Population Pharmacokinetics and Pharmacodynamics of Teicoplanin and C-Reactive Protein in Hospitalized Patients With Gram-Positive Infections.

Teicoplanin is an antibiotic agent used for the treatment of Gram-positive infections. The clinical benefit of teicoplanin is associated with its blood concentrations, but the optimal dosing regimen is not yet known. To explore the optimal individual dosing regimen, we performed a population pharmacokinetic (PK) and pharmacodynamic (PD) analysis targeting a large-scale population, including patients with a wide range of ages, body weights, and renal functions. The PK of teicoplanin was described with a 2-compartment model, and the PD of C-reactive protein (CRP) concentrations was described with a turnover maximum inhibition model. The elimination half-life of teicoplanin calculated from the final estimated parameters was 169 hours, and renal function was a significant covariate of teicoplanin clearance. The teicoplanin concentration producing 50% of the maximum inhibition of CRP production was estimated to be 2.66 mg/L. The minimum concentration of teicoplanin in patients with higher loading doses (15 mg/kg) reached the target range (15-30 mg/L) with a probability of >50% in the dosing simulation. We described the influence of body size, body composition, and renal function on the PK of teicoplanin. The population PKPD model of teicoplanin and CRP in this study should provide useful information for development of a dosing strategy including the sequential clinical benefit of teicoplanin.

Impact of physical activity and sedentary time on glycated hemoglobin levels and body composition: Cross-sectional study using outpatient clinical data of Japanese patients with type 2 diabetes.

AIMS/INTRODUCTION: This study examined the association among sedentary time (ST), physical activity (PA), glycated hemoglobin and body composition in Japanese type 2 diabetes patients. MATERIALS AND METHODS: Patients with type 2 diabetes who visited the outpatient clinic at Kawasaki Medical School Hospital, Okayama, Japan, comprised the study's participants. Self-administered International Physical Activity Questionnaire short forms were obtained and analyzed for 1,053 patients, including 158 patients for whom waist circumference and visceral fat accumulation were measured. From the questionnaire, three categorical data (low, moderate, high) and continuous data (METs/h/week) regarding PA and ST (min/day), respectively, were obtained. RESULTS: The patients categorized as having low PA had significantly higher body mass index than those categorized as having high levels, after adjustment was made for confounders. Continuous data of PA were negatively associated with waist circumference and visceral fat accumulation. ST was positively associated with body mass index. After dividing the participants into four groups according to medians of ST and PA, the following categories were established: long ST and low PA, long ST but high PA, short ST but low PA and short ST and high PA. In terms of body mass index, short ST and high PA measured significantly lower than long ST and low PA. For waist circumference and visceral fat accumulation, short ST but low PA and short ST and high PA measured significantly lower than long ST and low PA and long ST but high. CONCLUSIONS: These results imply that the combination of avoiding sedentary behavior and increasing PA might be important in the prevention bodyweight gain and in the avoidance of central obesity, respectively, in Japanese type 2 diabetes patients.

Idiopathic and isolated adrenocorticotropic hormone deficiency presenting as continuous epigastric discomfort without symptoms of hypoglycemia: a case report.

BACKGROUND: Isolated adrenocorticotropic hormone deficiency is one kind of hypopituitarism and is triggered by various diseases including autoimmune disorder and/or autoimmune hypophysitis. Adrenocorticotropic hormone deficiency brings out various serious symptoms such as severe hypoglycemia, hypotensive shock, and disturbance of consciousness. CASE PRESENTATION: Here we report a case of 65-year-old Japanese man who developed idiopathic and isolated adrenocorticotropic hormone deficiency. He had continued epigastric comfort without any symptom of hypoglycemia or any autoimmune abnormality. Since he continued to complain of mild epigastric discomfort and general malaise, he was misdiagnosed as having functional dyspepsia and a depression state and took medicine for them for several months. Infection markers and several antibodies which we examined were all negative. An abdominal computed tomography scan showed no mass in adrenal tissue; contrast magnetic resonance imaging of his brain showed that pituitary size was within normal range, and pituitary gland deep dyeing delay and/or deeply stained deficit were not observed. However, in a corticotropin-releasing hormone load test, response of adrenocorticotropic hormone and cortisol was poor after corticotropin-releasing hormone loading, and in growth hormone-releasing peptide 2 load test, adrenocorticotropic hormone response was poor, suggesting the presence of adrenocorticotropic hormone deficiency. Therefore, we started treatment with hydrocortisone, and his various symptoms were soon mitigated. CONCLUSIONS: We should bear in mind the possibility of adrenocorticotropic hormone deficiency even when patients complain of epigastric discomfort or general malaise alone.

