ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma.

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600 mutant cells1-3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.

Modeling Approach with Therapeutic Drug Monitoring Data to Describe Time Course of Clozapine Exposure and Positive and Negative Syndrome Scale Scores.

OBJECTIVE: The Positive and Negative Syndrome Scale (PANSS) is commonly used to assess the severity of the clinical symptoms of schizophrenia (SCZ). This study aimed to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model based on therapeutic drug monitoring (TDM) data to characterize the relationship between clozapine exposure and the PANSS scores in patients with SCZ. METHODS: TDM data for clozapine and PANSS scores from 45 patients with SCZ were included in this modeling analysis using NONMEM. Based on published data, intensive PK sampling data collected up to 12 hours postdose from 23 patients was incorporated into the PK data set to improve the fitting of absorption and disposition. For PD model development, the PANSS score was assessed at baseline, followed by 8 and 18 weeks after the initiation of clozapine dosing. Visual predictive check plots, the precision of parameter estimates, and decreases in the minimum objective function values were used for the model evaluation. RESULTS: A 2-compartment model with an absorption lag and a combined error model adequately described the PK of clozapine. The implementation of disease progression with placebo and drug effects improved the model's ability to describe the time course of the PANSS scores. In the final PK/PD model, Weibull and maximum effect (E max ) models were selected as disease progression models for the placebo and drug effect models, respectively. The model evaluation results supported the adequacy of the final model. CONCLUSIONS: A clozapine PK/PD model based on clinical settings adequately described the PANSS time course in patients with SCZ. These findings may aid the development of treatment strategies for patients with SCZ.

Early Bactericidal Activity of Delpazolid (LCB01-0371) in Patients with Pulmonary Tuberculosis.

Delpazolid, an oxazolidinone, has been studied in non-clinical studies of efficacy and toxicity and Phase 1 clinical studies. Delpazolid has in vitro activity against Gram-positive bacteria, including Mycobacterium tuberculosis. This study evaluated the bactericidal activity, safety, and pharmacokinetics of delpazolid in patients with pulmonary tuberculosis (TB). Seventy-nine subjects, aged 19 to 75 years with newly diagnosed smear-positive TB with no prior treatment for the current episode and no confirmed resistance to rifampin or isoniazid, were randomized to receive delpazolid 800 mg once a day (QD), 400 mg twice a day (BID), 800 mg BID or 1,200 mg QD or an active control of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) or linezolid 600 mg BID. The primary endpoint was the average daily reduction in log transformed bacterial load, assessed on 7H11 solid-media culture, from days 0 to 14. The average daily decline in log-CFU was 0.044 ± 0.016, 0.053 ± 0.017, 0.043 ± 0.016, and 0.019 ± 0.017, for the delpazolid 800 mg QD, 400 mg BID, 800 mg BID, and the 1,200 mg QD groups, respectively. The average daily decline in log-CFU was 0.192 ± 0.028 for the HRZE group and 0.154 ± 0.023 for the linezolid 600 mg BID group. Three serious adverse events (SAE) were reported, one each in the delpazolid 400 mg BID group (death due to worsening of TB at day 2), the HRZE group (hospitalization due to pleural effusion) and the linezolid group (hyperkalemia); none of the SAEs were assessed as related to study drugs. This study has been registered at ClinicalTrials.gov with registration number NCT02836483.

A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer.

Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m2) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m2. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017).

Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy.

BACKGROUND: Ambroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD. METHODS: ABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed. RESULTS: Enhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2-8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events. CONCLUSIONS: Long-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD.

Pharmacokinetic modeling analysis of cilostazol and its active metabolites (OPC-13015 and OPC-13213) after multiple oral doses of cilostazol in healthy Korean volunteers.

