizing enzymes are well known and have been investigated for many years. Recently, the exploding field of pharmacogenetics has focused not only on the characterization of enzymes responsible for drug biotransformation but also, on describing the sources of variability in enzyme activity. While initial observations and studies focused on populations of Caucasian origin, reports for other populations followed. The incidence of a poor or slow metabolizer phenotype for a given enzyme caused by allelic variants may vary significantly between populations. The question arises as to whether a prediction of the phenotype (i.e. distribution and/or enzyme activity) can be accurately ascertained from genotype information gathered in a related population. This is exemplified by NAD(P):quinone oxidoreductase (NQO1) investigated in Canadian Native Indian (CNI), Inuit and Chinese populations and the cytochromes P4502C19 and 2D6. While the two North American Native populations are genetically distinct, they are both descendants from northern Asia. Consequently, one might suspect that on a pharmacogenetic basis, CNI and Inuit would be more comparable to Chinese as opposed to Caucasian populations. This is certainly not the case as demonstrated for all three enzymes. Also, for a reliable phenotype prediction, one needs to pay attention to ethnic “mixing” which occurs between certain populations. Ethnic diversity constitutes both a challenge and an opportunity to prudently apply pharmacogenetics so that variability in both drug disposition and effect may be better understood.Correspondence to:
Dr. A. Gaedigk; The Children’s Mercy Hospital, Department of Clinical Pharmacology, 2401 Gillham Rd, Kansas City, MO 64108, USA
Congress report
P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs
M.F. Fromm
Abstract
M.F. Fromm
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
Abstract. Transport by ATP-dependent efflux pumps such as P-glycoprotein is an increasingly recognized determinant of drug disposition. P-glycoprotein does not only contribute to multidrug resistance (MDR) in tumor cells, it is also expressed in normal tissues with excretory function such as liver, kidney and intestine. Apical expression of P-glycoprotein in such tissues results in reduced drug absorption from the gastrointestinal tract and enhanced drug elimination into bile and urine. Moreover, expression of P-glycoprotein in the endothelial cells of the blood-brain barrier prevents entry of certain drugs into the central nervous system. Human P-glycoprotein has been shown to transport a wide range of structurally unrelated drugs such as digoxin, quinidine, cyclosporine and HIV-1 protease inhibitors. Drug administration to P-glycoprotein knock-out and control mice provided data on the importance of P-glycoprotein for absorption after oral administration and penetration through the blood-brain barrier. Moreover, P-glycoprotein knock-out mice were used to identify inhibition of P-glycoprotein-mediated transport as a mechanism for drug interactions such as the digoxin-quinidine interaction. Studies in humans indicate a particular importance of intestinal P-glycoprotein for bioavailability of the immunosuppressant cyclosporine. Moreover, induction of intestinal P-glycoprotein by rifampin has now been identified as the major underlying mechanism of reduced digoxin plasma concentrations during concomitant rifampin therapy. In summary, P-glycoprotein functions as a defense mechanism, which determines bioavailability and CNS concentrations of drugs. Modification of P-glycoprotein function is an important underlying mechanism of drug interactions in humans. However, disposition of a drug and its metabolites frequently is not only determined by P-glycoprotein, but also by drug-metabolizing enzymes and possibly by drug transporters other than P-glycoprotein [e.g. members of the MRP family (MRP = multidrug resistance-associated proteins)].Correspondence to:
Dr. M. Fromm; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstraße 112, D-70376 Stuttgart, Germany
Congress report
Effect of race on hypertension and antihypertensive therapy
A.D. Richardson and R.W. Piepho
Abstract
A.D. Richardson and R.W. Piepho
University of Missouri, Kansas City School of Pharmacy, Kansas City, Missouri, USA
The presence of hypertension in individual patients confers significant risk in terms of coronary artery disease, myocardial infarction, stroke and congestive heart failure. However, it is also a modifiable risk factor, as risk may be decreased through either lifestyle changes or pharmacotherapy to reduce the elevated blood pressure. Over the past 3 decades, there has been strenuous debate among clinical scientists regarding the role played by racial background in both the pathogenesis and response to pharmacotherapy. A number of studies, such as the third National Health and Nutrition Examination Survey (NHANES III) have demonstrated a higher prevalence of hypertension in black populations. The Hispanic Health and Nutrition Examination Survey (HHANES) suggested that the prevalence of hypertension in Hispanics of Caribbean descent was similar to that of African Americans, while Mexican Americans had lower rates of the disease. It appears that the pathophysiological consequences of elevated blood pressure may also be more severe in black patients. Thus, these