Effect of mild exercise on glycemic and bodyweight control in Japanese type 2 diabetes patients: A retrospective analysis.

We retrospectively evaluated the effects of mild physical exercise (P) in a routine clinical setting on glycemic and bodyweight control in Japanese type 2 diabetes patients with and without individualized nutritional therapy (D). We analyzed 49 patients who participated in P that measured 2.5 metabolic equivalents and was held once every 2 weeks, compared with 83 non-participant controls, followed over a period of approximately 1.6 years. With a Cox model, the adjusted hazard ratio for improved glycated hemoglobin by numerical count of P was 1.03 (95% confidence interval [CI] 1.00-1.07; P = 0.025). Among four categories - with neither P nor D, only P, only D, and both P and D - the hazard ratios for reduced body mass index were 1.0, 0.87 (95% CI 0.46-1.67), 0.58 (95% CI 0.25-1.30) and 2.17 (95% CI 1.03-4.59), respectively. Even mild physical exercise contributed to glycemic control. The combination of P and D exerted beneficial effects on bodyweight control.

Verification of Kumamoto Declaration 2013 and Glycemic Targets for Elderly Patients with Diabetes in Japan for prevention of diabetic complications: A retrospective longitudinal study using outpatient clinical data.

AIMS/INTRODUCTION: The present study examined the association between the onset of micro- and macroangiopathy in type 2 diabetes mellitus patients and levels of glycated hemoglobin (HbA1c) described in the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013 or those indicated in the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes. MATERIALS AND METHODS: Patients with type 2 diabetes mellitus who visited the outpatient clinic at Kawasaki Medical School Hospital between 2000 and 2016 and received follow up for >2 years were eligible for the present study. Two datasets, comprising 2,424 or 3,316 patients without micro- or macroangiopathy at the start of follow up, were used, respectively. The Cox model was used in two categories of patients, younger and elderly, with the dividing line set at the age of 65 years. RESULTS: For the prevention of microangiopathy, in all patients, there was found to be no advantage in controlling HbA1c at a level of <6.0% based on the categories in the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013, and there was found to be a disadvantage in maintaining HbA1c ≥8.5% based on the categories in the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes guideline. For the prevention of macroangiopathy in younger patients, there seemed to be an advantage in maintaining HbA1c within the range of 6.0-6.9% and <7.0% based on the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013 and the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes, respectively. CONCLUSIONS: In all type 2 diabetes mellitus patients, average HbA1c should be maintained <7.0% to prevent microangiopathy. However, in elderly patients, no optimal target for preventing macroangiopathy was found, in contrast to the younger patients in the present study.

Efficacy and Safety of Switching from Insulin Glargine 100 U/mL to the Same Dose of Glargine 300 U/mL in Japanese Type 1 and 2 Diabetes Patients: A Retrospective Analysis.

Objective Insulin glargine [300 U/mL (Gla-300)] achieved better glycemic control and reduced the risk of hypoglycemia in comparison to glargine [100 U/mL; (Gla-100)] in phase 3 trials. This is the first study to retrospectively evaluate the efficacy and safety of Gla-300 in Japanese type 1 and 2 diabetes patients in a routine clinical setting. Methods We analyzed 20 type 1 diabetes patients and 62 type 2 diabetes patients who switched from Gla-100 to the same dose of Gla-300. Sixty type 2 diabetes patients who continued the use of Gla-100 during the study were included as controls. Results At three months after switching, the HbA1c levels were decreased in the patients with type 1 diabetes, but not to a significant extent. In the type 2 diabetes patients, the HbA1c levels were significantly decreased after switching (p<0.01). In contrast, there was no change in the HbA1c levels of the type 2 diabetes patients who continued the use of Gla-100 over the same period. The BMI values of the type 1 diabetes patients tended to decrease (p=0.06) and there was a significant decrease in the BMI values of the type 2 diabetes patients (p<0.05). There was no change in the BMI values of the type 2 diabetes patients who continued the use of Gla-100. The rates of hypoglycemia and adverse events did not change during the follow-up period. Conclusion In the clinical setting, switching from Gla-100 to the same dose of Gla-300 had a favorable effect on glycemic control and body weight control in Japanese type 1 and type 2 diabetes patients, without any increase in adverse events; however, a prospective study should be performed to confirm these findings.