Cilostazol is a selective inhibitor of phosphodiesterase III (PDE III), which is prescribed for patients with peripheral arterial disease, especially intermittent claudication. The purpose of the study was to investigate the pharmacokinetic (PK) of cilostazol and its metabolites on the immediate (IR) formulation of cilostazol in healthy Korean male volunteers by population PK modeling analysis implemented using NONMEM software.A 2 × 2 crossover study comparing multiple oral doses of IR and SR formulations of cilostazol were conducted. Serial plasma concentrations of cilostazol and its active metabolites were used in this analysis.The PK was best depicted by one-compartment model, with absorption kinetics of cilostazol having mixed first- and zero-order kinetics with a time delay at the beginning of absorption. The introduction of interoccasion variabilities into zero-order (D1), first-order (Ka), and relative bioavailability (F1) significantly improved the model fit, and total body water (TBW) was identified as a significant covariate positively affecting the clearance of cilostazol. The model validation suggested that the model constructed in this study predicted the plasma concentration of cilostazol and its two active metabolites reasonably well.The PK model we developed explored the PK characteristics of cilostazol in Korean male subjects, and may be useful for identifying optimal individual dosing regimens of cilostazol.

Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of CTB-001, a Recently Developed Generic of Bivalirudin.

PURPOSE: CTB-001, a recently developed generic version of bivalirudin, an FDA-approved anticoagulant used for prophylaxis and treatment of cardiovascular diseases, has shown good efficacy and safety in clinical trials. We characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of CTB-001 by modeling and simulation analysis. METHODS: PK/PD data were collected from a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase 1 study conducted in 24 healthy Korean male subjects. PK/PD analysis was conducted sequentially by nonlinear mixed-effects modeling implemented in NONMEM®. Monte-Carlo simulations were conducted for PK, activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT). RESULTS: The CTB-101 PK was best described by a three-compartment linear model with a saturable binding peripheral compartment. All PD endpoints showed dose-response relationship, and their changes over time paralleled those of CTB-101 concentrations. A simple maximum effect model best described the aPTT, PT in INR, PT in seconds, and TT, whereas an inhibitory simple maximum effect model best described PT in percentages. The maximum duration of effect of CTB-001 on aPTT prolongation was 52.1 s. CONCLUSIONS: The modeling and simulation analysis well-characterized the PK and PD of CTB-001 in healthy Koreans, which will be valuable for identifying optimal dosing regimens of CBT-001.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Single-Dose Oral LCB01-0371, a Novel Oxazolidinone with Broad-Spectrum Activity, in Healthy Volunteers.

LCB01-0371 is a novel oxazolidinone with broad-spectrum activity against Gram-positive pathogens in both in vitro studies and animal infection models. The objectives of this study were to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics following single ascending doses. Single oral doses of 600 mg linezolid, a placebo, or LCB01-0371 of between 50 mg and 3,200 mg were tested in 69 healthy male subjects. Blood and urine were sampled, LCB01-0371 concentrations were measured, and the serum inhibitory and bactericidal titers of LCB01-0371 and linezolid were determined. LCB01-0371 was well tolerated up to 2,400 mg. The most common drug-related clinical and laboratory adverse events were nausea with or without vomiting, decreased neutrophil counts, and increased total bilirubin levels. The frequency of adverse events and drug-related adverse events was similar among the treatment groups. The systemic exposure was approximately dose proportional over the range of 50 mg to 800 mg, which includes the anticipated clinical dose. The mean clearance, renal clearance, and volume of distribution were significantly decreased at higher doses (above 800 mg). LCB01-0371 exhibited early bacteriostatic activity against all tested strains except for Streptococcus pneumoniae strains, and the potency of LCB01-0371 at 800 mg was similar to that of linezolid at the therapeutic dose (600 mg). However, LCB01-0371 had less bactericidal activity than linezolid. Taken together, LCB01-0371 was well tolerated, exhibited approximate dose proportionality within the anticipated clinically relevant dose range, and showed bacteriostatic and bactericidal activity comparable to that of linezolid. These results support the further clinical development of LCB01-0371. (This study has been registered at ClinicalTrials.gov under registration no. NCT01554995.).

