Efficacy and safety of omalizumab for the treatment of refractory chronic spontaneous urticaria in Japanese patients: Subgroup analysis of the phase 3 POLARIS study.

BACKGROUND: Omalizumab, a humanized anti-IgE monoclonal antibody, proved efficacious and well tolerated in patients with chronic spontaneous urticaria (CSU) refractory to H1 antihistamines (H1AH) in the POLARIS study (NCT02329223), a randomized, double-blind, placebo-controlled trial in East Asian patients. However, data in Japanese patients, who have specific baseline characteristics (e.g., low angioedema incidence, different background medications) that may impact clinical outcomes, are lacking. This pre-specified analysis presents additional patient-level data over time, pharmacokinetic and pharmacodynamics data for omalizumab and IgE, and efficacy and safety data for omalizumab in Japanese patients. METHODS: Japanese patients (N = 105) were randomized 1:1:1 to omalizumab 300 mg, 150 mg, or placebo by subcutaneous injection every 4 weeks. Efficacy and safety were assessed primarily based on changes from baseline to Week 12 in weekly itch-severity scores (ISS7) and weekly urticaria activity scores (UAS7), and incidence of adverse events (AEs), respectively. Patient-level UAS7 data over time were also reviewed. RESULTS: At Week 12, least squares mean (LSM) changes from baseline in ISS7 were greater with omalizumab vs. placebo (-9.54 and -7.29 for omalizumab 300 mg and 150 mg, respectively, vs. placebo [-5.17]). Corresponding LSM changes from baseline in UAS7 were -21.61 and -15.59 (vs. placebo [-10.88]). Most responders in the omalizumab 300 mg group displayed improvement of disease activity within 2-4 weeks and had well-controlled symptoms during the treatment period. Overall AE incidence was similar across treatment arms. CONCLUSIONS: This subgroup analysis demonstrated that omalizumab is a well-tolerated, beneficial option for treatment of CSU in H1AH-refractory Japanese patients.

Systemic pharmacokinetics of indacaterol, an inhaled once-daily long-acting beta2-agonist, in different ethnic populations.

RATIONALE: To assess ethnic sensitivity of indacaterol systemic pharmacokinetics in Japanese vs. non-Japanese patients. METHODS: Analyses were in three parts: data from a single "all Asian" clinical study; and two on pooled data - one using a linear mixed effects (LME) model and the other a non-linear mixed effects (NLME) model. The NLME model analyzed pharmacokinetic data from nine indacaterol studies; the LME model analyzed peak (C(max)) and trough (C(min)) serum concentration using data from four of these studies. RESULTS: In the all-Asian study, indacaterol serum concentration-time pharmacokinetic profiles in Japanese patients (n = 102) were similar to those in the overall population (n = 229). In the LME model, C(max) (4,392 observations, 1,845 patients) and C(min) (4,664 observations, 1,796 patients) for Japanese patients (n = 94) were on average 25% and 18% higher, respectively, than non-Japanese patients. However, after adjusting for study differences, this apparent ethnicity effect was not significant (p = 0.25 and 0.39, respectively). In the NLME model (25,540 observations, 2,857 patients), there was no statistically significant effect of Japanese (n = 230) ethnicity on indacaterol serum pharmacokinetics. CONCLUSION: No ethnicity effect was observed on indacaterol systemic pharmacokinetic profile for Japanese patients when compared with the overall Asian patient population or with the Caucasian patient population.

Efficacy, safety and pharmacokinetics of indacaterol in Caucasian and Japanese patients with chronic obstructive pulmonary disease: a comparison of data from two randomized, placebo-controlled studies.

BACKGROUND: Indacaterol is a novel, inhaled, once-daily, ultra-long-acting ß2-adrenoceptor agonist that has been approved in the EU for the treatment of chronic obstructive pulmonary disease (COPD). Ethnic differences may influence the pharmacokinetics and pharmacodynamics of a drug, and it is therefore important to compare these parameters in different populations. OBJECTIVE: To compare the efficacy, safety and pharmacokinetics of indacaterol between Caucasian and Japanese patients with COPD. METHODS: Data from two randomized, double-blind, single-dose crossover, placebo-controlled studies in Caucasian and Japanese patients with moderate-to-severe COPD were compared. The two studies were similar in terms of study design, study population (inclusion/exclusion criteria), parameters examined and the indacaterol doses (150, 300 or 600 µg) tested. Efficacy (primary endpoint: 24-hour post-dose [trough] forced expiratory volume in 1 second [FEV1]), pharmacokinetics, and safety were assessed for 24 hours post-dose in each treatment period. RESULTS: Fifty-one Caucasian (86.3% male; mean age 61.8 years) patients were randomized into the first study and 50 Japanese (92.0% male; mean age 67.2 years) patients were randomized into the second study; ≥90% of patients completed the studies. In both studies, 24-hour post-dose trough FEV1 was significantly higher for all indacaterol doses versus placebo (p<0.001), with clinically relevant differences of 140 and 130 mL for the lowest (150 µg) dose in the Caucasian and Japanese studies, respectively. In both studies, single doses of indacaterol provided improvements in FEV1 that were sustained for 24 hours (p<0.001 vs placebo at all time points). In both populations, the average maximum serum concentration (Cmax) of indacaterol was observed at the first sampling time point and pharmacokinetic profiles were similar between populations. The increase in exposure (Cmax and area under the serum concentration-time curve from time zero to 24 hours) with increasing indacaterol dose was similar in both populations. All indacaterol doses in both studies demonstrated similar safety profiles. CONCLUSION: Indacaterol provided 24-hour bronchodilation with a fast onset of action and similar pharmacokinetic and safety profiles in Caucasian and Japanese patients. These findings suggest that ethnic factors do not influence the treatment of COPD with indacaterol.

