First-in-human study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors.

Preclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n = 3; other, n = 8) received IM156 100 to 1,200 mg either QOD or QD. There were no DLTs. However, 1,200 mg QD was not well tolerated due to nausea; 800 mg QD was determined as the RP2D. The most frequent treatment-related AEs (TRAEs) were nausea (n = 15; 68%), diarrhea (n = 10; 46%), emesis (n = 9; 41%), fatigue (n = 4; 18%) and abdominal pain, constipation, and blood lactate increased (n = 2 each; 9%). Grade 3 nausea (n = 3; 14%) was the only grade ≥ 3 TRAE. Plasma exposures increased dose proportionally; mean Day 27 area under the curve (AUC0-24) values were higher following QD administration compared to the respective QOD regimen. Stable disease (SD), observed in 7 (32%) patients (confirmed in 2 [9%]), was the best response. To our knowledge, this is the first phase 1 study of an OXPHOS inhibitor that established a RP2D for further clinical development in cancer. Observed AEs of IM156 were manageable and SD was the best response.

Potency and plasma protein binding of drugs in vitro-a potentially misleading pair for predicting in vivo efficacious concentrations in humans.

In drug discovery or preclinical stages of development, potency parameters such as IC50, K i, or K d in vitro have been routinely used to predict the parameters of efficacious exposure (AUC, C min, etc.) in humans. However, to our knowledge, the fundamental assumption that the potency in vitro is correlated with the efficacious concentration in vivo in humans has not been investigated extensively. Thus, the present review examined this assumption by comparing a wide range of published pharmacokinetic (PK) and potency data. If the drug potency in vitro and its in vivo effectiveness in humans are well correlated, the steady-state average unbound concentrations in humans [C u_ss.avg = f u·F·Dose/(CL·τ) = f u·AUCss/τ] after treatment with approved dosage regimens should be higher than, or at least comparable to, the potency parameters assessed in vitro. We reviewed the ratios of C u_ss.avg/potency in vitro for a total of 54 drug entities (13 major therapeutic classes) using the dosage, PK, and in vitro potency reported in the published literature. For 54 drugs, the C u_ss.avg/in vitro potency ratios were < 1 for 38 (69%) and < 0.1 for 22 (34%) drugs. When the ratios were plotted against f u (unbound fraction), "ratio < 1" was predominant for drugs with high protein binding (90% of drugs with f u ≤ 5%; i.e., 28 of 31 drugs). Thus, predicting the in vivo efficacious unbound concentrations in humans using only in vitro potency data and f u should be avoided, especially for molecules with high protein binding.

Evaluation of Omeprazole Limited Sampling Strategies to Estimate Constitutive Cytochrome P450 2C19 Activity in Healthy Adults.

BACKGROUND: Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity. METHODS: Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile. RESULTS: Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r, range: 0.14-0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r (range: 0.02-0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers. CONCLUSIONS: Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.

Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans.

It was recently reported that the Cmax and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect racial differences in rosuvastatin exposure. In the telmisartan-rosuvastatin case, simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without telmisartan) ratios were 1.92 and 1.14, respectively, and the Tmax changed from 3.35 h to 1.40 h with coadministration of telmisartan, which were consistent with the aforementioned report (CmaxI/Cmax: 2.01, AUCI/AUC:1.18, Tmax: 5 h → 0.75 h). In the next case of cyclosporine-rosuvastatin, the simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without cyclosporine) ratios were 3.29 and 1.30, respectively. The decrease in the CLint,BCRP,intestine of rosuvastatin by telmisartan and cyclosporine in the PBPK model was pivotal to reproducing this finding in Simcyp. Our PBPK model demonstrated that the major causes of increase in rosuvastatin exposure are mediated by intestinal BCRP (rosuvastatin-telmisartan interaction) or by both of BCRP and OATP1B1/3 (rosuvastatin-cyclosporine interaction).

Bortezomib pharmacokinetics in tumor response and peripheral neuropathy in multiple myeloma patients receiving bortezomib-containing therapy.