Pharmacokinetic Equivalence of the High Dose Strength Fixed-Dose Combination Tablet of Gemigliptin/Metformin Sustained Release (SR) and Individual Component Gemigliptin and Metformin XR Tablets in Healthy Subjects.

BACKGROUND: In type 2 diabetes mellitus therapy, fixed-dose combination (FDC) can offer not only benefits in glucose control via the combined use of agents, but also increase patient compliance. The aim of this study was to assess the pharmacokinetic equivalence of the high dose of the FDC tablet (gemigliptin/metformin sustained release [SR] 50/1,000 mg) and a corresponding co-administered dose of individual tablets. METHODS: This study was randomized, open-label, single dose, two treatments, two-period, crossover study, which included 24 healthy subjects. Subjects received the FDC or individual tablets of gemigliptin (50 mg) and metformin XR (1,000 mg) in each period. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of the FDC tablet and co-administration of individual tablet for both gemigliptin and metformin were calculated. RESULTS: The GMRs (FDC tablets/co-administration; 90% CIs) for Cmax and AUClast of gemigliptin were 1.079 (0.986-1.180) and 1.047 (1.014-1.080), respectively. For metformin, the GMRs for Cmax, and AUClast were 1.038 (0.995-1.083) and 1.041 (0.997-1.088), respectively. The 90% CIs for GMRs of Cmax and AUClast for gemigliptin and metformin fell entirely within bounds of 0.800-1.250. Both administration of FDC tablet and co-administration of individual tablets were well tolerated. CONCLUSION: FDC tablet exhibited pharmacokinetic equivalence and comparable safety and tolerability to co-administration of corresponding doses of gemigliptin and metformin XR as individual tablets. Trial registry at ClinicalTrials.gov, NCT02056600.

Efficacy and Safety of a New 10% Intravenous Immunoglobulin Product in Patients with Primary Immune Thrombocytopenia (ITP).

BACKGROUND: In the current study, we aimed to investigate the efficacy and safety of intravenous immunoglobulin (IVIg)-SN 10%, a new 10% IVIg formulation, in adult patients with severe primary immune thrombocytopenia (ITP; platelet count < 20 × 109/L). METHODS: Patients diagnosed as primary ITP, aged 19 years old or more, and had a platelet count of < 20 × 109/L by screening complete blood cell count performed within 2 weeks of study commencement were eligible. Patients received IVIg-SN 10% at a dose of 1 g/kg/day for two consecutive days. Response was defined as the achievement of a platelet count of ≥ 50 × 109/L at day 8. RESULTS: Out of 81 eligible patients, 31 patients were newly diagnosed, 7 patients had persistent ITP, and 43 patients had chronic ITP. In intent-to-treat analysis, 61.3 patients (75.7%) achieved response and satisfied the pre-defined non-inferiority condition. Median time to response was 2 days and mean duration of maintaining response after the completion of IVIg therapy was 9.13 ± 8.40 days. Response rates were not found to be dependent on the phase of ITP or previous treatment for ITP. The drug was well tolerated and the frequency of mucocutaneous bleeding decreased during the study period. CONCLUSION: In summary, IVIg-SN 10% formulation was found to be safe and effective in adult ITP patients (Trial registry at ClinicalTrials.gov, NCT02063789).

A Phase I/IIa Study of DHP107, a Novel Oral Paclitaxel Formulation, in Patients with Advanced Solid Tumors or Gastric Cancer.

