Ethnic Differences In Pharmacokinetics Research Articles

A Phase 1 Study to Assess the Pharmacokinetics, Food Effect, Safety, and Tolerability of Sepiapterin in Healthy Japanese and Non-Japanese Participants

Background: Sepiapterin is a natural precursor of tetrahydrobiopterin (BH4), a key cofactor for phenylalanine hydroxylase. It is being developed for the treatment of patients with phenylketonuria. In this study, the ethnic differences in pharmacokinetics and safety of sepiapterin in Japanese and non-Japanese participants and food effects were evaluated. Methods: Healthy participants (n = 60) received a single oral dose of sepiapterin at either 20, 40, or 60 mg/kg with a low-fat diet. The Japanese participants received two doses at 40 mg/kg, either under fasted conditions or with a low-fat diet with a 3-day washout period in between. Results: Sepiapterin was well tolerated in all participants, with no serious adverse events. Sepiapterin was quickly absorbed (Tmax 1.4–4.5 h) and rapidly and extensively converted to BH4 (Tmax ~4 h). Exposures to sepiapterin were <1% of BH4. BH4 exposures were essentially dose-independent between 20 and 60 mg/kg. A low-fat diet increased BH4 exposures in Japanese participants by 1.7-fold compared with fasted conditions. Conclusions: BH4 exposures (Cmax and AUC0–last) in Japanese participants were 10–30% higher than in non-Japanese participants, which is deemed not clinically relevant; no dose adjustment is warranted. The slightly higher BH4 exposures in Japanese participants are likely due to the higher frequency of ABCG2 c.421C>A mutation in the Japanese population.

Exploration of pharmacokinetic differences between East Asians and Caucasians: insights from pharmacokinetic studies in healthy subjects.

Interethnic differences in the pharmacokinetics of drugs result from a complex interplay of environmental, genetic, and demographic factors. Identifying ethnic differences in pharmacokinetics is challenging due to the multifaceted contributions of the underlying factors. To address these challenges, this paper reviews 9 pharmacokinetic studies meeting the following criteria: (A) Conducted at Seoul National University Hospital from 2013 to 2022 as a single-center study. (B) Pharmacokinetic studies involving both East Asians (Korean, Japanese, or Chinese) and Caucasians. (C) Study drugs were administered orally. (D) Raw data was provided for reanalysis. This retrospective analysis aimed to investigate the existence of ethnic differences in drug exposure and understand the possible factors contributing to these variabilities. Pharmacokinetic, demographic, and clinical laboratory test data were analyzed to assess potential pharmacokinetic differences between East Asians and Caucasians. This assessment involved calculating the geometric mean ratio of dose-normalized area under the time-concentration curve (AUC) and dose- and weight-normalized AUC, along with their 90% confidence intervals. Additionally, pharmacological information, including metabolic pathways, was gathered from the investigational brochure or the respective country's drug label. Among 9 studies, 4 studies demonstrated approximately 1.3 to 1.8 times higher drug exposure in East Asians compared to Caucasians. These drugs were primarily eliminated through hepatic metabolism, with less than 5% excreted unchanged in the urine. Two drugs were metabolized by hepatic cytochrome P450 3A4, one by glutathione S-transferase, and specific metabolic pathways for another drug were not identified. Further research is needed to assess the causes of ethnic variability in these drugs.

Population pharmacokinetic analysis of transdermal granisetron in healthy Chinese and Caucasian volunteers.

