No abstract

No abstract

This paper investigates the market timing hypothesis of capital structure using a sample of 1,077 Chinese firms for the period 1992 to 2007. We find that market timing plays a significant role in capital structure decisions. However, market timing effects are not persistent and disappear within three years. The results suggest the prominent role played by the government in timing of security issues.

BackgroundFetal drug exposure during pregnancy can be a determinant of fetal drug toxicity or efficacy. Fetal exposure is usually derived from the cord-to-maternal (ctm) concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure-effect relationship. Pregnancy physiologically-based pharmacokinetic (p-PB-PK) modelling could provide a solution, although incor-poration of placental transfer remains challenging. Here, we aimed to include placental transfer parameters de-rived from an ex vivo human cotyledon perfusion model into a p-PBPK model, to quantitatively simulate fetal ex-posure to the antiretroviral agent darunavir, co-adminis-tered with ritonavir, at term.MethodsAn existing and validated p-PBPK model of ma-ternal darunavir/ritonavir exposure was coded in Berkeley Madonna syntax to allow expansion with a feto-placental unit. Bidirectional placental transport of darunavir at term was included. In order to parameterize the model, we determined maternal-to-fetal (mtf) and fetal-to-maternal (ftm) darunavir/ritonavir placental clearances with an ex vivo human cotyledon perfusion model. Simulated ma-ternal PK profiles were compared with observed clinical data to verify the validity of the maternal model aspect. Next, population fetal PK profiles were simulated for different darunavir/ritonavir dosing regimens. These profiles were compared with available cord blood concen-trations in vivo. Additionally, we explored the influence of different DRV/r dosing regimens on fetal exposure and antiviral effects.ResultsAn average (±SD) mtf cotyledon clearance of 0.91±0.11 mL/min and ftm of 1.6±0.3 mL/min was de-termined (n=6 perfusions). Scaled placental transfer was included into a feto-placental unit and integrated in the p-PBPK model. For darunavir 600/100 mg twice daily, the simulated fetal plasma Cmax, Ctrough, Tmax and T1/2 at steady state were; 1.1 mg/L, 0.57 mg/L, 3 hours, and 21 hours, respectively. This indicates that the fetal population Ctrough is above the protein-adjusted EC90 for inhibit-ing the replication of wild type (0.20 mg/L) and around the EC90 for resistant virus (0.55 mg/L). The simulated ftm plasma concentration ratio (range) over a dosing interval was 0.30 (0.16–0.37), compared to a median (range) ratio for observed darunavir ctm plasma ratio of 0.18 (0–0.82; 0 reported if cord blood concentrations were below the lower limit of quantification [<0.09 mg/L] and hence no ratio could be determined).ConclusionA p-PBPK model for maternal darunavir exposure was extended with a feto-placental unit. The simulated fetal darunavir plasma concentrations were in the range of observed cord blood concentrations. This advanced model provides a valuable tool in assessing the implications of new dosing regimens, optimising the safety of maternal pharmacotherapy and fetal antiretro-viral treatment.

BackgroundThe number of pregnancies in the kid-ney transplant patient population is high. During gesta-tion these women continue using immunosuppressant drugs, but knowledge about their placental disposition and toxicity is scarce. We now investigated placental transfer of the immunosuppressive drug tacrolimus (TAC) as well as the potential effects on trophoblast cell viability and barrier function.MethodsIsolated dual side perfusions of human pla-cental cotyledons were performed to study disposition of TAC. Additionally, clinical data on TAC concentrations in placental tissue of kidney transplant recipients and ma-ternal whole blood concentrations were gathered. BeWo choriocarcinoma cells were used to evaluate effects on trophoblast cell viability, while interaction with placental ATP-binding cassette transporters was studied in mem-brane vesicles derived from HEK293 cells recombinantly overexpressing human Breast Cancer Resistance Protein (BCRP) or P-glycoprotein (P-gp).ResultsWe found that maternal perfusate levels de-creased during 180 min of perfusion, while being unde-tectable in the fetal circulation. At t=180 min a concen-tration of 220±50 nM was measured in placental tissue, which is almost 100-fold higher than the maternal per-fusate concentration. Analysis of placental tissue of renal transplant recipients revealed a 13-fold higher tacrolimus concentration compared to the maternal blood concen-tration (88±7 nM and 6.8±1.1 nM, respectively). TAC did not affect BeWo cell viability up to the maximum concen-tration of 1 µM tested. In transporter studies we did find stimulation of P-gp-mediated transport and inhibition of BCRP-mediated transport, at 1 and 10 µM, respectively.ConclusionTAC demonstrates strong accumulation in placental tissue and distribution across the tissue was not homongenously. However, the tissue concentrations reached are unlikely to affect trophoblast cell viability or BCRP and P-gp transport function.