Efficient clinical trials in Japan: Bridging studies versus participation in global clinical trials.

The required number of Japanese subjects was compared between the Bridging (BG) filing strategy described in ICH-E5 for drugs approved from 1998 to 2012, in which foreign phase 3 results were used together with a BG study conducted to confirm optimum Japanese dose, and global clinical trial (GCT) strategies in which the number was simulated from the foreign phase 3 studies. The simulated number from the GCT strategy was smaller than that of the BG, suggesting that the GCT strategy could be expected to reduce Japanese clinical trial costs. However, two exceptions were found, namely for preventive drugs and drugs for children, because of the large scales of foreign phase 3 studies.

Low-molecular-weight heparin pharmacokinetics: a dual absorption model approach.

OBJECTIVE: The aim of this study was to develop a novel population pharmacokinetic (PPK) model of dalteparin after subcutaneous (s.c.) injection, to describe the impact of the "flip-flop" phenomenon and to demonstrate any ethnic difference between Asian and Caucasian subjects. MATERIALS AND METHODS: The PPK model was constructed based on data collected from Asian (Japanese) and Caucasian (French) subjects with a total of 931 plasma anti-Xa activity measurements. After s.c. injection, the apparent elimination half-life of the dalteparin was about 4 hours, longer than that reported after intravenous (i.v.) injection, indicating a "flip-flop" phenomenon. In addition, following the mono-exponential decline profile after s.c. injection, a longer secondary phase was apparently observed in 70% of subjects. To investigate the phenomenon, we applied a dual absorption model including fast first-order and slow zero-order inputs as the structural model. RESULTS: The PPK model for s.c. injection provided the half-life consistent with that of i.v. injection and could account for the observed bi-phasic profile. Body weight and gender for clearance and body weight for volume of distribution were identified as covariates. Due to lower body weight in Asian subjects, an ethnic difference might occur but it would not be reflected by per kg body weight injection. CONCLUSIONS: Dalteparin PK profiles after s.c. injection were described reasonably by the novel PPK model based on flip-flop pharmacokinetics and a dual absorption process.

Potential factors correlating to the PMDA's decision to waive Japanese Phase 2 and 3 studies for oncology drugs New Drug Application in Japan.

Current status of oncology drugs approved in Japan without supporting Japanese Phase 2 and 3 clinical trial (J-P2/3) data and potential factors correlating to the decision of Japanese health agency Pharmaceuticals and Medical Devices Agency (PMDA) to waive J-P2/3 data were investigated. Approximately 15 % of 61 investigated recently-approved oncology drugs were granted a J-P2/3 waiver. Drugs that were designated as Fast Track in the United States tended to be granted a J-P2/3 waiver. The orphan drug designation in Japan was also suggested to be correlated with the decision of J-P2/3 waiver, even though the trend was not significant. Specific factors related to the clinical importance, such as the designation of US Fast Track status, may have a correlation with the likelihood of J-P2/3 waiver, suggesting that the clinical importance of the drug is common in both countries. If the key criteria used to determine the waiving of Japanese clinical trial data were clearly disclosed by the regulatory agency, the development of some clinically important oncology drugs could be further expedited.

Different truncation methods of AUC between Japan and the EU for bioequivalence assessment: influence on the regulatory judgment.

In regulatory guidelines for bioequivalence (BE) assessment, the definitions of AUC for primary assessment are different in ICH countries, i.e., AUC from zero to the last sampling point (AUCall) in Japan, AUC from zero to infinity (AUCinf) or AUC from zero to the last measurable point (AUClast) in the US, and AUClast in the EU. To assure sufficient accuracy of truncated AUC for BE assessment, the ratio of truncated AUC (AUCall or AUClast) to AUCinf should be more than 80% both in Japanese and EU guidelines. We investigated how the difference in the definition of truncated AUC affects BE assessment of sustained release (SR) formulation. Our simulation result demonstrated that AUCall/AUCinf could be ≥80% despite AUClast/AUCinf being <80% and AUCall failed to detect formulation difference. In Japanese package inserts of generic drugs in SR formulation, there were products for which AUCall/AUCinf was ≥80% though AUClast/AUCinf was <80%. In conclusion, it was confirmed that the difference in definition of truncated AUC affected the judgment of validity of truncated AUC for BE assessment, and AUCall could fail to detect the substantially different in vivo dissolution profile of generic drugs with SR formulation from the original drug.