Granisetron patches are a prolonged delivery transdermal system that is used to prevent Chemotherapy-induced nausea and vomiting (CINV). To date, no pharmacokinetics comparison between Chinese and Caucasian populations has been conducted for granisetron patches. This study focused on the ethnic differences in pharmacokinetics (PK) of granisetron transdermal delivery system (GTDS) between Chinese and Caucasians and the influence of demographic covariates on pharmacokinetics (age, weight, height, body mass index, sex). To achieve this, blood concentration data were collected from 112 Caucasian healthy subjects participating in four clinical trials and 24 Chinese healthy subjects from one clinical trial, after a single application of the granisetron transdermal delivery system. A nonlinear mixed-effects model method of Phoenix NLME software was used to establish a population pharmacokinetic (Pop PK) model for Caucasian subjects. Bootstrap and visual predictive check (VPC) were used to validate the model. Based on the analysis a one-compartment model with first-order absorption and a first-order elimination well described the PK characteristics of GTDS. The apparent systemic clearance was determined to be 31316.3mL/h and the central compartment volume of distribution was 6299.03L. None of the five covariates (age, weight, height, body mass index, and sex) included in the Pop PK were significant covariates affecting PK. The final Pop PK model was used to simulate the Caucasian blood concentration by applying the dosing regimen used for the Chinese population. Comparison of the simulated Caucasian PK data with observed clinical PK data from Chinese healthy subjects revealed no significant differences in the main parameters, AUClast and Cavg, between the two groups. These findings suggested that no dose adjustment was required when applied to the Chinese population. In conclusion, this Pop PK study comparing the transdermal patch in Chinese and Caucasian healthy subjects provided valuable insights for optimizing dosage across ethnicities.

Ethnic Differences in Pharmacokinetics and Dermatopharmacokinetics

Ethnic Differences in Pharmacokinetics and Dermatopharmacokinetics

Pharmacokinetics of Perfluorobutane after Intra-Venous Bolus Injection of Sonazoid in Healthy Chinese Volunteers

Sonazoid is an ultrasound contrast agent based on microbubbles (MB) containing perfluorobutane (PFB) gas. Sonazoid is approved in Japan, Korea and Norway for contrast-enhanced ultrasonography of focal liver lesions and focal breast lesions (Japan only). The objective of this study was to determine the pharmacokinetics (PKs) and safety of Sonazoid in Chinese healthy volunteers (HVs) and to evaluate the potential for ethnic differences in PKs between Chinese and Caucasian HVs. Sonazoid was administered as an intra-venous bolus injection at the clinical dose of 0.12 μL or 0.60 μL MB/kg body weight to two groups of eight Chinese HVs. Expired air and blood samples were collected and analyzed using a validated gas chromatographic tandem mass spectrometry method, and the main PK parameters were calculated. The highest PFB concentrations in blood were observed shortly after intra-venous administration of Sonazoid, and elimination of PFB was rapid. In the 0.12 μL MB/kg body weight cohort, PFB concentrations above the limit of quantification were observed for only 10 to 15 min post-injection. In the 0.60 μL MB/kg body weight cohort, PFB concentrations above the limit of quantification were observed for 60 min post-injection, and the shape of the elimination curve suggested a biphasic elimination profile. The maximum observed concentration (Cmax) values of PFB in blood were 2.3 ± 1.1 and 19.1 ± 9.2 ng/g for the 0.12 and 0.60 μL MB/kg body weight dose groups (mean ± standard deviation). Area under the curve values were 10.1 ± 2.7 and 90.1 ± 38.3 ng × min/g for the 0.12 and 0.60 μL MB/kg body weight dose groups. Cmax values of PFB in exhaled air were 0.35 ± 0.2 and 2.4 ± 0.7 ng/mL for the 0.12 and 0.60 μL MB/kg body weight dose groups. Assessment of laboratory parameters, vital signs, oxygen saturation and electrocardiograms revealed no changes indicative of a concern. The PK profile and safety data generated in the Chinese HVs were comparable to previous data for Caucasian HVs.

Combining 'Bottom-Up' and 'Top-Down' Methods to Assess Ethnic Difference in Clearance: Bitopertin as an Example.