Population pharmacokinetics and pharmacodynamics of linezolid-induced thrombocytopenia in hospitalized patients.

AIMS: Thrombocytopenia is among the most important adverse effects of linezolid treatment. Linezolid-induced thrombocytopenia incidence varies considerably but has been associated with impaired renal function. We investigated the pharmacodynamic mechanism (myelosuppression or enhanced platelet destruction) and the role of impaired renal function (RF) in the development of thrombocytopenia. METHODS: The pharmacokinetics of linezolid were described with a two-compartment distribution model with first-order absorption and elimination. RF was calculated using the expected creatinine clearance. The decrease platelets by linezolid exposure was assumed to occur by one of two mechanisms: inhibition of the formation of platelets (PDI) or stimulation of the elimination (PDS) of platelets. RESULTS: About 50% of elimination was found to be explained by renal clearance (normal RF). The population mean estimated plasma protein binding of linezolid was 18% [95% confidence interval (CI) 16%, 20%] and was independent of the observed concentrations. The estimated mixture model fraction of patients with a platelet count decreased due to PDI was 0.97 (95% CI 0.87, 1.00), so the fraction due to PDS was 0.03. RF had no influence on linezolid pharmacodynamics. CONCLUSION: We have described the influence of weight, renal function, age and plasma protein binding on the pharmacokinetics of linezolid. This combined pharmacokinetic, pharmacodynamic and turnover model identified that the most common mechanism of thrombocytopenia associated with linezolid is PDI. Impaired RF increases thrombocytopenia by a pharmacokinetic mechanism. The linezolid dose should be reduced in RF.

Population Pharmacokinetic Approach to the Use of Low Dose Cyclosporine in Patients with Connective Tissue Diseases.

This study describes the population pharmacokinetics and dose personalization of cyclosporine in 36 patients with connective tissue diseases. A one-compartment open model with absorption was adopted as a pharmacokinetic model, and a nonlinear mixed effects model was used to analyze the population pharmacokinetic models. In the final model, age (AGE) and total body weight (TBW) were influential covariates on clearance (CL/F), which was expressed as CL/F (L/h)=17.8×(AGE/60)(-0.269)×(TBW/46.9)(0.408), in addition to the volume of distribution (Vd/F), (L)=98.0 and absorption rate constant (Ka) (h(-1))=0.67 (fixed). The results of the present study provide novel insights into factors involved in determining the most suitable dose and dosing strategy for individual patients with connective tissue disease.

Population pharmacokinetic analysis of linezolid in low body weight patients with renal dysfunction.

Linezolid has antibacterial activity against aerobic Gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA). Adjustment of the dose of linezolid has been proposed to be unnecessary in patients with reduced renal function. However, platelet counts and hemoglobin levels were shown to be significantly lower in such patients than in patients with normal renal function. The population pharmacokinetic (PPK) of linezolid was investigated in MRSA infected patients with renal dysfunction. Linezolid concentrations in serum were measured by high-performance liquid chromatography. PPK analysis was performed in the nonlinear mixed effects model (NONMEM) computer program. In the final PPK model, total body weight (TBW), estimated glomerular filtration rate (eGFR), hemoglobin (HB), and alanine amino transferase (ALT) were influential covariates on total body clearance (CL), and the volume of distribution (Vd) was affected by TBW, which was expressed as CL (L/h) = 0.00327 × TBW × eGFR(0.428) × HB(0.502) × 0.283 (ALT ≥ 100 IU/L) and CL (L/h) = 0.00327 × TBW × eGFR(0.428) × HB(0.502) (ALT < 100 IU/L), Vd (L) = 1.310 × TBW. The PPK parameters of linezolid obtained here are useful for the optimal use of linezolid with similar patient population characteristics.

Pharmacokinetics of linezolid in the mediastinum and pleural space.