The pharmacokinetics and pharmacodynamics of PF-00734200, a DPP-IV inhibitor, in healthy Japanese subjects.

OBJECTIVE: To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of PF-00734200, a potent dipeptidyl peptidase-IV (DPP-IV) inhibitor, in Japanese subjects, and compare the results with those in Western subjects. MATERIALS AND METHODS: Eight healthy Japanese subjects received a single dose of PF-00734200 10 mg, 100 mg, or placebo. Another 8 subjects received PF-00734200 20 mg or placebo single dose once daily for 6 days. Serum and urine PK, plasma DPP-IV activity, and plasma glucagon-like peptide 1 (GLP-1) levels were measured. RESULTS: Linear pharmacokinetics was observed over the single dose range 10 - 100 mg. Following multiple-dose administration, 37.3 ± 4.33% of the unchanged PF-00734200 was excreted in the urine and renal clearance was calculated as 33.9 ± 6.56 ml/min. After the standardized meals, GLP- 1 levels increased ~ 2-fold compared with placebo, and no further increase in GLP-1 levels was observed at doses above 10 mg. The steady state DPP-IV inhibition at 24 h was ~ 75%. CONCLUSION: Pharmacokinetics of PF-00734200, inhibition of DPP-IV, and non-linear increases in GLP-1 were similar between healthy Japanese and Western subjects.

Inter-individual variability of in vivo CYP2D6 activity in different genotypes.

Cytochrome P450 2D6 (CYP2D6), which has a large number of genetic polymorphisms, is involved in the metabolism of a wide range of substrates. Dextromethorphan (DM) is a well-known probe drug for CYP2D6 and metabolic ratio (MR) is often used to measure the enzyme activity in vivo. Using the literature values of DM MR, we estimated the inter-individual variability of CYP2D6 hepatic intrinsic clearance (CL(int,h,2D6)) in each genotype by Monte Carlo simulation and found that the homozygote of CYP2D6*1 and the heterozygote of CYP2D6*1 and null alleles had a coefficient of variation (CV) of 43% and 56%, respectively. The variability of homozygotes of CYP2D6*2 and CYP2D6*10 was 63% and 66%, while that of the heterozygotes of CYP2D6*2 and null alleles and CYP2D6*10 and null alleles was 125% and 109%, respectively. Based on the variability and reported frequency of the CYP2D6 genotype in Asians and Caucasians, the inter-individual variability of CL(int,h,2D6) of extensive metabolizers was estimated at 60-70%, which provided comparable variability of AUC with the literature values of DM, tolterodine, risperidone and atomoxetine. It is suggested that the produced inter-individual variability of CL(int,h,2D6) in each genotype is useful for estimating AUC variability of the CYP2D6 substrates in the regional population.

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.

Population pharmacokinetic and pharmacodynamic modeling of pegvisomant in asian and Western acromegaly patients.

Pegvisomant is a growth hormone (GH) receptor antagonist that normalizes insulin-like growth factor I (IGF-I) levels in patients with acromegaly. Although the dose of pegvisomant is determined by the IGF-I level, the pharmacokinetic and pharmacodynamic (PK/PD) model for pegvisomant concentration and IGF-I reduction has not been established. This study was conducted to characterize PK/PD of pegvisomant, and to determine the influence of covariates on the pegvisomant PK/PD. Based on the data from 5 phase III studies in 168 acromegaly patients, models were developed to characterize the PK/PD of pegvisomant. The PD variables were IGF-I serum concentrations. The modeling was performed with a nonlinear mixed-effects approach using NONMEM. After subcutaneous dosing, the PK of pegvisomant was described by a steady state PK model with dose- dependent clearance. Baseline GH and age were significant covariates for the clearance. A sigmoid E(max) model adequately described the relationship between IGF-I and pegvisomant concentrations. Baseline GH was found to be a significant covariate for the baseline effect (E(0)) and IC(50). The PK/PD properties of pegvisomant were not significantly different between Asian and Western patients.