Background and ObjectivesWe propose a strategy for studying ethnopharmacology by conducting sequential physiologically based pharmacokinetic (PBPK) prediction (a ‘bottom-up’ approach) and population pharmacokinetic (popPK) confirmation (a ‘top-down’ approach), or in reverse order, depending on whether the purpose is ethnic effect assessment for a new molecular entity under development or a tool for ethnic sensitivity prediction for a given pathway. The strategy is exemplified with bitopertin.MethodsA PBPK model was built using Simcyp® to simulate the pharmacokinetics of bitopertin and to predict the ethnic sensitivity in clearance, given pharmacokinetic data in just one ethnicity. Subsequently, a popPK model was built using NONMEM® to assess the effect of ethnicity on clearance, using human data from multiple ethnic groups. A comparison was made to confirm the PBPK-based ethnic sensitivity prediction, using the results of the popPK analysis.ResultsPBPK modelling predicted that the bitopertin geometric mean clearance values after 20 mg oral administration in Caucasians would be 1.32-fold and 1.27-fold higher than the values in Chinese and Japanese, respectively. The ratios of typical clearance in Caucasians to the values in Chinese and Japanese estimated by popPK analysis were 1.20 and 1.17, respectively. The popPK analysis results were similar to the PBPK modelling results.ConclusionAs a general framework, we propose that PBPK modelling should be considered to predict ethnic sensitivity of pharmacokinetics prior to any human data and/or with data in only one ethnicity. In some cases, this will be sufficient to guide initial dose selection in different ethnicities. After clinical trials in different ethnicities, popPK analysis can be used to confirm ethnic differences and to support dose justification and labelling. PBPK modelling prediction and popPK analysis confirmation can complement each other to assess ethnic differences in pharmacokinetics at different drug development stages.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-015-0356-1) contains supplementary material, which is available to authorized users.

A comprehensive review of the pharmacokinetics of approved therapeutic monoclonal antibodies in Japan: Are Japanese phase I studies still needed?

Ethnic evaluation of the pharmacokinetics and safety of new drugs is required in Japan before implementing bridging or joining global studies. As therapeutic monoclonal antibodies (mAbs) show limited ethnic differences, their pharmacokinetics and safety in Japanese individuals could be estimated from prior non-Japanese studies. Therefore, there is potential to re-evaluate the development program for mAbs in Japan. We reviewed the pharmacokinetics of mAbs approved in Japan. Although some differences had been observed in pharmacokinetics of mAbs between Japanese and non-Japanese populations (mainly Caucasians), these differences were attributed to differences of body weight and/or antigen levels. Moreover, the influential factors can be estimated without conducting regional pharmacokinetic/safety studies. The pharmacokinetics of some mAbs is presumably non-linear and show differences between healthy volunteers and patients because of differences in antigen levels. However, for 10/24 mAbs approved in Japan, Japanese healthy volunteer studies were conducted before the patient studies. Additionally, for the mAbs that showed ethnic differences in pharmacokinetics, the doses selected in subsequent patient studies were the same as the doses approved in the United States. In this review, we discuss new drug development strategies in various regions, and assess the need for regional pharmacokinetics/safety studies before joining global studies.

Abstract 29: Phase I study of intravenous PI3K inhibitor BAY 80-6946 in Japanese subjects.