The inhibition of human multidrug and toxin extrusion 1 is involved in the drug-drug interaction caused by cimetidine.

Cimetidine is known to cause drug-drug interactions (DDIs) with organic cations in the kidney, and a previous clinical study showed that coadministration of cimetidine or probenecid with fexofenadine (FEX) decreased its renal clearance. FEX was taken up into human kidney by human organic anion transporter (hOAT) 3 (SLC22A8), but the mechanism of its luminal efflux has not been clarified. The present study examined the molecular mechanism of these DDIs. Saturable uptake of FEX was observed in human kidney slices, with K(m) and V(max) values of 157+/-7 microM and 418+/-16 nmol/15 min/g kidney, respectively. Cimetidine only slightly inhibited its uptake even at 100 microM, far greater than its clinically relevant concentration, whereas 10 microM probenecid markedly inhibited its uptake. As candidate transporters for the luminal efflux of FEX, we focused on human multidrug and toxin extrusions MATE1 (SLC47A1) and MATE2-K (SLC47A2). Saturable uptake of FEX could be observed in human embryonic kidney 293 cells expressing human MATE1 (hMATE1), whereas hMATE2-K-specific uptake of FEX was too small to conduct its further kinetic analysis. The hMATE1-mediated uptake clearance of FEX was inhibited by cimetidine in a concentration-dependent manner, and it was decreased to 60% of the control value in the presence of 3 microM cimetidine. Taken together, our results suggest that the DDI of FEX with probenecid can be explained by the inhibition of renal uptake mediated by hOAT3, whereas the DDI with cimetidine is mainly caused by the inhibition of hMATE1-mediated efflux of FEX rather than the inhibition of its renal uptake process.

Involvement of multiple efflux transporters in hepatic disposition of fexofenadine.

Fexofenadine (FEX) is mainly eliminated from the liver into bile in unchanged form. We demonstrated previously that organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are involved in the hepatic uptake of FEX. However, little is known about the mechanisms controlling the hepatic efflux of FEX from the liver to bile and blood. In the present study, the involvement of hepatic efflux transporters in the pharmacokinetics of FEX was investigated in both in vitro and in vivo studies. Vectorial transport of FEX was observed in OATP1B3/human bile salt export pump (hBSEP) double transfectants but not in OATP1B3/human breast cancer resistance protein double transfectants, which indicates the possible contribution of hBSEP to the biliary excretion of FEX in humans. In multidrug resistance-associated protein 2 (Mrp2)(-/-) mice, the biliary excretion clearance based on the plasma concentration and the liver-to-plasma concentration ratio significantly decreased, whereas the biliary excretion clearance based on the liver concentration decreased only with 20%, suggesting the minimum contribution of Mrp2 to its biliary excretion. ATP-dependent transport of FEX was observed in hMRP3-enriched membrane vesicles but not hMRP4. In Mrp3(-/-) mice, the biliary excretion clearance based on both the plasma and liver concentration and the liver-to-plasma concentration ratio increased, suggesting the significant contribution of Mrp3 to its sinusoidal efflux and the up-regulation of its biliary excretion in Mrp3(-/-) mice. On the other hand, pharmacokinetics of FEX remained unchanged in Mrp4(-/-) mice. This information provides a novel insight into the transporters important for FEX disposition.

Investigation of the inhibitory effects of various drugs on the hepatic uptake of fexofenadine in humans.