The usefulness of pharmacokinetics of bortezomib for multiple myeloma (MM) with respect to the maximum response to bortezomib and bortezomib-induced peripheral neuropathy (BIPN) development was studied. Maximum response to subcutaneous bortezomib therapy and BIPN occurrence for the first 12 weeks of treatment in 35 MM patients treated by bortezomib-dexamethasone (VD) and bortezomib-melphalan-prednisone (VMP) were evaluated. On day 1 of cycle 1, seven whole-blood samples were collected for 3 h after dosing completion to obtain the maximum plasma concentration and area under the time-concentration curve during 3 h postdose (AUC0-3) in each patient. A total of 35 patients with complete data were analyzed and the overall response rate was 91.4%. Complete response (CR) was observed in 42.9% patients. The maximum plasma concentration (Cmax) was significant for the CR rate in two different models [full model: odds ratio (OR)=1.092; P=0.038, final model: OR=1.081; P=0.038]. In addition, Cmax was associated with a progression-free survival advantage. Overall, 48.6% of patients developed BIPN including peripheral sensory neuropathy and neuralgia. The VMP-treated patients had a higher risk compared with the VD-treated patients (OR=21.662; P=0.029). Cmax had a tendency to affect the occurrence of BIPN (≥grade 2) (OR=1.064; P=0.092). In real-world clinical practice using bortezomib for MM patients, Cmax among pharmacokinetic factors significantly affected the achievement of CR. The VMP-treated patients showed vulnerability to BIPN, suggesting the necessity for more careful monitoring.

Retracted: Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans.

'Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans' by Soo Hyeon Bae, Wan-Su Park, Seunghoon Han, Gab-jin Park, Jongtae Lee, Taegon Hong, Sangil Jeon and Dong-Seok Yim The above article, published online on 06 February 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief, K. Sandy Pang, and John Wiley & Sons, Ltd. The authors retracted the paper due to errors associated with use of log D vs. log P of telmisartan as inputs of the PBPK model. The authors concluded that there are too many changes in the article to be resolved by an Erratum, and had requested a retraction. Reference Bae, S. H., Park, W.-S., Han, S., Park, G., Lee, J., Hong, T., Jeon, S., and Yim, D.-S. (2016) Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans. Biopharm. Drug Dispos., doi: 10.1002/bdd.2060.

Therapeutic drug monitoring and safety of intravenous voriconazole formulated with sulfobutylether ß-cyclodextrin in haematological patients with renal impairment.

Because of concerns about accumulation of cyclodextrin, oral voriconazole is recommended for patients with renal impairment. However, intravenous voriconazole may occasionally be imperative in critically ill patients with life-threatening invasive aspergillosis. We investigated the clinical effects of intravenous voriconazole formulated with sulfobutylether ß-cyclodextrin (SBECD) in patients with renal impairment. A prospective observational study was conducted on 25 adult patients with haematological malignancies who were treated with intravenous voriconazole for invasive aspergillosis. Among them, seven patients had a baseline creatinine clearance (CrCl) <50 ml min(-1) (case). Although voriconazole trough concentrations were significantly higher in cases (5.84 mg l(-1) ) than controls (2.28 mg l(-1) ), the proportion of concentrations within the target range did not differ between two groups (4/7 and 12/18, respectively; P = 0.658). The frequency of severe adverse events in cases (3/7) was comparable to that of controls (4/18; P = 0.355). No patients showed significant deterioration in renal function after the voriconazole therapy even in patients with renal impairment. Although CrCl <50 ml min(-1) was associated with higher voriconazole concentrations, its clinical impact remains unclear. SBECD-formulated intravenous voriconazole did not lead to a higher incidence of severe adverse events including nephrotoxicity in haematological patients with CrCl <50 ml min(-1) .

Validation of a liquid chromatography-triple quadrupole mass spectrometric method for the determination of 5-nitro-5'-hydroxy-indirubin-3'-oxime (AGM-130) in human plasma and its application to microdose clinical trial.

