Purpose: Physiologically based pharmacokinetic (PBPK) analyses have been frequently used in the clinical pharmacology section of regulatory applications. However, whether models developed and validated in healthy populations can be extrapolated to untested populations is not well known. This study aimed to determine whether a drug-specific PBPK model validated in a healthy population could be used to predict drug disposition in populations with different ethnicities, ages, genetic phenotypes, and pregnant population considering an example for risperidone and its active metabolite, paliperidone. Methods: PBPK modeling and simulation were performed using Simcyp Population-based ADME Simulator version 20. The risperidone and paliperidone compound models were developed based on physicochemical and pharmacokinetic parameters reported in the literature. The model was validated using observed values from 25 clinical studies including 15 in the adult population (8 Caucasian, 5 Chinese, and 2 Japanese), 8 in the pediatric population (5 Caucasian, 2 Chinese, and 1 Japanese), and 2 in the pregnant population. Visual predictive checks (VPC) for predicted and observed plasma concentrations, goodness-of-fit plots, prediction fold error, mean error (ME), and root-mean-square error (RMSE) were used for the graphical and statistical analyses. Results: Almost all (98.9%) of observed serum risperidone and paliperidone concentrations werewithin the 90% prediction intervals of each concentration by the PBPK simulation. All predicted values of serum risperidone concentration and AUC values in adult, pediatric, and pregnant populations met the 2fold acceptance criterion. A 91.8% of predicted values of paliperidone concentration and 97.4% of AUC values fall within the 2-fold criterion in all populations. The mean error (ME) and root-mean-square error (RMSE) for all predicted Cmax for risperidone were 0.61±0.4%, and 2.85%, respectively. Regarding paliperidone, the values were -0.038±0.45% and 3.16%, respectively. Conclusion: This study successfully shows an experimental application of PBPK modeling for the adaptation of ethnic variety and pediatric population.

Background: Fentanyl is widely used for sedation in preterm neonates requiring artificial ventilation. Neonates are especially vulnerable to side effects such as respiratory depression with oversedation which has a direct concentration-effect relation. The dosage regimen is usually derived from adults employing an extrapolation based on body weight which cannot accurately determine organ maturation in neonates. There is a necessity for model-based precision dosing of fentanyl that includes maturation. This study aimed to develop a pragmatic physiologically based pharmacokinetic (PBPK) model of fentanyl and to evaluate its prediction accuracy in neonates. Methods: PBPK modeling and simulation were performed using SimCYP Population-based ADME Simulator version 20. The fentanyl compound model was developed based on physicochemical and pharmacokinetic parameters reported in the literature. The model was validated using observed values from 25 clinical studies on adults and 4 on pediatrics. Serum samples of 14 neonates were collected as routine care. Serum fentanyl concentration was measured by liquid chromatography-mass spectrometry. Results: 100% of the predicted values of serum fentanyl concentration in adult and pediatric patients met the 2-fold acceptance criterion. Mean error (ME) and root-mean-square error (RMSE) for all predicted values were 0.28±0.15%, and 1.16%, respectively. In our neonatal patients, 95.5% of the predicted values were within the 2-fold acceptance criterion with ME and RMSE of 0.05±0.075%, and 0.34%, respectively. Median predicted fentanyl AUC value in patients with severe oxygen desaturation (sODS) (percutaneous oxygen saturation <80%) was higher than non- or moderate- ODS (nmODS) patients (ODS: 213 ng/mL·h, nmODS:25.2 ng/mL·h, P=0.043), while no significant difference was observed in fentanyl clearance depending on ODS (sODS: 1.33 L/h, nmODS: 1.39 L/h, P=0.35). Conclusion: This study shows that PBPK modeling can provide a precise prediction of serum fentanyl concentration in neonates. This model may be a useful tool for dose optimization and individualization strategies to avoid oversedation.

This study aimed to determine the effects of pregnancy and ontogeny on risperidone and paliperidone pharmacokinetics by assessing their serum concentrations in two subjects and constructing a customized physiologically‐based pharmacokinetic (PBPK) model. Risperidone and paliperidone serum concentrations were determined in a pregnant woman and her newborn. PBPK models for risperidone and paliperidone in adults, pediatric, and pregnant populations were developed and verified using the Simcyp simulator. These models were then applied to our two subjects, generating their “virtual twins.” Effects of pregnancy on both drugs were examined using models with fixed pharmacokinetic parameters. In the neonatal PBPK simulation, 10 different models for estimating the renal function of neonates were evaluated. Risperidone was not detected in the serum of both pregnant woman and her newborn …

Background: Skeletal involvement in patients with type 1 diabetes mellitus (T1DM) has complex pathogenesis and despite numerous researches on this problem, many questions remain unanswered.

Objective: This study aimed to assess bone status by measurement parathormone (PTH), 25-hydroxy vitamin D [25(OH)D] serum levels in children and adolescents with T1DM and its relation to insulin-like growth factor-1 (IGF-1), disease duration, puberty stage, and metabolic control.

Patients and methods: This study included 36 children and adolescents with T1DM and 15 apparently healthy controls. Serum levels of 25(OH)D, PTH, IGF-1 measured using enzyme-linked immunosorbent assay (ELISA), while glycosylated hemoglobin (HbA1c), calcium (Ca), inorganic phosphorus (PO₄) using autoanalyzer. Bone quality assessed using dual energy X-ray absorptiometry (DEXA).

Results: Diabetic patients showed significant increase in PO₄ and PTH levels, while significant decrease in Ca, IGF-1, and 25(OH)D serum levels. As much as 52.8% of patients showed reduced 25(OH)D, and 30.65% showed elevated PTH serum levels. In diabetic patients, abnormal bone status (osteopenia-osteoporosis) found mostly in total body (94.40%) then lumber-spine (88.90%), ribs (88.90%), pelvis (86.10%), thoracic-spine (80.60%), arms (80.60%) and legs (77.80%), while head bones showed no abnormalities. Long diabetic duration had negative; meanwhile PTH, onset age, and puberty age had positive impact on bone status.

Conclusions: Children and adolescent with T1DM have abnormal bone status mostly in axial skeleton which may be contributed to impairment of formation of 25(OH)D and IGF-1. Physical activity, calcium and vitamin D supplement seem important in T1DM. Elevated serum PTH level in diabetic patients is not uncommon and its positive correlation with bone status needs further investigations.

Aim

This case control study aimed to investigate relationship between appetite hormones (ghrelin and leptin) and body mass index (BMI), insulin and oxidative stress in simple obese and type 2 diabetes (T2DM) obese patients.

Methods

Thirty healthy controls; 30 simple obese and 30 T2DM obese patients were enrolled. Demographic and clinical data of all participants were reported. Serum levels of fasting blood glucose (FBG), postprandial blood glucose (PBG), lipid peroxide (LPO) and nitric oxide (NO) were measured by chemical methods while, insulin, leptin and ghrelin by ELISA kits.

Results

Serum levels of insulin, leptin, LPO were significantly higher while, ghrelin was significantly lower in simple obese and obese patients with diabetes versus controls. Insulin resistance was found in 76.67% simple obese and 93.33% obese patients with diabetes. Ghrelin showed a positive correlation with PBG in controls; but negative correlation with BMI in simple obese and with NO in obese patients with diabetes. Positive correlations were found between LPO and FBG, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and between leptin and FBG in obese patients with diabetes.

Conclusions

Our results suggested that hyperinsulinemia and hyperleptinemia may be most important mechanisms in decreasing ghrelin and inducing oxidative stress in simple obese and T2DM obese patients.