Fexofenadine (FEX), an H(1)-receptor antagonist, is eliminated from the liver mainly in an unchanged form. Our previous study suggested that organic anion-transporting polypeptide (OATP) 1B3 contributes mainly to the hepatic uptake of FEX. On the other hand, a clinical report demonstrated that a T521C mutation of OATP1B1 increased its plasma area under the plasma concentration-time curve. Several compounds are reported to have a drug interaction with FEX, and some of this may be caused by the inhibition of its hepatic uptake. We determined which transporters are involved in the hepatobiliary transport of FEX by using double transfectants and examined whether clinically reported drug interactions with FEX could be explained by the inhibition of its hepatic uptake. Vectorial basal-to-apical transport of FEX was observed in double transfectants expressing OATP1B1/multidrug resistance-associated protein 2 (MRP2) and OATP1B3/MRP2, suggesting that OATP1B1 as well as OATP1B3 is involved in the hepatic uptake of FEX and that MRP2 can recognize FEX as a substrate. The inhibitory effects of compounds on FEX uptake in OATP1B3-expressing HEK293 cells were investigated, and the maximal degree of increase in plasma AUC of FEX by drug interaction in clinical situations was estimated. As a result, cyclosporin A and rifampicin were found to have the potential to interact with OATP1B3-mediated uptake at clinical concentrations. From these results, most of the reported drug interaction cannot be explained by the inhibition of hepatic uptake of FEX, and different mechanisms such as the inhibition of intestinal efflux should be considered.

Establishment of a set of double transfectants coexpressing organic anion transporting polypeptide 1B3 and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide.

In the hepatic uptake of organic anions, organic anion transporting polypeptide (OATP) 1B1 is believed to be mainly involved. We have constructed a set of double-transfected cells coexpressing OATP1B1 and hepatic efflux transporters and characterized the transcellular transport of several anions. Recent reports have also suggested the importance of OATP1B3 in the hepatic uptake of some compounds. However, there is little information about OATP1B3-selective substrate and no good tool for the evaluation of efflux transporters of OATP1B3 substrates. In the present study, we found an OATP1B3-selective substrate and established a novel set of double transfectants expressing OATP1B3. Telmisartan acylglucuronide (tel-glu) is a main metabolite of telmisartan, an angiotensin II receptor antagonist. Tel-glu is recognized by hepatobiliary transport systems and efficiently distributed to liver. Several studies using rat and human hepatocytes and transporter-expressing cells revealed that OATP1B3 was responsible for the hepatic uptake of tel-glu in humans. By using double transfectants expressing OATP1B3, we investigated the transcellular transport of tel-glu as well as estradiol 17beta-d-glucuronide (E(2)17betaG) and cholecystokinin octapeptide (CCK-8) to identify the responsible efflux transporters in their biliary excretion. Vectorial basal-to-apical transport of tel-glu was observed in all kinds of double transfectants expressing OATP1B3. In contrast, basal-to-apical transport of E(2)17betaG and CCK-8 was seen only in the OATP1B3/MRP2 double transfectant compared with OATP1B3-expressing cells. Therefore, the newly established set of double transfectants expressing OATP1B3 combined with OATP1B1-expressing double transfectants can be used as a powerful tool for the rapid identification of hepatic uptake and efflux transporters of organic anions.

Efficacy and safety of omalizumab in Japanese and Korean patients with refractory chronic spontaneous urticaria.

BACKGROUND: Many patients with chronic spontaneous/idiopathic urticaria (CSU/CIU) do not respond adequately to treatment with non-sedating H1 antihistamines (H1AH). There are limited studies on use of omalizumab as add-on therapy for treatment of CSU in an Asian population. OBJECTIVE: The POLARIS study (NCT02329223), representing the first randomized, double-blind, placebo-controlled phase III trial of omalizumab for CSU in an Eastern Asian population, evaluated efficacy and safety of omalizumab as add-on therapy for treatment of CSU. METHODS: This 26-week multicenter (41 Japanese/Korean sites) study enrolled patients (12-75 years) who were symptomatic despite H1AH treatment. Eligible participants (N=218) were randomized 1:1:1 to receive three subcutaneous injections of omalizumab 300mg, 150mg, or placebo every 4 weeks, followed by 12 weeks of follow-up. Primary outcome was change from baseline to Week 12 (Wk12) in weekly itch severity score (ISS7). Safety was assessed through the summary of adverse events (AEs). RESULTS: Baseline demographics and disease characteristics were generally well balanced across treatment groups. At Wk12, statistically significant decreases from baseline were observed in ISS7 with omalizumab vs placebo (mean changes -10.22, -8.80, and -6.51 for omalizumab 300mg, 150mg and placebo; p<0.001 and p=0.006 vs placebo, respectively). Overall AE incidence was similar across treatment groups (54.8%, 57.7%, and 55.4% in omalizumab 300mg, 150mg, and placebo groups, respectively); nasopharyngitis was the most frequently reported AE in all treatment arms. CONCLUSION: The POLARIS study demonstrates that omalizumab is an efficacious and well-tolerated add-on therapy in Japanese and Korean H1AH-refractory patients with CSU.