A liquid chromatography-triple quadrupole mass spectrometric (LC-MS/MS) method was developed and validated for the determination of 5-nitro-5'-hydroxy-indirubin-3'-oxime (AGM-130) in human plasma to support a microdose clinical trial. The method consisted of a liquid-liquid extraction for sample preparation and LC-MS/MS analysis in the positive ion mode using TurboIonSpray(TM) for analysis. d3 -AGM-130 was used as the internal standard. A linear regression (weighted 1/concentration) was used to fit calibration curves over the concentration range of 10-2000 pg/mL for AGM-130. There were no endogenous interference components in the blank human plasma tested. The accuracy at the lower limit of quantitation was 96.6% with a precision (coefficient of variation, CV) of 4.4%. For quality control samples at 30, 160 and 1600 pg/mL, the between run CV was ≤5.0 %. Between-run accuracy ranged from 98.1 to 101.0%. AGM-130 was stable in 50% acetonitrile for 168 h at 4°C and 6 h at room temperature. AGM-130 was also stable in human plasma at room temperature for 6 h and through three freeze-thaw cycles. The variability of selected samples for the incurred sample reanalysis was ≤12.7% when compared with the original sample concentrations. This validated LC-MS/MS method for determination of AGM-130 was used to support a phase 0 microdose clinical trial.

Simulation of PET scan timings for receptor occupancy studies of CNS drugs: a simple fixed-time design performed as well as scattered time point designs.

PURPOSE: This study aimed to determine the effect of PET scan timings on the reliability of occupancy parameter estimates and to identify the scan timing design that gives the most reliable occupancy parameter estimates. METHODS: We compared the performance of designs with various sets of sampling time points using the stochastic simulation and estimation method in Perl-speaks-NONMEM. Biases, relative standard errors, relative estimation errors, and root mean square errors were used to compare the performance of designs. RESULTS: Unlike the results of a previous report, we found that rather complicated designs where each subject or group of subjects are allocated to different scan timings were not superior to the simple, conventional fixed-time designs regardless of whether effect compartment or receptor binding models were used. CONCLUSIONS: We conclude that the conventional fixed-time designs that have been used so far may give robust PD parameter estimates for occupancy data obtained from human PET studies of CNS drugs.

SAFETY OF A CRM197-CONJUGATED HAEMOPHILUS INFLUENZAE TYPE B VACCINE IN KOREAN CHILDREN.

Haemophilus influenzae type b (Hib) is a major cause of meningitis and pneumonia with high morbidity and mortality rates in young children. The introduction of effective and well-tolerated conjugate Hib vaccines, has nearly eradicated this disease in many countries. We investigated the safety of the Hib PRP-CRM197 vaccine in a multi-center post-marketing surveillance (PMS) study. Korean children (N = 764) aged 1-33 months were enrolled when receiving a routine primary immunization or a booster vaccine with Hib PRP-CRM197 and solicited and unsolicited adverse events (AEs) were recorded using a diary card for 7 and 28 days after each vaccination, respectively. In this study, AEs were reported by 66% of subjects but were generally mild, with 42% of subjects reporting solicited AEs and 46% reporting unsolicited AEs. Among the unsolicited AEs, 98% were determined to be unrelated to the study vaccine. The studied Hib PRP-CRM197 vaccine was well tolerated by the study group and found to have a similar safety profile to that reported in other clinical studies. This vaccine is suitable for routine immunization against Hib disease among Korean children. AEs due to this vaccine will continue to be monitored.

Population pharmacokinetic analysis of piperacillin in burn patients.

Piperacillin in combination with tazobactam, a ß-lactamase inhibitor, is a commonly used intravenous antibiotic for the empirical treatment of infection in intensive care patients, including burn patients. The purpose of this study was to develop a population pharmacokinetic (PK) model for piperacillin in burn patients and to predict the probability of target attainment (PTA) using MICs and concentrations simulated from the PK model. Fifty burn patients treated with piperacillin-tazobactam were enrolled. Piperacillin-tazobactam was administered via infusion for approximately 30 min at a dose of 4.5 g (4 g piperacillin and 0.5 g tazobactam) every 8 h. Blood samples were collected just prior to and at 1, 2, 3, 4, and 6 h after the end of the infusion at steady state. The population PK model of piperacillin was developed using NONMEM. A two-compartment first-order elimination PK model was finally chosen. The covariates included were creatinine clearance (CLCR), day after burn injury (DAI), and sepsis. The final PK parameters were clearance (liters/h) (equal to 16.6 × [CLCR/132] + DAI × [-0.0874]), central volume (liters) (equal to 25.3 + 14.8 × sepsis [0 for the absence or 1 for the presence of sepsis]), peripheral volume (liters) (equal to 16.1), and intercompartmental clearance (liters/h) (equal to 0.636). The clearance and volume of piperacillin were higher than those reported in patients without burns, and the terminal half-life and PTA decreased with the increased CLCR. Our PK model suggests that higher daily doses or longer durations of infusion of piperacillin should be considered, especially for burn patients with a CLCR of ≥ 160 ml/min.