patients will have a worse prognosis than their white counterparts at any given blood pressure level. The incidence of end-stage renal disease has been reported to be as much as 17 times more common in African American patients. A number of individual factors have been postulated for these differences including increased sodium intake, differences in sodium handling, decreased potassium intake, decreased calcium intake, elevated fasting insulin levels, lower levels of plasma renin activity and urinary kallikrein excretion. These differences in prevalence and pathophysiology have resulted in recommendations for differential therapeutic approaches in the treatment of hypertension. A major trial conducted in the Veteran Affairs Medical Centers in the USA noted that African Americans are generally more responsive to diuretics and calcium channel blockers than to ACE inhibitors or b-blockers. However, it has been reported that this resistance may be overcome by increasing the dose of these agents. It has been postulated that these differences may be related to lower plasma renin activity noted in the black population, since diuretics and calcium channel blockers appear to be better suited to this population. These differential therapeutic recommendations will be reviewed in light of our current knowledge of the disease.Correspondence to:
Dr. A.D. Richardson; University of Missouri, Kansas City Drug Information Center, 2411 Holmes St., Suite MG-200, Kansas City, MO 64108-2792, USA
Congress report
Necessity and requirements of bridging studies and their present status in Japan
C. Naito
Abstract
C. Naito
Tokyo Teishin Hospital, Chiyoda-ku, Tokyo
The mainstays of the harmonized final document about ethnic factors in the acceptability of foreign clinical data include a complete clinical data package and a bridging study (for efficacy and/or for safety). A clinical data package that meets all of the regional regulatory requirements is defined as a complete clinical data package for submission and potential approval, irrespective of its geographic origin. The acceptability of the foreign clinical data component of the complete data package depends upon whether it can be extrapolated or employed as a bridge to the population of the new region. Ethnic factors can be defined as the intrinsic characteristics of recipients of a medicine, and extrinsic characteristics associated with the environment and culture in which the subjects reside. Based on retrospective studies, inter-ethnic differences in ADME seem to be not greater than intra-ethnic variations for most medicines, and extrinsic factors appear to be more important than intrinsic factors for the assessment of efficacy and safety of the drug across ethnicity. Medical practice may represent one of the biggest differences and may perhaps prove to be very difficult to provide a harmonization for these extrinsic factors. The bridging study concept has primarily been brought up to overcome the difficulties inherent to extrinsic factors caused by different ethnicity. In Japan, the clinical trials advice division of the organization for pharmaceutical safety and research (OPSR) has been dealing with consultations about bridging studies since February 1998. The contents of consultations can be classified into 5 types. The most common type involves the desire by industries to bridge or extrapolate the results of foreign, phase III, clinical studies by conducting the dose-response studies domestically in the form of bridging studies. Until we have more information and have collected experiences in the variations caused by the regional differences as a result of extrinsic as well as intrinsic ethnic factors, we hope and believe that this document will serve to help provide great advancements in the acceptance of foreign clinical data.Correspondence to:
Dr. C. Naito; Tokyo Teishin Hospital, The Organization for Pharmaceutical Safety and Research (OPSR), 2-14-23 Fujimi, Chiyoda-ku, Tokyo 102-8798, Japan
Congress report
East-West development: understanding the usability and acceptance of foreign data in Japan
R. Nagata, H. Fukase and J.-D. Rafizadeh-Kabe
Abstract
R. Nagata1, H. Fukase2 and J.-D. Rafizadeh-Kabe3
1Shin Nippon Biomedical Laboratories (SNBL), Kagoshima, SNBL USA, Ltd., Seattle WA, USA, 2SNBL Clinical Pharmacology Center and CPC Clinic, Kagoshima, and 3Sciences-Po, SNBL, Tokyo, Japan
The introduction in Japan of New GCP regulations, as well as the internationalization of clinical trials under the ICH process (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use), has meant that the system is now faced with a number of serious challenges. This is shown by the dramatic decrease in registration of new drugs. Identifying the actors in the new context is essential. We shall first define precisely what is the Regulatory Authority in Japan, and which are the Regulatory Requirements to be fulfilled. We shall then describe the new process for evaluation of foreign clinical data. One of the major issues will be to determine in which cases a complete clinical data package will be sufficient to support regulatory submission, and in which cases additional clinical studies or bridging studies, and what kind of bridging studies will be required.Correspondence to:
Dr. R. Nagata, SNBL, 2438 Miyanoura, Yoshida, Kagoshima 891-1394, Japan