LESSONS LEARNED: Ideally, patients should have access to an oral formulation of paclitaxel, as well as an intravenous formulation, to allow development of regimens exploring alternate schedules and to avoid reactions to Cremophor EL (BASF Corp., Ludwigshafen, Germany, https://www.basf.com).DHP107 is a novel oral paclitaxel formulation that is a tolerable and feasible regimen for patients with gastric cancer, with data suggesting efficacy similar to that of intravenous paclitaxel. BACKGROUND: We evaluated the maximum tolerated dose (MTD) of DHP107, a novel oral paclitaxel formulation, and the efficacy and safety of the agent in patients with advanced solid tumors. PATIENTS AND METHODS: Phase I study: cohorts of 3-6 patients with advanced solid tumors received escalating DHP107 doses. Phase IIa study: patients with measurable advanced gastric cancer received DHP107, 200 mg/m2 b.i.d., on days 1, 8, and 15 every 4 weeks. Pharmacokinetics, safety, and efficacy were analyzed. RESULTS: Phase I: 17 patients received a dose-escalating regimen of DHP107, 150-250 mg/m2 b.i.d. Dose-limiting toxicities were neutropenia and febrile neutropenia. The MTD (recommended dose) for phase IIa was 200 mg/m2 b.i.d. Phase IIa: 11 patients with measurable advanced gastric cancer in whom first-line therapy failed received DHP107 (MTD). Three confirmed partial responses were observed. Median progression-free survival of gastric cancer patients (n = 16) treated at the MTD was 2.97 (95% confidence interval, 1.67-5.40) months (Fig. 1). The most frequent grade 3/4 adverse events were neutropenia (35.3%) and leukopenia (17.6%) at the MTD (phase I and IIa combined; n = 17). CONCLUSION: DHP107 showed good antitumor efficacy and was tolerable. The MTD (200 mg/m2 b.i.d.) is recommended for use in further studies comparing DHP107 with standard intravenous paclitaxel therapy. The Oncologist 2017;22:129-e8.

Emergency Department Visits Can Be Reduced by Having a Regular Doctor for Adults with Diabetes Mellitus: Secondary Analysis of 2013 Korea Health Panel Data.

Chronic diseases pose a major challenge to population health worldwide. Diabetes is a major chronic disease that is managed overwhelmingly in primary care. There is an increasing recognition of the role that primary care physicians play to achieve high-quality care for patients with diabetes. By analyzing 2013 Korean Health Panel data, the authors aimed to determine the current status of having a regular doctor (RD) for adults (aged 18 years or older) with diabetes. In addition, the association of having a RD with the experience of emergency department (ED) visits was determined in this study. Among adults with diabetes, those with RD accounted for 41.0%. The older the age group and the higher the Charlson comorbidity index score, the higher the percentage of adults with diabetes had RD. Even for those with RD, coordination of care was very poor (positive answer: 27.1%). After adjustment for confounding variables, those having (vs. not having) a RD (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.35-0.94), especially those whose RDs delivered good comprehensiveness of care (OR, 0.47; 95% CI, 0.26-0.84) or worked at a primary care clinic (OR, 0.43; 95% CI, 0.22-0.81), and those whose longitudinal relationship with a RD was 5 years or less (OR, 0.45; 95% CI, 0.22-0.91) were less likely to have ED visits within the last year. In conclusion, health care policies that promote having a RD who delivers high-quality primary care could decrease unnecessary ED visits by diabetic adults. This can partly reduce ED overcrowding in Korea.

Dynamic contrast-enhanced MRI for oncology drug development.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a promising tool for evaluating tumor vascularity, as it can provide vasculature-derived, functional, and quantitative parameters. To implement DCE-MRI parameters as biomarkers for monitoring the effect of antiangiogenic or vascular-disrupting treatment, two crucial elements of surrogate endpoint, ie, validation and qualification, should be satisfied. Although early studies have shown the accuracy and reliability of DCE-MRI parameters for evaluating treatment-driven vascular alterations, there have been an increasing number of studies demonstrating the limitations of DCE-MRI parameters as surrogate endpoints. Therefore, in order to improve the application of DCE-MRI parameters in drug development, it is necessary to establish a standardized evaluation method and to determine the correct therapeutics-oriented meaning of individual DCE-MRI parameter. In this regard, this article describes the biophysical background and data acquisition/analysis techniques of DCE-MRI while focusing on the validation and qualification issues. Specifically, the causes of disagreement and confusion encountered in the preclinical and clinical trials using DCE-MRI are presented in detail. Finally, considering these limitations, we present potential strategies to optimize implementation of DCE-MRI. J. Magn. Reson. Imaging 2016;44:251-264.