Modeling of the parathyroid hormone response after calcium intake in healthy subjects.

Plasma ionized calcium (Ca(2+)) concentrations are tightly regulated in the body and maintained within a narrow range; thus it is challenging to quantify calcium absorption under normal physiologic conditions. This study aimed to develop a mechanistic model for the parathyroid hormone (PTH) response after calcium intake and indirectly compare the difference in oral calcium absorption from PTH responses. PTH and Ca(2+) concentrations were collected from 24 subjects from a clinical trial performed to evaluate the safety and calcium absorption of Geumjin Thermal Water in comparison with calcium carbonate tablets in healthy subjects. Indirect response models (NONMEM Ver. 7.2.0) were fitted to observed Ca(2+) and PTH data, respectively, in a manner that absorbed but unobserved Ca(2+) inhibits the secretion of PTH. Without notable changes in Ca(2+) levels, PTH responses were modeled and used as a marker for the extent of calcium absorption.

Population pharmacokinetic analysis of colistin in burn patients.

Colistin is increasingly used as a salvage therapy for nosocomial infections caused by multidrug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. However, the available pharmacokinetic (PK) data for colistin are limited to guide dosing. The aim of this study was to develop a population PK model of colistin and to identify the optimal dosage regimens for burn patients. Fifty patients with burns ranging from 4% to 85% of total body surface area who had been treated with colistimethate sodium (CMS) were studied. CMS, which is hydrolyzed in vivo to an active metabolite, was intravenously administered every 12 h. Blood samples were collected at 0, 1, 2, 4, 6, and 8 h after more than five infusions to measure the colistin concentration using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. The population PK model was developed using nonlinear mixed effect modeling (NONMEM, v. 6.2). A one-compartment linear PK model for colistin best described the data. The covariates included in the final model were creatinine clearance for the relative fraction of CMS converted into colistin and the presence of edema for the turnover rate constant of CMS converted into colistin. A steady-state 24-h area under the concentration-time curve was simulated from 1,000 virtual patients receiving 150 mg colistin base activity every 12 h using the final model. Relative to previous studies with critically ill patients, the elimination half-life of colistin (6.6 h) was much shorter, and continuous renal replacement therapy was not a significant covariate for any PK parameters.

Population pharmacokinetic analysis of fluconazole to predict therapeutic outcome in burn patients with Candida infection.

The pharmacokinetic (PK) property of fluconazole might be significantly altered in major burn patients by medical interventions and physiologic changes. In this study, our aims were to investigate fluconazole PK in burn patients using a population approach and to recommend the optimal fluconazole regimen based upon the predicted therapeutic outcome. At steady state, blood samples for PK analysis were obtained from 60 burn patients receiving between 100 and ~400 mg fluconazole daily. A mixed-effect modeling was performed and the therapeutic outcome of antifungal therapy was predicted for 10,000 virtual patients using NONMEM (version 7.2). MIC values were sampled from the MIC distribution at the study site. An area under the free drug concentration-time curve (fAUC)/MIC measurement of >25 h was used as the criterion for therapeutic success. When the same dose was given, the plasma concentration of fluconazole was predicted to be lower in burn patients compared to the nonburn population because of the large PK parameter (clearance, volume of distribution) estimates and continuous renal replacement therapy (CRRT). This tendency was particularly predominant when the patients were within 30 postburn days. Based upon our findings, 400 mg/day fluconazole is recommended to obtain therapeutic successes in major burn patients.

Saturable human neopterin response to interferon-α assessed by a pharmacokinetic-pharmacodynamic model.