Pharmacokinetic-pharmacodynamic analysis of azithromycin extended release in Japanese patients with common respiratory tract infectious disease.

OBJECTIVES: it is known that the efficacy of azithromycin, in animal infection models, is best correlated with AUC/MIC. The pharmacokinetic-pharmacodynamic (PK-PD) relationship for azithromycin, however, has not been previously confirmed with clinical data. The objectives of this PK-PD analysis were to characterize exposure-response relationships for the efficacy and safety of azithromycin extended release (ER) in Japanese patients, and to evaluate the effects of potential covariates on the prediction of response. METHODS: sparse serum azithromycin concentration, MIC, efficacy and safety data were collected from three Japanese Phase 3 studies of a 2 g single dose of azithromycin-ER for respiratory tract infections. These sparse concentration data were combined with data from eight Phase 1 PK studies in Japanese and Western populations, to develop a robust population PK model using a non-linear mixed effects approach. The exposure-response relationships for efficacy and safety were evaluated using logistic regression. RESULTS: a two-compartment model with first-order absorption and first-order elimination with a lag time adequately described the PK of azithromycin-ER, without any significant ethnic differences in AUC. The percentage of bacteriological and clinical success in patients with AUC/MIC  >  5 (95.8% and 100%, respectively) was much higher than in those with AUC/MIC  ≤  5 (60.0% and 83.3%, respectively). CONCLUSIONS: as expected, the probabilities of success in the clinical and bacteriological responses were positively associated with AUC/MIC, but not with AUC. For the exposure-safety relationship, the incidence of treatment-related diarrhoea was inversely associated with azithromycin exposure.

Effect of the CYP2D6*10 genotype on tolterodine pharmacokinetics.

This study was conducted to investigate the effect of the reduced function allele CYP2D6*10, which can be the cause of an intermediate metabolizer (IM), on tolterodine pharmacokinetics. Tolterodine is mainly metabolized to an active 5-hydroxymethyl metabolite (5-HM) by CYP2D6, and 5-HM is also metabolized by CYP2D6. Asian and white healthy volunteers (n = 108) received once daily multiple doses of tolterodine, and the serum concentrations of tolterodine and 5-HM were measured. All subjects were genotyped for CYP2D6. Tolterodine exposures [area under the curve (AUC)] increased in order of CYP2D6*1/*1 [extensive metabolizer (EM)] < CYP2D6*1/*10 < CYP2D6*10/*10 < CYP2D6*5/*10. It was expected that the order of 5-HM exposure would be reversed. However, the 5-HM AUC increased in the same order as that of tolterodine. This phenomenon was explained by considering CYP2D6 mediation of both production and elimination of 5-HM. The tolterodine and 5-HM exposures in CYP2D6*10/*10 were statistically higher than those for CYP2D6*1/*1 (3- and 1.5-fold, respectively). In CYP2D6*4/*4 [poor metabolizer (PM)], 5-HM was not produced and tolterodine exposure was 20-fold higher than that in CYP2D6*1/*1. With consideration for higher protein binding of tolterodine than 5-HM, the exposure as a sum of the unbound fraction of tolterodine and 5-HM (active moiety) in CYP2D6*10/*10 was 1.8-fold higher than that in CYP2D6*1/*1 and was also higher than that in CYP2D6*4/*4. Simulation using the values of EM and PM demonstrated that the maximum possible active moiety exposure was around the observed values of CYP2D6*5/*10, which were 1.9-fold higher than those for CYP2D6*1/*1. This is the first report to provide an example in which the IM shows higher exposure to pharmacological active moiety than the EM and PM.

Population pharmacokinetic analysis of linezolid in patients with infectious disease: application to lower body weight and elderly patients.