A phase II study of perioperative S-1 combined with weekly docetaxel in patients with locally advanced gastric carcinoma: clinical outcomes and clinicopathological and pharmacogenetic predictors for survival.

BACKGROUND: We conducted a phase II study to evaluate the efficacy and safety of perioperative S-1 plus docetaxel in locally advanced gastric cancer (LAGC) and to investigate the association between CYP2A6 genotype and outcome. METHODS: Patients with LAGC [clinical stage III-IV (M0) by the Japanese staging system] received three cycles of pre- and postoperative chemotherapy (S-1 40 mg/m(2) twice daily on days 1-14; intravenous docetaxel 35 mg/m(2) on days 1 and 8, every 3 weeks) followed by gastrectomy with D2 dissection. We also performed a pharmacokinetic and CYP2A6 genotyping study (*1, *4, *7, *9, *10) for S-1. RESULTS: From October 2006 to June 2008, 44 patients entered the study. 43 eligible patients completed preoperative chemotherapy and 40 completed postoperative chemotherapy. The most common G3/4 toxicities during pre- and postoperative chemotherapy were neutropenia, stomatitis, and abdominal pain. The clinical response rate by RECIST was 74.4 % (95 % CI, 61.4-87.4 %), and the R0 resection rate was 97.7 %. Clinical downstaging in T or N occurred in 41.9 % of patients. The 3-year progression-free survival (PFS) rate was 62.8 % and 5-year overall survival (OS) rate was 69.6 %. PFS and OS differed significantly according to clinical response, clinical downstaging, and CYP2A6 genotype. Patients with CYP2A6 variant/variant genotypes had a higher tegafur C max and worse survival than those with wild/wild or wild/variant genotypes. CONCLUSION: Perioperative S-1 plus docetaxel is active with a manageable toxicity in patients with LAGC receiving D2 surgery. Clinical tumor response, clinical downstaging, and CYP2A6 genotype may predict efficacy.

Prospective validation of a novel dosing scheme for intravenous busulfan in adult patients undergoing hematopoietic stem cell transplantation.

The objective of this study was to externally validate a new dosing scheme for busulfan. Thirty-seven adult patients who received busulfan as conditioning therapy for hematopoietic stem cell transplantation (HCT) participated in this prospective study. Patients were randomized to receive intravenous busulfan, either as the conventional dosage (3.2 mg/kg daily) or according to the new dosing scheme based on their actual body weight (ABW) (23×ABW(0.5) mg daily) targeting an area under the concentration-time curve (AUC) of 5924 µM·min. Pharmacokinetic profiles were collected using a limited sampling strategy by randomly selecting 2 time points at 3.5, 5, 6, 7 or 22 hours after starting busulfan administration. Using an established population pharmacokinetic model with NONMEM software, busulfan concentrations at the available blood sampling times were predicted from dosage history and demographic data. The predicted and measured concentrations were compared by a visual predictive check (VPC). Maximum a posteriori Bayesian estimators were estimated to calculate the predicted AUC (AUCPRED). The accuracy and precision of the AUCPRED values were assessed by calculating the mean prediction error (MPE) and root mean squared prediction error (RMSE), and compared with the target AUC of 5924 µM·min. VPC showed that most data fell within the 95% prediction interval. MPE and RMSE of AUCPRED were -5.8% and 20.6%, respectively, in the conventional dosing group and -2.1% and 14.0%, respectively, in the new dosing scheme group. These fi ndings demonstrated the validity of a new dosing scheme for daily intravenous busulfan used as conditioning therapy for HCT.

Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid.