BACKGROUND: In this study, we developed a pharmacokinetic (PK)- pharmacodynamic (PD) model of a new sustained release formulation of interferon-α-2a (SR-IFN-α) using the blood concentration of IFN-α and neopterin in order to quantify the magnitude and saturation of neopterin production over time in healthy volunteers. The SR-IFN-α in this study is a solid microparticular formulation manufactured by spray drying of a feeding solution containing IFN-α, a biocompatible polymer (polyethylene glycol) and sodium hyaluronate. METHODS: The full PK and PD (neopterin concentration) datasets from 24 healthy subjects obtained after single doses of 9, 18, 27 and 36 MIU of subcutaneous SR-IFN-α were used to build the mixed-effect model using NONMEM (version 7.2) with the GFORTRAN compiler. RESULTS: A one-compartment model with first-order elimination and a mixture of zero- and first-order absorption was chosen to describe the PK of SR-IFN-α. The time-concentration profile of neopterin, the PD marker, was described by a turnover model combined with a single transit compartment. The saturable pattern of the neopterin response blurring the dose-response relationship of SR-IFN-α was addressed by introducing the concept of the EC50 increasing over time. CONCLUSIONS: The PK-PD model of SR-IFN-α developed in this study has presented a quantitative tool to assess the time-course of a saturable neopterin response in humans.

Phase II trial of capecitabine and everolimus (RAD001) combination in refractory gastric cancer patients.

BACKGROUND: The aim of this study was to assess the efficacy and safety of combination regimen of capecitabine plus everolimus in patients with refractory gastric cancer who have failed to at least two cytotoxic regimens. METHODS: Patients received capecitabine 650 mg/m(2) twice daily (D1-14) and everolimus 5 mg twice daily (D1-21) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint of the study was overall response (partial or complete response) and the secondary endpoints were progression-free survival (time between registration and disease progression or death) and overall survival. Pharmacokinetic analysis was also performed. Patients who have failed to at least two cytotoxic regimens were enrolled. RESULTS: Between March 2010 and June 2012, 47 patients were enrolled. 33 patients (70.2%) had received more than three previous regimens prior to enrolment. Among 43 evaluable patients for treatment response, 5 patients achieved confirmed partial response and 18 patients showed stable disease, resulting in an overall response rate (ORR) of 10.6% (95% C.I.: 1.8-19.4%) and disease control rate of 48.9% (95% C.I.:34.6-63.2%). At a median follow-up of 106 weeks (range, 21-141 weeks), the median progression-free survival and overall survival were 11.0 weeks (95% C.I.: 5.7-16.3 weeks) and 21.0 weeks (95% C.I.: 14.3-27.7 weeks), respectively. Grade 3 nausea, diarrhea and stomatitis occurred in two, three and three patients, respectively. Elevated liver enzyme was observed in 21 patients and no patient had pulmonary fibrosis. CONCLUSIONS: The combination of capecitabine 650 mg/m(2) twice daily and everolimus 5 mg twice daily was found to be effective in a small subset of GC patients who were heavily pre-treated.

A phase I study of everolimus and CHOP in newly diagnosed peripheral T-cell lymphomas.

BACKGROUND: We performed a phase I study to determine the dose and safety of everolimus as a combination chemotherapy in peripheral T-cell lymphoma (PTCL). METHODS: Four dose levels (2.5 to 10 mg) of everolimus from days 1 to 14 with CHOP (750 mg/m(2) cyclophosphamide, 50 mg/m(2) doxorubicin, and 1.4 mg/m(2) (maximum 2 mg) vincristine on day 1, and 100 mg/day prednisone on days 1 to 5) every 21 days were planned. RESULTS: Fifteen patients newly diagnosed with stage III/IV PTCL were enrolled. One of 6 patients at dose level 2 (5 mg everolimus) had grade 3 hepatotoxicity and 3 of 6 patients at level 3 (7.5 mg everolimus) had grade 4 hematologic toxicities (two grade 4 thrombocytopenia and one grade 4 neutropenia with fever lasting more than 3 days). The recommended dose of everolimus for combination was 5 mg. There were no differences in steady state trough concentrations of everolimus between cycles 1 and 2 for all three dose levels. All evaluable patients achieved response (8 complete and 6 partial). CONCLUSIONS: Everolimus (5 mg) can be safely combined with CHOP leading to a feasible and effective regimen for PTCL. The subsequent phase II is now in progress.

Pharmacokinetic-pharmacodynamic model of fimasartan applied to predict the influence of a high fat diet on its blood pressure-lowering effect in healthy subjects.