Ethnic sensitivity assessment - pharmacokinetic comparability between Japanese and non-Japanese healthy subjects on selected mAbs.

OBJECTIVE: Ethnic sensitivity studies (ESSs), where safety and pharmacokinetics (PK) are assessed in Japanese subjects, are routinely conducted according to Japanese regulatory requirement before the subsequent clinical studies. The necessity of ESSs is questionable in case of mAbs, where inherent IgG characteristics are considered ethnically insensitive. This report investigated PK profiles and immunogenicity (IG) following a single administration of mAbs in Japanese and non-Japanese healthy subjects. RESEARCH DESIGN AND METHODS: PK and IG comparison between Japanese and non-Japanese healthy subjects was made on mAbs data available from public domain and unpublished internal reports. PK comparison was made based on statistical approach as well as assumed typical IgG profile using modeling and simulation. RESULTS: When compared directly, most mAbs showed no difference between ethnic groups. When profiles of various mAbs were fit to an assumed typical IgG PK model, the majority of mAbs follow the expected behavior regardless of ethnicities. Deviations from this behavior did not appear to be due to inherent ethnic differences. When the incidence of IG was assessed, only Adalimumab showed apparent ethnic difference. CONCLUSIONS: The overall lack of observational difference may facilitate discussion of mAbs' early clinical development in Japan, including the utility of dedicated ESSs.

Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin.

Pitavastatin, a novel potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is distributed selectively to the liver and excreted into bile in unchanged form in rats. We reported previously that the hepatic uptake is mainly mediated by organic anion transporting polypeptide (OATP) 1B1, whereas the biliary excretion mechanism remains to be clarified. In the present study, we investigated the role of breast cancer resistance protein (BCRP) in the biliary excretion of pitavastatin. The ATP-dependent uptake of pitavastatin by human and mouse BCRP-expressing membrane vesicles was significantly higher compared with that by control vesicles with Km values of 5.73 and 4.77 microM, respectively. The biliary excretion clearance of pitavastatin in Bcrp1-/- mice was decreased to one-tenth of that in control mice. The biliary excretion of pitavastatin was unchanged between control and Eisai hyperbilirubinemic rats, indicating a minor contribution of multidrug resistance-associated protein (Mrp) 2. This observation differs radically from that for a more hydrophilic statin, pravastatin, of which biliary excretion is largely mediated by Mrp2. These data suggest that the biliary clearance of pitavastatin can be largely accounted for by BCRP in mice. In the case of humans, transcellular transport of pitavastatin was determined in the Madin-Darby canine kidney II cells expressing OATP1B1 and human canalicular efflux transporters. A significant basal-to-apical transport of pitavastatin was observed in OATP1B1/MDR1 and OATP1B1/MRP2 double transfectants as well as OATP1B1/BCRP double transfectants, implying the involvement of multiple transporters in the biliary excretion of pitavastatin in humans. This is in contrast to a previous belief that the biliary excretion of statins is mediated mainly by MRP2.

Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein.

Until recently, it was generally believed that the transport of various organic anions across the bile canalicular membrane was mainly mediated by multidrug resistance-associated protein 2 (MRP2/ABCC2). However, a number of new reports have shown that some organic anions are also substrates of multidrug resistance 1 (MDR1/ABCB1) and/or breast cancer resistance protein (BCRP/ABCG2), implying MDR1 and BCRP could also be involved in the biliary excretion of organic anions in humans. In the present study, we constructed new double-transfected Madin-Darby canine kidney II (MDCKII) cells expressing organic anion-transporting polypeptide 1B1 (OATP1B1)/MDR1 and OATP1B1/BCRP, and we investigated the transcellular transport of four kinds of organic anions, estradiol-17beta-d-glucuronide (EG), estrone-3-sulfate (ES), pravastatin (PRA), and cerivastatin (CER), to identify which efflux transporters mediate the biliary excretion of compounds using double-transfected cells. We observed the vectorial transport of EG and ES in all the double transfectants. MRP2 showed the highest efflux clearance of EG among these efflux transporters, whereas BCRP-mediated clearance of ES was the highest in these double transfectants. In addition, two kinds of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, CER and PRA, were also substrates of all these efflux transporters. The rank order of the efflux clearance of PRA mediated by each transporter was the same as that of EG, whereas the contribution of MDR1 to the efflux of CER was relatively greater than for PRA. This experimental system is very useful for identifying which transporters are involved in the biliary excretion of organic anions that cannot easily penetrate the plasma membrane.