OBJECTIVE: The effects of various polymorphisms in cytochrome P450 (CYP) enzyme and transporter genes on the pharmacokinetics (PK) of simvastatin were evaluated in healthy Korean men. METHODS: Plasma concentration data for simvastatin and simvastatin acid were pooled from four phase I studies comprising 133 participants. The polymorphisms CYP2D6*4, CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, CYP2C19*2, CYP2C19*3, CYP2A6*7, and CYP2A6*9; SLCO1B1 rs4149056, rs2306283, and rs4149015; ABCB1 rs1128503, rs2032582, and rs1045642; and ABCG2 rs2231142 were evaluated in each participant. Noncompartmental PK results were compared by genotype. RESULTS: CYP2D6*5 and CYP2D6*14 were found to be associated with a higher area under the curve (AUC) for simvastatin, whereas the AUC of simvastatin acid was significantly increased in patients with the SLCO1B1 rs4149056, ABCG2 rs2231142, and CYP2D6*41 allele variants. Patients with the CYP2D6*41 variant showed a higher peak serum concentration (Cmax) of both simvastatin and simvastatin acid. The SLCO1B1 rs4149056 and rs4149015 polymorphisms were associated with an increased AUC ratio (i.e. ratio of simvastatin acid to simvastatin), whereas the SLCO1B1 rs4149056 and CYP2D6*5 variants were related to a higher Cmax ratio. CONCLUSION: The CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, SLCO1B1 rs4149056 and rs4149015, and ABCG2 rs2231142 genetic polymorphisms are associated with the PK of both simvastatin and simvastatin acid. This could potentially be used as a basis for individualized simvastatin therapy by predicting the clinical outcomes of this treatment.

Therapeutic dosage assessment based on population pharmacokinetics of a novel single-dose transdermal donepezil patch in healthy volunteers.

PURPOSE: We performed population pharmacokinetic (PK) analysis of a novel transdermal donepezil patch in healthy subjects who participated in a phase I trial. We also studied the optimal dosage regimen with repeated patch application for achieving a therapeutic range using a PK simulation model. METHODS: This study used data from a randomized, single-dose escalation phase I clinical trial conducted in Korea. The population PK analysis was performed using NONMEM software, version 7.3. From the final PK model, we simulated repeat patch application results assuming various transdermal absorption rates. RESULTS: Based on the clinical trial data, novel donepezil patches with doses of 43.75 mg/12.5 cm(2), 87.5 mg/25 cm(2), and 175 mg/50 cm(2) were placed on each subject. A linear one-compartment, first-order elimination with sequential zero- and first-order absorption model best described the donepezil plasma concentrations after patch application. Simulated results on the basis of the PK model showed that repeat application of the patches of 87.5 mg/25 cm(2) and 175 mg/50 cm(2) every 72 h would cover the therapeutic range of donepezil and reach steady-state faster with fewer fluctuations in concentration compared to typical oral administrations. CONCLUSION: A linear one-compartment with sequential zero- and first-order absorption model was effective for describing the PKs of donepezil after application of patch. Based on this analysis, 87.5 mg/25 cm(2) or 175 mg/50 cm(2) patch application every 72 h is expected to achieve the desired plasma concentration of donepezil.

Population pharmacokinetic analysis of simvastatin and its active metabolite with the characterization of atypical complex absorption kinetics.

PURPOSE: The pharmacokinetics of simvastatin is complex with multiple peaks in the absorption phase, which cannot be adequately described by a conventional first order absorption model. The biotransformation of simvastatin into simvastatin acid, an active metabolite, is reversible. This study evaluated the pharmacokinetics of simvastatin and simvastatin acid, focusing on the absorption kinetics. METHODS: Data were collected from three bioequivalence studies, in which subjects were administered 60 mg simvastatin, and from one crossover study, in which subjects were administered two doses randomly selected from 10, 20, 30, 40 to 80 mg simvastatin with washout period. The pharmacokinetics of simvastatin was assessed in 133 healthy males. Plasma concentrations of simvastatin and simvastatin acid were measured in 2,182 and 2,130 samples, respectively, and the pharmacokinetic data were analyzed using NONMEM. RESULTS: The time course of changes in the plasma simvastatin concentration was best described by a two-compartment linear model with three parallel absorption processes, each of which consisted of mixed zero-and first order absorption. Additions of inter-occasional variability to the absorption parameters significantly improved the model's fit. The disposition parameter estimates were significantly different when different absorption models were applied, indicating the importance of the appropriate absorption modeling. Pharmacokinetic modeling preferred the inter-conversion between simvastatin and simvastatin acid. CONCLUSION: A pharmacokinetic model describing the complex, multiple peak, absorption kinetics of simvastatin was formulated using three parallel, mixed zero and first-order absorptions. This type of absorption model may be applicable to other drugs that show irregular, multiple-peak concentrations during their absorption phase.