PURPOSE: Fimasartan is a non-peptide angiotensin II receptor antagonist which selectively blocks the AT(1) receptor. The aim of our study was to perform a population pharmacokinetic-pharmacodynamic (PK-PD) analysis of fimasartan to evaluate the effect of food on the mechanistic PK-PD relationship. METHODS: This was a food-drug interaction single-center study involving 24 healthy subjects that was designed as a randomized, open-label, single-dosing, two-way crossover trial. Extensive PK data was obtained on blood samples collected at 0, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, and 24 h post-dosing and five systolic/diastolic blood pressure (BP) measurements made at 0, 4, 8, 12 and 24 h post-dosing and used to construct a mixed effect model (NONMEM, ver. 6.2). RESULTS: A two-compartment linear PK model with zero-order (fasted) or Weibull (fed with high-fat diet) absorption best described the PK of fimasartan. Relative bioavailability decreased by 37 % when the subjects were given a high-fat diet. CONCLUSIONS: The turnover PK-PD model combined with pre-defined cosine function for circadian rhythm described the BP changes measured within 24 h after dosing better than the effect compartment or transduction models. To predict the influence of a high-fat diet on the blood pressure-lowering effect of fimasartan in healthy subjects, we simulated changes in BP when fimasartan was given daily for 30 days. The overlapping pattern of simulated BP curves in the fasted versus fed group demonstrated that a high-fat diet would not cause a clinically significant reduction in the BP-lowering effect of fimasartan, despite a significant reduction in bioavailability.

Phase 1 trial of S-1 in combination with sorafenib for patients with advanced hepatocellular carcinoma.

PURPOSE: Sorafenib is a multi-kinase inhibitor, which was approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). We conducted a phase 1 study of sorafenib plus S-1 in patients with advanced HCC. EXPERIMENTAL DESIGN: We designed to escalate S-1 at 4 different dose levels with fixed dose of sorafenib. Four dose levels were as follows: level 1, D1-14 S-1 50 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 2, D1-14 S-1 60 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 3,, D1-14 S-1 70 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 4, D1-14 S-1 80 mg/m(2)/day + D1-21 sorafenib 400 mg bid. The treatment was repeated every 3 weeks. RESULTS: From August 2009 to July 2010, 20 patients with advanced HCC were enrolled. The median age was 48 years (range, 29-74). Eighteen (90%) patients had hepatitis B viral infection and 19 (95%) patients were rated as Child-Pugh class A. The dose-limiting toxicities were grade 4 infection and thrombocytopenia. After a median follow-up duration of 8.6 months (range, 3.7-14.2 months), median PFS was 3.9 months (95% CI, 0.8-7.0 months) and median OS was 10.4 months (95% CI, 0-22.4 months). In pharmacokinetic analysis, there was no statistically significant drug interaction between sorafenib and S-1. CONCLUSIONS: The combination of sorafenib and S-1 showed tolerable toxicity profile and modest clinical efficacy in patients with advanced HCC. The recommended dose of sorafenib and S-1 was 400 mg twice daily and 40 mg/m(2) twice daily, respectively.

Mixed-effect circadian rhythm model for human erythrocyte acetylcholinesterase activity--application to the proof of concept of cholinesterase inhibition by acorn extract in healthy subjects with galantamine as positive control.

PURPOSE: The aim of this study was to develop a non-linear mixed effect circadian rhythm model of acetylcholinesterase (AChE) activity variation and to evaluate the inhibitory effect of acorn extract (2 g) and galantamine (16 mg), used as positive control, on human AChE in red blood cells (RBC). METHODS: This was an open-label, randomized, three-way crossover study involving 12 healthy subjects who received one of the treatments in each study period: no treatment, acorn extract, and galantamine. RBC AChE activity was measured in peripheral blood samples collected at 0 (pre-dose), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16 and 24 h post-dose administration. Non-linear mixed effect modeling was performed using NONMEM (ver. 7.0). RESULTS: The circadian variation of AChE activity was best described using two mixed effect cosine functions, with periods of 24 and 12 h, respectively. When the inhibitory effect terms were added, the model was significantly improved for both acorn extract and galantamine. In terms of the effect, a 2-g single dose of acorn extract showed AChE inhibition (about 5%) similar to that of a 16-mg single dose of galantamine, in the first 24 h after administration. CONCLUSIONS: Based on the very pronounced inter- and intra-day variation in AChE activity in RBC, we conclude that the model-based approach is essential for the proof of concept and quantitation of AChE inhibition in human subjects.