Pharmacokinetics and safety of rilpivirine in healthy Japanese subjects and exploration of ethnic sensitivity of rilpivirine pharmacokinetics with physiologically based pharmacokinetic model approach.

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor, used for the treatment of human immunodeficiency virus type-1 infection. An open label study was conducted to investigate the pharmacokinetics (PK) and safety of a single oral dose of rilpivirine 25 mg in Japanese healthy adult subjects. No adverse events were reported. The mean Cmax (144.3 ng/mL) and AUCinf (4542 ng h/mL) in Japanese subjects were approximately 30 % higher than those reported from a similar study in Caucasian healthy subjects, whereas the median tmax and mean t1/2 values were comparable between studies. A simple physiologically based PK model was developed to characterize the rilpivirine PK profile. The model adequately described rilpivirine PK profiles, and well-predicted drug-drug interactions. With exploration using the model, body size and CYP3A4 abundance were identified as factors which explained the observed inter-ethnic difference in rilpivirine exposure. The inter-ethnic difference in rilpivirine exposure was however considered not clinically relevant, since inter-individual variabilities of those intrinsic factors are larger than inter-ethnic ones; and the observed AUCinf in Japanese subjects was within the range of AUCtau associated with efficacy and safety in Phase 3 studies. This study results support the use of rilpivirine without dose modification specific to Japanese patients.

A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors.

OBJECTIVE: The objective was to determine the maximum tolerated dose and the dose-limiting toxicity of panobinostat (LBH589) when administered as a single agent to adult patients with advanced solid tumors or cutaneous T-cell lymphoma whose disease had progressed despite standard therapy or for whom no standard therapy existed. METHODS: Panobinostat was administered orally once daily on Monday, Wednesday, and Friday of each week. A total of 13 patients were treated with one of three initial doses: 10 mg (n = 3), 15 mg (n = 4), or 20 mg (n = 6). RESULTS: No dose-limiting toxicity was observed in 12 evaluable patients. The most frequently reported adverse events, regardless of whether they were related to the study drug, were diarrhea and nausea in 10 patients (76.9%). Thrombocytopenia was reported in 12 of 13 patients (92.3%). Five of 11 patients (45.4%) had stable disease. CONCLUSION: Panobinostat administered orally once daily on Monday, Wednesday, and Friday of each week was well tolerated at doses up to 20 mg in Japanese patients. Dose escalation did not proceed after exploration of the 20 mg dose due to emerging global clinical data at that time.

Phase I dose-escalating study of panobinostat (LBH589) administered intravenously to Japanese patients with advanced solid tumors.

Panobinostat (LBH589) is a potent pan-histone deacetylase inhibitor. As a result of promising preclinical data, Phase I and II clinical trials of intravenous and oral panobinostat have been conducted in patients with a wide variety of hematologic and solid tumors. This is the first report of a phase I study to evaluate intravenous panobinostat given on days 1 and 8 of a 21-day cycle in patients with solid tumors. The primary objective was to characterize the safety and tolerability of panobinostat by evaluating the occurrence of dose-limiting toxicity (DLT) and determining the maximum tolerated dose (MTD) in Japanese patients with advanced solid tumors. Secondary objectives included characterizing the pharmacokinetics and assessing antitumor activity. Fourteen patients were assigned to three dose levels (Cohort 1: 10 mg/m(2) [three patients], Cohort 2: 15 mg/m(2) [three patients], Cohort 3: 20 mg/m(2) [eight patients]), according to a standard "3 + 3" design. One patient who received 20 mg/m(2) had a DLT (grade 3 elevation of γ-glutamyl transpeptidase for >7 days). Thrombocytopenia was observed in all patients (grade 3 or 4 in 8), the severity of which was dependent on the dose and platelet count at baseline. The thrombocytopenia rapidly resolved within 8 days. Plasma panobinostat levels increased dose dependently, without clinically significant drug accumulation. Stable disease for ≥4 months was observed in six patients; however, there were no complete or partial responses. It is feasible to conclude that 20 mg/m(2) was the MTD and recommend as the starting dose for phase II clinical trials.

Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women.

PURPOSE: Letrozole is an orally active aromatase inhibitor for the treatment of breast cancer. The objectives of this study were to examine the pharmacokinetic profile of letrozole in Japanese subjects and to identify factors that influence variability in the pharmacokinetics of letrozole using population pharmacokinetic (PPK) analysis. METHODS: Twenty-five healthy postmenopausal Japanese women were enrolled in the study and received 2.5 mg letrozole once daily for 14 or 28 days. A PPK model was developed using NONMEM software. Age, body weight (WT), AST, ALT, total bilirubin, serum creatinine (CRE), and genotype of CYP2A6 were studied as covariates. Estrone, estrone sulfate, and estradiol in plasma were measured as pharmacodynamic markers. RESULTS: CYP2A6 genotype, CRE, and AST were significant covariates for apparent systemic clearance (CL/F), and WT was a significant covariate for apparent distribution volume (Vd/F). Population mean estimates of CL/F and Vd/F in subjects without CYP2A6 mutation were 1.03 × (CRE/0.70)(-1.27) × (AST/17.5)(-0.793) L/h and 94.2 × (WT/51.1)(1.12) L respectively. CL/F in subjects possessing 1 and 2 CYP2A6 mutation alleles were 84.3% and 44.8% of the value in the subjects without mutation respectively. Estrogen levels fell to below detection limits in most subjects after letrozole administration. Three mild and transient adverse events (upper respiratory tract inflammation, arthralgia, and vomiting) were reported in the study. CONCLUSIONS: CYP2A6 genotype largely influences CL/F of letrozole. Genetic polymorphism of CYP2A6 and body weight will be causes of ethnic difference in PK. However, dose adjustment is not necessary, because of the wide therapeutic range.

