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Linagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, for type 2 diabetes exhibits nonlinear plasma protein binding in the therapeutic concentration range due to its high affinity binding to the pharmacological target DPP-4, and its pharmacokinetics both in plasma and urine is also nonlinear. The purpose of the present study was to explain the nonlinear pharmacokinetic profiles using a physiologically based pharmacokinetic (PBPK) model with saturable binding of linagliptin to soluble and membrane-bound DPP-4 in blood and organs including kidneys. The model was first fitted to previously reported full-scale plasma concentrations and urinary excretion data at 4 intravenous (iv) dose levels. Additional fitting to the data from 4 oral (po) dose levels was then performed to yield the final iv-po based model including gastrointestinal absorption-associated parameters. Data from [14C]linagliptin mass balance study were also used for optimizing parameters related to enterohepatic circulation. The PBPK model was thus constructed and well describes the nonlinear pharmacokinetic profiles of linagliptin in both plasma and urine, demonstrating that the nonlinear pharmacokinetics are fully explained by its specific binding to target protein. The present study thus introduces the involvement of target-mediated disposition for linagliptin in humans.

AIM To determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin.

AIMS The main objective of this study was to characterize the population pharmacokinetics of tamsulosin hydrochloride (HCl) in paediatric patients with neuropathic and non-neuropathic bladder. A secondary objective was to compare the pharmacokinetics in paediatric patients and adults.

Aims Our objective was to develop a population pharmacokinetic (PPK) model for epinastine, a histamine H1 receptor antagonist, in adults and children and to obtain pharmacokinetic information to support dosing recommendations in children. Methods A total of 1510 plasma samples were collected from 62 healthy adult volunteers and 62 paediatric atopic dermatitis patients. The data were analysed using the NONMEM program according to a two-compartment model with first-order absorption. In addition, the final PPK model was evaluated by means of bootstrapping resampling. Results The oral clearance (CL/F) was found to be associated with body weight, formulation and food status. The volume of distribution of the central compartment (V1/F) was related to body weight and food status. An absorption lag time was apparent in fed subjects. On the other hand, other covariates (formulation on V1/F, volume of distribution of the peripheral compartment (V2/F), first-order absorption rate constant (Ka) and absorption lag time (ALAG); food status on V2/F and Ka; body weight on V2/F) were not statistically significant. No effect of age on CL/F, V1/F or V2/F was found. The mean parameter estimates obtained with an additional 200 bootstrap replicates of data were within 90–117% of those obtained with the original data set. These results suggest that the pharmacokinetics of epinastine are similar in adults and in children, except for the effect of the difference of body weight. The result of the application of the PPK model to the clinical trial in paediatric patients, in which dosage was determined based on the body weight (from14 kg to less than 24 kg; 10 mg dose, 24 kg or more; 20 mg dose), showed that the Cmax and AUC (25.6 ± 6.9 ng ml−1 and 246.8 ± 68.2 ng h ml−1) were almost same levels with those of adults after administration of 20 mg (26.9 ± 9.1 ng ml−1 and 281.6 ± 90.5 ng h ml−1). Conclusions A PPK model for epinastine was established and further evaluation by bootstrapping indicated that this model is stable. The model shows that, if dosage is adjusted based on the body weight, the epinastine exposure in paediatric patients is similar to that in adults.

The objective of this study was to clarify the relationship between the pharmacokinetic parameters of telmisartan and the occurrence of adverse events. In order to perform this study, a total of 1500 adverse events was collected from the eight clinical trials performed in Europe and the United States and the pharmacokinetic parameters (C(max) and AUC) were calculated with the parameters obtained from the population pharmacokinetic model which we have built. Using these data, the pharmacokinetic parameters (C(max) and AUC) were compared between subjects with or without the occurrence of adverse events. The Mann-Whitney test was performed to analyze ten adverse events selected based on the order of frequency. For eight of these ten adverse events, no significant between-group difference was observed in any pharmacokinetic parameter. For two adverse events, pain and sinusitis, the pharmacokinetic parameters, C(max) and AUC, were greater in subjects with adverse events as compared with those without adverse events, but the intersubject variability of pharmacokinetic parameters was large and there were many subjects in whom C(max) and AUC were high without any adverse event. These results suggest that there is no clear relationship between pharmacokinetic parameters of telmisartan and the occurrence of adverse events.