Linezolid (Zyvox), belonging to oxazolidinone antibiotics, is commonly used for the treatment of patients infected with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Although linezolid has been approved worldwide, the Japanese pharmacokinetic (PK) profile has not been characterized in detail. The objective of this study is to develop a population PK model for linezolid that can be applied to a Japanese population. This population PK model was established based on the 1 Japanese phase III and 4 Caucasian phase II/III studies. A total of 2539 linezolid plasma concentration measurements from 455 patients, aged 18 to 98 years and body weight 30 to 190.5 kg, were used for the analysis. The data were analyzed using nonlinear mixed effects modeling. Body weight (BW), age, ethnicity, and gender were investigated as covariates. The final model was validated by the bootstrap technique. The PK profiles of linezolid were described with a 1-compartment PK model with first-order absorption and first-order elimination. In the final population PK model, BW and age were influential covariates on clearance, and the distribution volume was affected by BW. The present population PK model of linezolid described well the PK profiles in Japanese patients who have lower BW and are relatively older compared with those in the United States/European Union.

Prediction of theophylline clearance in CCl4-treated rats using in vivo CYP1A2 and CYP3A2 contents assessed with the PKCYP test.

We previously established a method to predict the drug metabolism capacity of injured liver based on pharmacokinetic estimation of the amount of cytochrome P450 (CYP) in vivo (PKCYP test), by introducing the apparent liver-to-blood free concentration gradient in vivo (qg) as a parameter. Here we show that the amount of CYP3A2 in CCl(4)-treated rats can be estimated appropriately by applying the PKCYP test using midazolam (MDZ) as a probe, assuming that the qg value in control rats does not change. We applied the results to predict the clearance of theophylline as a model drug with a physiologically based pharmacokinetic model. Male Sprague-Dawley rats were pretreated with CCl4, and the amount of CYP (A-CYP(vivo)) was quantified by Western blotting. The qg value of MDZ was determined in control rats and used to estimate the amounts of CYP3A2 in CCl4-treated rats; the result agreed well with the observed values. The qg value of CYP3A2 estimated with MDZ as a probe was used together with our previously reported value for CYP1A2 (theophylline metabolism in the liver is known to be almost entirely mediated by CYP3A2 and CYP1A2) to predict the total body clearance (CL(tot)) of theophylline in CCl4-treated rats. The predicted CL(tot) was about one-third of the observed value, which was considered acceptable. The time-course of theophylline concentration in serum simulated with a physiologically-based pharmacokinetic model agreed well with the observed values. Thus, the PKCYP test using MDZ as a probe can be used to predict the amount of CYP3A2 and the CL(tot) of theophylline in CCl4-treated rats.

CYP isoforms involved in the metabolism of clarithromycin in vitro: comparison between the identification from disappearance rate and that from formation rate of metabolites.

To clarify whether CYP2C19 is involved in the overall metabolism of clarithromycin (CAM) or not, in vitro studies using human liver microsomes and recombinant CYPs were performed by an approach based on the disappearance rate of parent compound from the incubation mixture. In addition, the results of disappearance rate were compared with those obtained from the formation rates of the major metabolites of CAM, 14-(R)-hydroxy-CAM and N-demethyl-CAM. The intrinsic clearance (CL(int)) values determined from the disappearance of CAM in nine different human liver microsomes were highly correlated with the testosterone 6beta-hydroxylation activity (r=0.957, p<0.001). The CL(int) of CAM was markedly reduced by selective inhibitors of CYP3A4 (ketoconazole and troleandomycin) and by polyclonal antibodies raised against CYP3A4/5 in human liver microsomes. Among the 11 isoforms of recombinant human CYP, only CYP3A4 revealed the metabolic activity for the disappearance of CAM. These results were fairly consistent with those obtained from the conventional approach based on the formation of major metabolites of CAM. Comparison of the kinetic parameters estimated from the disappearance rate of CAM and the formation rates of 14-(R)-hydroxy-CAM and N-demethyl-CAM indicates that N-demethylation and 14-(R)-hydroxylation account for 65% of CL(int) derived from the disappearance of CAM in human liver microsomes. The findings suggest that CYP3A4 plays a predominant role in the overall metabolic clearance of CAM as well as in the formation of 14-(R)-hydroxy-CAM and N-demethyl-CAM. CYP2C19 does not appear to be involved in the overall metabolism of CAM at least in human liver microsomes. A combination of the disappearance rate of a parent compound and the formation rate of metabolites appears to be a useful approach for estimating the percentage contribution of the formation of metabolites to the overall metabolic clearance of a parent compound in vitro.