Abstract Background: BAY 80-6946 is an intravenous, potent and highly selective pan-Class I PI3K inhibitor with anti-tumor activity in a panel of preclinical models. A phase I study to evaluate safety, tolerability and pharmacokinetics at the maximum tolerated dose (MTD) in Western patients was performed in Japanese patients with advanced or refractory solid tumors. Methods: Ten patients received 1-hr intravenous infusions of BAY 80-6946 at doses of 0.4 mg/kg (3 patients) and 0.8 mg/kg (7 patients); 0.8 mg/kg had been determined as the MTD in a previous phase I study conducted in the US (Patnaik et al., J Clin Oncol 29: 2011; suppl, abstr 3035). A cycle consisted of 3 weekly doses, every 4 weeks, with treatment continuing until disease progression or unacceptable toxicity. Tumor types included 4 colorectal, 2 non-small cell lung, 1 renal, pancreatic, GIST and bladder cancer, respectively. Pharmacokinetics (PK) were evaluated following the first and third doses. Safety evaluations included monitoring of glucose and blood pressure, EKGs and echocardiogram. Results: Safety and tolerability were evaluated in cycle 1 and no DLTs were observed in the either cohort. Anticipated adverse events (AEs), hyperglycemia and hypertension related to BAY 80-6946, were observed but easily managed by appropriate medication. Transient hyperglycemia Gr 1 was seen in 4 (40%), Gr 2 in 2 (20%) and Gr 3 in 1 patient (10%), respectively. Transient hypertension Gr 1 was seen in 2 (20%) and Gr 2 in 4 (40%) patients, respectively. Other drug-related AEs more than 2 patients in the cycle 1 included Gr 1/2 anemia (20%), oral mucositis (20%), nausea (20%), neutropenia (40%), leukocytopenia (40%), pruritus (20%) and skin acneiform (20%) and Gr 2/3 lymphocytopenia. One patient with a serious adverse event related to the study drug was observed showing Gr 3 diarrhea with Gr 2 pre-syncope in the 2nd cycle whom recovered but needed prolonged hospitalization. Seven patients discontinued the study due to progressive disease and 3 due to AEs; 2 in 1st, 5 in 2nd, 2 in 3rd and 1 in 5th cycle, respectively. The GIST patient previously progressed on both imatinib and sunitinib had stable disease (SD) through the end of 5th cycle but discontinued due to the drug-related thrombocytopenia. PK analyses yielded results similar to that reported in Western patients. The AUC for BAY 80-6946 was approximately dose proportional. There was no accumulation between Day 1 and Day 15 in AUC for BAY 80-6946. The half-life of BAY 80-6946 averaged approximately 32 to 36 hours after C1D1 of dosing. Conclusions: BAY 80-6946 was generally well tolerated at the MTD of 0.8 mg/kg. Study drug related hyperglycemia and hypertension were well managed. There are no relevant ethnic differences in PK between Japanese and Western patients. Citation Format: Toshihiko Doi, Nozomu Fuse, Takayuki Yoshino, Takashi Kojima, Hideaki Bando, Hideaki Miyamoto, Masato Kaneko, Motonobu Osada, Atsushi Ohtsu. Phase I study of intravenous PI3K inhibitor BAY 80-6946 in Japanese subjects. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 29. doi:10.1158/1538-7445.AM2013-29

Ethnic Differences in Pharmacokinetics in New Drug Applications and Approved Doses in Japan

Ethnic Differences in Pharmacokinetics in New Drug Applications and Approved Doses in Japan

Pharmacokinetics of Tolterodine in Japanese and Koreans: Physiological and Stochastic Assessment of Ethnic Differences

Tolterodine is known as a drug which exhibits ethnic differences in pharmacokinetics between Japanese and Koreans despite genetic similarities among the populations of East Asian countries. Tolterodine is mainly metabolized by CYP2D6 to a 5-hydroxymethyl metabolite (5-HM), and 5-HM is also metabolized by CYP2D6. The reduced-function allele CYP2D6*10 is frequently observed in Asian populations. We investigated differences in the pharmacokinetics of tolterodine between small Japanese and Korean study populations by physiological and stochastic approaches with consideration of the CYP2D6 genotype. The genotype frequencies of CYP2D6*10/*10 and CYP2D6*5/*10 were found to be higher in Koreans than in Japanese, which suggested that this frequency difference occurred incidentally. The effects of CYP2D6 genotype and ethnicity on the intrinsic clearance of tolterodine by CYP2D6 were tested and only genotype was found to be a significant factor by ANCOVA. A simulation was conducted to confirm whether the observed differences in tolterodine exposure could be explained by the differences in genotype frequency found in this study. It was confirmed that the variability of intrinsic clearance could be responsible for the incidental exposure differences. In conclusion, apparent differences in exposure were found between small Japanese and Korean study populations because of the variability of intrinsic clearances and genotype frequencies.

