Dapagliflozin was well tolerated and showed predictable dose-proportional PK and PD parameters in both healthy and T2DM Japanese subjects.
Daclatasvir is a nonstructural protein 5A replication complex inhibitor, and asunaprevir is a nonstructural protein 3 protease inhibitor for hepatitis C virus (HCV). In 2014, the combination therapy of daclatasvir and asunaprevir received the first global approval in Japan as the first nonribavirin, all‐oral therapy for HCV treatment. The population pharmacokinetics (popPK) of daclatasvir and asunaprevir were characterized by nonlinear mixed‐effects modeling using 3801 and 2626 concentration data from 336 and 265 Japanese HCV subjects, respectively. The plasma pharmacokinetic profiles of daclatasvir and asunaprevir were described by a 1‐compartment model. Parameter estimates (interindividual variability) of daclatasvir apparent clearance (CL/F) and apparent volume of the central compartment (V/F) were 5.29 L/h (39.4%) and 64.2 L (38.1%). The effects of all statistically significant covariates on daclatasvir PK parameters were within or overlapped the 80% to 125% boundaries, suggesting a lack of clinical relevance. Parameter estimates (interindividual variability) of asunaprevir CL/F and V/F were 52.1 L/h (41.5%) and 75.1 L (93.4%), respectively. Baseline and time‐varying aspartate aminotransferase (AST) and cirrhosis on CL/F and formulation (soft‐gel capsule or tablet) on F were included as significant covariates in the asunaprevir popPK model. The effects of all covariates exceeded the 80% to 125% boundaries, indicating that the asunaprevir soft‐gel capsule had higher bioavailability than the tablet and that asunaprevir exposure increased with cirrhosis and increasing baseline and time‐varying AST values. The popPK models adequately described the PK profiles of daclatasvir and asunaprevir in Japanese HCV subjects.
A simple and convenient method for measuring K(L)a in large-scale fermentors was proposed. This method was based on the measurement of the dissolved oxygen concentration under steady state conditions established by an equivalency of the sulfite ion feed and chemical oxidation rates. This method had the following advantages: It was a steady state method, and so it was not necessary to consider the response lag of a dissolved oxygen probe and the response lag due to gas phase mixing in fermentors. The oxygen content of the effluent gas in this measuring system was nearly the same as that of the sparged air. Therefore, it was possible to use the oxygen partial pressure of the sparged air for the calculation of the driving force of oxygen transfer. The detailed information on the kinetics of sulfite oxidation was not necessary, because the dissolved oxygen concentration in steady state was not influenced by sulfite oxidation rates. The K(L)a measurement was finished in as short a period as 150 s, even in a fermentor with a volume of 10 m(3). Since the amount of Na(2)SO(4) accumulation in the test fermentors was very small because of the quick measurement, the K(L)a values obtained by this method were applicable to the electrolyte-free system. Furthermore, we could discharge the used liquid from the fermentors into a drain without any pretreatment due to the low salt concentration.
IntroductionDapagliflozin is an orally administered selective sodium-glucose cotransporter 2 (SGLT2) inhibitor under development for the treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin lowers blood glucose through a reduction in renal glucose reabsorption. This study was performed to assess the effect of the oral antidiabetic agent voglibose [0.2 mg thrice daily (t.i.d.)] at steady-state, on the pharmacokinetics, safety and tolerability of dapagliflozin administered as a single oral dose (10 mg) to Japanese patients with T2DM.MethodsThis was an open-label, multi-center, drug–drug interaction study. A single oral dose of dapagliflozin (10 mg) was administered to 22 Japanese patients with T2DM in the presence and absence of voglibose (0.2 mg t.i.d.). Serial blood samples were collected before and at regular prespecified intervals after each dapagliflozin dose to determine dapagliflozin plasma concentrations and to evaluate pharmacokinetic parameters. Based on a mixed effect analysis of variance model, including the dosing condition as a fixed effect and patients as a random effect, the ratios of geometric means of area under curve from time 0 to infinity (AUC0-inf) and maximum observed plasma concentration (Cmax) with and without voglibose were estimated along with two-sided 90% confidence intervals (CIs).ResultsIn Japanese patients with T2DM, the exposure to dapagliflozin following a single oral dose of dapagliflozin 10 mg was not influenced by the concomitant administration of voglibose (0.2 mg t.i.d.). The geometric ratio (90% CI) for dapagliflozin AUC0-inf with/without voglibose was 1.009 (0.954, 1.067), and for Cmax 1.040 (0.899, 1.204). The median time to Cmax (tmax) and plasma clearance of dapagliflozin were also similar between treatments. The mean half-life (t½) for dapagliflozin was slightly higher when administered in combination with voglibose. Dapagliflozin 10 mg was well tolerated when administered alone and in combination with voglibose in Japanese patients with T2DM.ConclusionThe results presented here support the co-administration of dapagliflozin and voglibose without dose adjustment of either agent.
The objective of this study was to provide support for a body weight-tiered dosing regimen by characterizing abatacept pharmacokinetics (PK) and the relationship between exposure and the ACR20 (American College of Rheumatology criteria for 20% improvement) response in Japanese patients with rheumatoid arthritis (RA). A population PK model was developed using NONMEM with 2,535 samples from 344 Japanese RA patients in two clinical trials. The exposure-response relationship was characterized using a Generalized Estimating Equation (GEE) logistic regression model, with time-varying actual trough concentrations and ACR20 responder rates over 6 months in a randomized, placebo-controlled phase 2 trial for stable methotrexate. Abatacept exposure was well characterized using a linear, two-compartment model, in which body weight and the empirically calculated glomerular filtration rate were significant covariates for clearance. The ACR20 response model was developed by examining the quasi-likelihood information criterion, and the cumulative logit in the final model was specified by the log-transformed trough concentration. The predicted ACR20 responder rate was consistent with the actual values in the clinical trial and this model revealed trough concentrations higher than the recommended body weight-tiered dose are unlikely to result in substantial increases in clinical efficacy. Considering that ACR20 is a longitudinal binary variable and the response to RA treatment is delayed, the GEE model was useful for predicting the probability of an ACR20 response. In conclusion, the same dosing regimen as non-Japanese patients is recommended because a body weight-tiered dosing regimen achieves similar exposures across the wide range of body weight.
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