[Objectives] Linagliptin is a novel, highly selective and long acting DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM). Linagliptin exhibits non-linear pharmacokinetics (PK) due to saturable binding to plasma and tissue DPP-4. The aim of this study was to characterize the PK and PK/DPP-4 inhibition relationship of linagliptin in Japanese patients with T2DM using a population PK/DPP-4 model and to support the rationale for the therapeutic dose in Japanese patients by simulation. [Methods] Linagliptin plasma concentration and DPP-4 inhibition measurements from a placebo-controlled, parallel group multiple (28 days) dose trial that included 36 T2DM patients (18 patients each in 2.5 mg and 10 mg dose group) were used for analysis. Modeling was performed using FOCE INTERACTION estimation method implemented in NONMEM V. The linagliptin plasma concentration- and DPP-4 inhibition- time profiles were simulated for Japanese patients receiving 5 mg linagliptin once daily by the model established. [Results] Nonlinear PK of linagliptin in T2DM patients were well described by a 2-compartment model assuming concentration-dependent binding to DPP-4 in the central and peripheral compartment. Plasma DPP-4 inhibition was integrated in the model by relating the model-predicted DPP-4 occupancy with linagliptin linearly to DPP-4 inhibition. The simulation predicted that for the 5 mg dose group the trough DPP-4 inhibition at steady-state was 84.2%, which is higher than the target inhibition (≥80%) for an effective dose of DPP-4 inhibitor. In 2.5 mg dose group, steady-state DPP-4 inhibition of >80% was not maintained over 24 hours (observed and simulated). [Conclusions] The nonlinear PK of linagliptin and its plasma DPP-4 inhibition in patients were well characterized by a target-mediated drug disposition model relating DPP-4 occupancy with linagliptin to DPP-4 inhibition. Simulations of plasma DPP-4 inhibition suggest that 5 mg linagliptin once daily is an appropriate therapeutic dose for Japanese patients with T2DM.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Tamsulosin is available on prescription as a modified release capsule in the US (Flomax), and in most European countries for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). The pharmacokinetics of tamsulosin hydrochloride (HCl) have been extensively studied in adults, but no pharmacokinetic data for paediatrics have been published to date.A population pharmacokinetic model of tamsulosin HCl was developed in paediatric patients. Covariate analysis revealed that body weight and alpha(1)-acid glycoprotein influenced both the apparent clearance and the apparent volume of distribution. This study confirms that there is no major difference in the pharmacokinetics of tamsulosin HCl between paediatrics (age range 2-16 years) and adults when the effect of body weight is taken into consideration.The main objective of this study was to characterize the population pharmacokinetics of tamsulosin hydrochloride (HCl) in paediatric patients with neuropathic and non-neuropathic bladder. A secondary objective was to compare the pharmacokinetics in paediatric patients and adults.Tamsulosin HCl plasma concentrations in 1082 plasma samples from 189 paediatric patients (age range 2-16 years) were analyzed with NONMEM, applying a one compartment model with first-order absorption. Based on the principles of allometry, body weight was incorporated in the base model, along with fixed allometric exponents. Covariate analysis was performed by means of a stepwise forward inclusion and backward elimination procedure. Simulations based on the final model were used to compare the pharmacokinetics with those in adults.Beside the priori-implemented body weight, only alpha(1)-acid glycoprotein had an effect on both apparent clearance and apparent volume of distribution. No other investigated covariates, including gender, age, race, patient population and concomitant therapy with anti-cholinergics, significantly affected the pharmacokinetics of tamsulosin HCl (P0.001). The results of simulations indicated that the exposure in 12.5 kg paediatric patients was 3.5-4.3 fold higher than that in 70.0 kg adults. After a weight-based dose administration, the exposure in paediatric patients was comparable with that in healthy adults.A population pharmacokinetic model of tamsulosin HCl in paediatric patients was established and it described the data well. There was no major difference in the pharmacokinetics of tamsulosin HCl between paediatric patients (age range 2-16 years) and adults when the effect of body weight was taken into consideration.

Summary: Objective To describe the factors affecting pharmacokinetics of telmisartan, an angiotensin II receptor antagonist, a population pharmacokinetic (PPK) model has been developed based upon the data collected from healthy volunteers and hypertensive patients. Methods A total of 1566 plasma samples were collected from 20 healthy volunteers and 129 hypertensive patients, together with the demographic background. The data were analyzed by the NONMEM program using two-compartment model with first-order absorption. The robustness of the obtained PPK model was validated by the bootstrapping resampling method. Results The oral clearance (CL/F) was found to be associated with age, dose and alcohol consumption, but neither related to serum creatinine nor smoking history. The volume of distribution for the central compartment was related to age and dose, and the volume of distribution for the peripheral compartment was related to body weight and gender. The absorption rate constant (Ka) and the absorption lag time were described as function of dose. The CL/F decreased with advanced age. The CL/F decreased and Ka increased with higher dose, reflecting the super-proportional increase in the plasma levels of telmisartan. The AUC and C max values predicted by the present PPK model were well consistent with the observed values. The means of parameter estimates obtained with 200 bootstrap replicates were within 95-111% of the final parameter estimates from the original data set. Conclusion A PPK model for telmisartan developed here well described the individual variability and exposure, and robustness of the model has been validated by the bootstrapping method.

Summary: The objectives of this study were to develop a population pharmacokinetic (PPK) model for telmisartan based on the pooled data obtained from the different racial populations and then to identify the factors that affect the pharmacokinetics of telmisartan for the comparison between the regions. A PPK model was established based on the data of 1343 subjects in 12 clinical trials. The PK profiles of telmisartan were described with a 2­compartment model with first­order absorption. The obtained model could predict the observed plasma concentrations well. This PPK model suggested that CL/F was a function of age, dose, gender, race, alcohol consumption and liver function. A marked difference was observed in the plasma concentration profiles between Japanese and other countries' subjects. However, the effect of the factor “race” on CL/F was not large. In the present PPK model, “trial condition” affected all PK parameters except for V 2 /F. The condition differences were in food condition and formulation (Japanese: fed, capsule, US and EU: fasted, tablet). The extent of difference in the plasma concentration profiles simulated for Japanese and Caucasian using the PPK model under the same demographic condition was comparable with the results of the food effect study performed previously in Japan. The findings suggest that the difference in the plasma concentration profiles between Japanese and other countries' subjects was mainly due to the difference of food intake conditions under which the clinical trials were performed.