Effects of food on the pharmacokinetics of gemigliptin/metformin sustained-release 50/1,000 mg (25/500 mg x 2 tablets) fixeddose combination tablet in healthy male volunteers.

OBJECTIVES: For patient convenience, a gemigliptin/metformin sustainedrelease fixed-dose combination (FDC) tablet was developed. This study was conducted to investigate the effects of food on the pharmacokinetic (PK) profile of the FDC tablets. MATERIALS AND METHODS: This was an open-label, randomized, single dose, 2-period, 2-sequence crossover study in 24 healthy male volunteers. The FDC tablets (25/500 mg × 2 tablets) were administered in high-fat fed and fasted states on separate occasions, and each subject was randomly allocated to each sequence with a 7-day washout period. PK blood samplings were conducted from predose to 48 hours after dosing. Tolerability assessments were performed throughout the study. RESULTS: Nine adverse events (AEs) of mild intensity were reported from 8 subjects after study drug administration, and the AE frequency was similar between treatments. No serious AEs were reported. The PK parameters of gemigliptin and metformin were compared between fasting and fed states. For gemigliptin, the geometric mean ratios (GMRs) (fed : fasted state) of the Cmax and AUClast were 0.886 (90% confidence interval (CI) 0.781 - 1.006) and 1.021 (90% CI 0.949 - 1.099), respectively. For metformin, the GMRs of the Cmax and AUClast were 0.811 (90% CI 0.712 - 0.923) and 1.144 (90% CI 1.013 - 1.291), respectively. A prolonged tmax for metformin was observed. These results are similar to the effects of food on each component. CONCLUSION: The FDC tablet may have a similar PK profile as that of individual drugs and is generally tolerable when administered with food. These results indicate that the FDC tablet can be administered in the same dosing regimen as each component, especially that of metformin sustained-release.

Pharmacokinetic and Pharmacodynamic Modeling Analysis of Delpazolid (LCB01-0371) in Adult Patients with Pulmonary Tuberculosis.

Delpazolid (LCB01-0371) is a novel oxazolidinone derivative with a good safety profile for treating gram-positive pathogenic infections such as Mycobacterium abscessus, a highly pathogenic drug-resistant Mycobacterium. In this study, we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of delpazolid after 14 days of multiple oral administration, using data from adult patients with pulmonary tuberculosis. 800 mg once a day, 400 mg twice a day, 800 mg twice a day, and 1200 mg once a day delpazolid for 14 days were tested in 63 patients with pulmonary tuberculosis. For PK blood collection, inpatient and outpatient scheduling were separately implemented. Plasma concentrations of delpazolid were measured at visits 2, 4, 6, and 8 in outpatients, and four sparse blood samples were measured in inpatients. PD models were sequentially fitted using individual PK parameter estimates obtained from PK compartmental models. For PK modeling, 180 plasma concentrations of delpazolid from 56 patients were included. A two-compartment mixed first- and zero-order absorption model best described the time course of plasma concentration. For the PD model, 448 bacterial titer data from 60 patients were used. The time course of bacterial titers (log10 CFU/mL) was described by a model that consists of the growth and killing rate of bacteria with the sigmoid Emax model. The PK-PD simulation suggested that the bacterial titers are the lowest on the 800 mg bid regimen among the four, consistent with observed data, as all regimens substantially decrease. In the dose-response relationship, the effectiveness of delpazolid was suggested.