The purpose of this study was to investigate the penetration of linezolid into the mediastinum and pleural space by comparing its concentration in the serum, mediastinum, and pleural space. The linezolid area under the concentration-versus-time curve from zero to 12h (AUC)(mediastinum fluid/serum) and AUC(pleural fluid/serum) ratio were 1.32 and 1.64, respectively. The results suggest that the linezolid concentration in the mediastinum varies as in the serum, and that the concentration in the mediastinum is the same as or greater than that in the serum.

Evaluation of the pharmacokinetics of linezolid in an obese Japanese patient.

We evaluated the pharmacokinetics of linezolid in the case of an obese Japanese patient (body weight 116 kg; body mass index 37 kg/m(2)). Linezolid was administered at a dose of 600 mg by intravenous drip infusion for 60-90 min at 12-h intervals. The results showed increased clearance of linezolid and a reduced serum concentration compared to population pharmacokinetic parameters, with trough levels below the 90% minimum inhibitory concentration. However, linezolid was effective for improving lung infection and inflammation in our patient, which may be due to its particularly effective transfer into lung tissues. Linezolid undergoes slow non-enzymatic oxidation in vivo that may be increased in obese patients, and this may account for the greater clearance. Our findings are useful for the planning of linezolid therapy in obese patients.

Pharmacokinetics and protein binding of linezolid in cerebrospinal fluid and serum in a case of post-neurosurgical bacterial meningitis.

We describe a case of bacterial meningitis in a patient administered linezolid (LZD). The ratio of free to total LZD concentrations in cerebrospinal fluid (CSF) was 1 for all measurements, and the LZD concentration in CSF measured at the trough level was almost the same as the free serum concentration.

Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction.

It has been proposed that it is not necessary to adjust the dose of linezolid (LZD) in patients with reduced renal function. However, significantly lower platelet counts and hemoglobin levels have been reported in such patients compared to those in patients with normal renal function. This suggests that the appropriate dose and administration method for LZD are yet to be established in patients with renal dysfunction. The subjects in this study were patients with renal dysfunction who developed adverse effects of thrombocytopenia and anemia during treatment with LZD. We investigated the association of these adverse effects with the blood LZD concentration and the area under the concentration-time curve from zero to 24 h (AUC(0-24)), determined using a one-compartment Bayesian model (n = 20). The measured blood LZD concentration was significantly higher than the predicted concentration in a population pharmacokinetics approach (p < 0.01), and severe thrombocytopenia developed as the blood LZD concentration increased. The platelet count and hemoglobin level decreased as the AUC(0-24) of LZD increased in patients with renal dysfunction, and the correlations were significant: r = 0.593 and r = 0.783, respectively (p < 0.01). These findings suggest that LZD administered to patients with renal dysfunction may reach a high blood level and subsequently increase the AUC(0-24), which may then induce adverse effects of severe thrombocytopenia and anemia.

Pharmacokinetics of repeated dosing of linezolid in a hemodialysis patient with chronic renal failure.

Linezolid (LZD) is thought not to require dose adjustment in patients with renal dysfunction, making it a drug of choice for these patients. However, in the current study we show LZD accumulation occurring with repeated dosing during hemodialysis in a 64-year-old man receiving hemodialysis treatment. In this patient, methicillin-resistant Staphylococcus aureus (MRSA) caused an abscess under the abdominal wall due to wound infection after colon cancer surgery. Treatment was initiated with intravenous LZD (600 mg) every 12 h. However, pancytopenia and liver dysfunction occurred during the LZD administration period. A high trough level, of 15-20 microg/ml, during LZD administration was determined from stored blood biochemistry samples, and pharmacokinetic parameters, estimated by the Bayesian nonlinear least squares method, were as follows: clearance (CL), 1.56 l/h; clearance during hemodialysis (CL(HD)), 2.23 l/h; volume of distribution (Vd), 18.69 l; and area under the curve (AUC), 384.07 microg/ml . h. Simulation of the serum concentration-time profile from the estimated pharmacokinetic parameters gave a trough level about four to five times higher than that in healthy individuals in the early administration period, indicating LZD accumulation in blood. These findings suggest a causal relationship between the high LZD level and the adverse effects. The cause of the high LZD level is unclear, but the findings indicate that careful monitoring and dose adjustment of LZD is necessary in hemodialysis patients.