Phase I study of intravenous ASA404 (vadimezan) administered in combination with paclitaxel and carboplatin in Japanese patients with non-small cell lung cancer.

ASA404 (5,6-dimethylxanthenone-4-acetic acid, vadimezan), a flavone-8-acetic acid analogue, is a novel tumor-vascular disrupting agent. In this study, the safety and tolerability, pharmacokinetics and pharmacodynamics of ASA404 in combination with standard therapy of paclitaxel and carboplatin (P/C) were assessed. A total of 15 Japanese patients with stage IV advanced non-small cell lung cancer were enrolled and P/C plus ASA404 at three dose levels (600-1800 mg/m(2)) was administered every 3 weeks. Dose limiting toxicities were observed in two patients during Cycle 1 of ASA404 treatment (Grade 3 febrile neutropenia at ASA404 1200 mg/m(2) and Grade 3 QT prolongation at ASA404 1800 mg/m(2)) and the incidence of dose limiting toxicity was ≤1/3. The most frequently reported adverse events were injection site pain, peripheral sensory neuropathy, alopecia, neutropenia, nausea, anorexia and arthralgia, which were similar to those seen in previous Phase I/II studies. Pharmacokinetic analysis revealed the plasma area under the curve (AUC) of total ASA404 increased in a mostly dose-proportional manner within the dose range investigated. Administration of ASA404 raised plasma 5-hydroxyindole-3-acetic acid level dose-dependently by 116 and 204% after 1200 and 1800 mg/m(2) doses, respectively. Partial response was observed in four patients (27%), and seven patients (47%) exhibited stable disease. Overall, the safety and preliminary efficacy profiles were comparable to those seen in non-Japanese patients in previous Phase I and Phase II studies, and support the further evaluation of ASA404 (1800 mg/m(2)) in Phase III studies in combination with P/C in Japanese patients with advanced non-small cell lung cancer.

A Phase I/II study of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL.

Nilotinib is a second-generation BCR-ABL kinase inhibitor with improved potency and selectivity compared to imatinib. A Phase I/II dose-escalation study was designed to evaluate the efficacy, safety, and pharmacokinetics of nilotinib in Japanese patients with imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL). A total of 34 patients were evaluated in this analysis and had a median duration of drug exposure of 293 (range 13-615) days. All 6 CML-CP patients without complete hematologic response (CHR) at baseline rapidly achieved CHR. A major cytogenetic response was achieved in 94% of patients with CML-CP, including a complete cytogenetic response in 69%. A major molecular response was achieved by 56%. These responses were also observed in patients with CML in advanced stages and Ph+ ALL. Non-hematologic adverse events were mostly mild to moderate. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 50 and 28% of patients, respectively. Overall, the results of this study suggest that nilotinib induced significant responses in imatinib-resistant or -intolerant patients with CML-CP and CML in advanced stages and Ph+ ALL. The results of this study confirmed the efficacy and safety of nilotinib in Japanese patients.

A safety, pharmacokinetic and pharmacodynamic investigation of deferasirox (Exjade, ICL670) in patients with transfusion-dependent anemias and iron-overload: a Phase I study in Japan.

The pharmacokinetics (PK) and pharmacodynamics (PD) of the once-daily, oral ironchelating agent, deferasirox (Exjade, ICL670), have been evaluated further in a Phase I, openlabel, multicenter, dose-escalation study in Japanese patients with myelodysplastic syndromes, aplastic anemia, and other anemias. Deferasirox was initially administered as a single dose of 5 (n = 6), 10 (n = 7), 20 (n = 6) or 30 (n = 7) mg/(kg day) and then after 7 days seven daily doses were administered. Linear PK (C (max) and AUC) were observed at all doses after a single dose and at steady state, and dose-dependent iron excretion was observed. Pharmacokinetic/pharmacodynamic parameters were similar to those reported in a Caucasian beta-thalassemia cohort. Following the single- and multiple-dose phases, 21 of 26 patients progressed to a 3-year extension phase of the study, where dose reductions and increases [5-30 mg/(kg day)] were allowed following safety and efficacy assessments. In the interim, 1-year data show that deferasirox was well tolerated, with generally infrequent and mild adverse events. Reductions in serum ferritin levels were observed and a negative iron balance achieved at doses of 20-30 mg/(kg day). These data suggest that deferasirox has a stable and predictable PK/PD profile, irrespective of underlying disease or race, and a predictable and manageable safety profile suitable for chronic administration.