Cross-cultural psychopharmacology: a review

Cross-cultural psychopharmacology seeks to determine whether there are differences in responses to psychopharmacologic agents among various ethnic groups and the reason for such variations. During the past four decades numerous clinical reports have addressed potential differences in therapeutic dosages and side effects of psychotropic medications between various ethnic groups. In addition, several rigorously designed studies have focused on ethnic differences in pharmacokinetics (including absorption, metabolism, distribution and excretion) and pharmacodynamics (including receptor-coupling activity). These ethnic variations are mainly influenced by genetic predisposition but are also influenced by other factors such as culture, environment, psychosocial supports, and attitudes towards pharmacology. This presentation will provide a critical review of the existing information in regard to psychotropic medications including neuroleptics, antidepressants, lithium, and benzodiazepines among various ethnic groups. Also included will be data on neuroleptic-induced movement disorders, the clinical implications of genetic polymorphism of cytochrome P-450 isoenzymes, recommendations on how to better design a pharmacological approach in the treatment of psychiatric disorders among different ethnic groups, as well as recent advances and future directions regarding cross-cultural issues of psychopharmacology.

Assessment of Ethnic Differences in the Pharmacokinetics and Pharmacodynamics of Valsartan

Objective: To assess the potential ethnic differences in pharmacokinetics and pharmacodynamics of valsartan between Japanese and Caucasian subjects. Methods: This was an open-label, parallel-design study conducted in male Japanese (n=15) and Caucasian (n=15) subjects with similar age and body weight. All subjects received a single oral dose of 160 mg valsartan capsule, and the plasma levels of valsartan, aldosterone, and angiotensin II along with plasma renin activity (PRA) were determined at pre-set time intervals, post-dosing. Key findings: The time to reach peak plasma concentrations of valsartan (T max ) was in the range of 1–6 h in both groups. The mean C max of valsartan was 3.3 and 3.6 μg/ml; the mean plasma exposure (AUC 0- ∞ ) values were 23.0 and 23.8 μg.h/ml and the mean half-life (t 1/2 ) was 7.7 and 9.6 h in Japanese and Caucasian subjects, respectively. No significant difference (p>0.1) was found between two ethnic groups for PRA, angiotensin II and aldosterone at 2, 4 and 8 h, post dose. Conclusion: Pharmacokinetics and pharmacodynamics of valsartan were not found to be associated with ethnic differences between healthy male Caucasian and Japanese subjects following single oral dose administration of valsartan and hence no dose adjustment is required for these groups.

Pharmacokinetics of immunosuppressants: a perspective on ethnic differences.

Despite recent advancements in solid organ transplantation, African-American renal allograft recipients continue to exhibit poorer prognosis in long-term clinical outcome and graft survival compared to Caucasian patients. The role of immunosuppressants in post-transplant outcome is crucial, and associations between exposure-related pharmacokinetic parameters and clinical outcome have been made for several drugs in this class. Thus, ethnic differences in the pharmacokinetics of immunosuppressants are potentially a key factor in the observed differences in post-transplant outcome between African-Americans and Caucasians. Ethnic differences in pharmacokinetics of mycophenolate mofetil and azathioprine based on the current literature are either absent or only of minor relevance. Cyclosporine, tacrolimus, sirolimus and everolimus, however, have all been described to exhibit ethnicity-specific differences in bioavailability and/or dose-adjusted systemic exposure, although currently available reports are controversial for some of these drugs. Oral bioavailability of these drugs in African-Americans was between 20 and 50% lower than in Caucasians or Non-African-Americans, leading to higher dose requirements in African-Americans to maintain similar average concentrations of the respective immunosuppressant. Since all four drugs undergo extensive metabolism and are substrates for CYP3A isoenzymes as well as the drug transporter P-glycoprotein, interethnic variability in activity of these enzymes/transporter may provide a common mechanism for the observed ethnic differences. These ethnic differences are most likely mediated via several non-genetic as well as genetic factors, including known genetic variations that impair transporter/enzyme activity in genes such as CYP3A4, CYP3A5 and ABCB1 (MDR1). Appreciation of differences in immunosuppressant pharmacokinetics and dose requirements between African-Americans and Caucasians in clinical practice is expected to improve post-transplant immunosuppressive pharmacotherapy and may thus contribute to equalize prognostic outcome for all transplant patients.