Transplacental Pharmacokinetic Model of Digoxin Based on Ex Vivo Human Placental Perfusion Study.

Digoxin is used as first-line therapy to treat fetal supraventricular tachycardia; however, because of the narrow therapeutic window, it is essential to estimate digoxin exposure in the fetus. The data from ex vivo human placental perfusion study are used to predict in vivo fetal exposure noninvasively, but the ex vivo fetal-to-maternal concentration (F:M) ratios observed in digoxin perfusion studies were much lower than those in vivo. In the present study, we developed a human transplacental pharmacokinetic model of digoxin using previously reported ex vivo human placental perfusion data.

Augmented Clearance of Nivolumab Is Associated with Renal Functions in Chronic Renal Disease Model Rats.

The clinically approved dose of nivolumab is 240 mg every 2 weeks. However, previous studies have shown that baseline nivolumab clearance (CL) is associated with treatment outcomes in patients with solid cancers, thus motivating researchers to identify prognostic factors and indices influencing nivolumab CL. This study used chronic kidney disease model rats to investigate whether chronic renal impairment affected nivolumab CL and explored the surrogate markers associated with nivolumab CL.

Development of a Pharmacokinetic Model of Transplacental Transfer of Metformin to Predict In Vivo Fetal Exposure.

Two types of systems are used in ex vivo human placental perfusion studies to predict fetal drug exposures, that is, closed systems with recirculation of the maternal and fetal buffer and open systems using a single-pass mode without recirculation. The in vivo fetal/maternal (F:M) ratio of metformin, a cationic drug that crosses the placenta, is consistent with that reported in an open system ex vivo but not with that in a closed system. In the present study, we aimed to develop a pharmacokinetic (PK) model of transplacental transfer of metformin to predict in vivo fetal exposure to metformin and to resolve the apparent inconsistency between open and closed ex vivo systems.

Physiological based pharmacokinetic modeling to estimate in vivo Ki of ketoconazole on renal P-gp using human drug-drug interaction study result of fesoterodine and ketoconazole.

This study was conducted to estimate in vivo inhibition constant (Ki) of ketoconazole on renal P-glycoprotein (P-gp) using human drug-drug interaction (DDI) study result of fesoterodine and ketoconazole. Fesoterodine is a prodrug which is extensively hydrolyzed by non-specific esterases to the active metabolite 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is then further metabolized via Cytochrome P450 (CYP) 2D6 and CYP3A4.

The Relationship Between Development Start Lag and Approval Lag in Oncology Drug Development in Japan.

Background: The delay of initiation of clinical development is considered a causes of delay of approval of drugs (drug lag) in Japan.

Methods: For oncology drugs newly approved between 2000 and 2012 in Japan, a possible impact of delay of initiation of clinical development (development start lag [DSL]) on delay of approval (approval lag [AL]) was investigated, focusing on the delay from the US timelines. The equation defining the relationship between the DSL and AL of 33 oncology drugs was calculated by using simulation models, then the Pearson coefficient of correlation between parameters was calculated.

Pharmacokinetics of tolterodine in Japanese and Koreans: physiological and stochastic assessment of ethnic differences.

Tolterodine is known as a drug which exhibits ethnic differences in pharmacokinetics between Japanese and Koreans despite genetic similarities among the populations of East Asian countries. Tolterodine is mainly metabolized by CYP2D6 to a 5-hydroxymethyl metabolite (5-HM), and 5-HM is also metabolized by CYP2D6. The reduced-function allele CYP2D6*10 is frequently observed in Asian populations.

Enhancement of zidovudine uptake by dehydroepiandrosterone sulfate in rat syncytiotrophoblast cell line TR-TBT 18d-1.

AZT (3'-azido-3'-deoxythymidine; zidovudine), which is used for the prevention of mother-to-child transmission of HIV-1, is transplacentally transferred to the fetus across the blood-placenta barrier, which is composed of syncytiotrophoblasts. We recently showed that apical uptake of AZT by syncytiotrophoblasts is mediated by saturable transport system(s) in the TR-TBT 18d-1 cell line, and the cellular accumulation of AZT was increased in the presence of dehydroepiandrosterone sulfate (DHEAS). Here, we aimed to clarify the mechanism of this effect of DHEAS.