Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments.

BACKGROUND AND OBJECTIVE: Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling. METHODS: Ex vivo placenta perfusions were performed in a closed-closed configuration, in both maternal-to-fetal and fetal-to-maternal directions (n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration (Ctrough) values were compared with the target (0.23 mg/L) derived from in vivo exposure-response analysis. RESULTS: A decrease of 55% in maternal doravirine area under the plasma concentration-time curve (AUC)0-24h was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM Ctrough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure. CONCLUSION: Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data.

Placental transfer and vascular effects of pharmaceutical drugs in the human placenta ex vivo: A review.

At least 80% of pregnant woman in Europe use at least one medication during their pregnancy. The majority of these drugs are prescribed off-label. A better understanding of drug transport and effects in the placenta can provide an improved pharmacological basis to rationalize drug and dose selection for prescription. Here we provide a narrative review of studies that used the ex vivo placenta perfusion model to study placental drug transport and vascular effects of pharmaceuticals. For studies on placental transfer, we found that the methodology used varied substantially between studies as well as the way in which data was reported. Across the different therapeutic groups, ex vivo measurements of transfer generally corresponded well to in vivo findings. Still, further standardization of the perfusion technique would facilitate a broader use of perfusion data, e.g. in the context of quantitative systems pharmacology models as has been explored in recent years. Only few studies investigated the effects of drugs on the vascular tone using the ex vivo dual-side perfusion model. The model was particularly applied to study vasodilatory effects of pharmaceuticals in the fetoplacental circulation. In conclusion, the ex vivo dually perfused human cotyledon provides a relevant system to gain insights in placental drug disposition and study effects on the fetoplacental vasculature.

Transfer of uremic solutes across the human term placenta: An ex vivo study in the dual-side perfused cotyledon.

INTRODUCTION: An increasing number of women becomes pregnant while suffering from chronic kidney disease (CKD). As a result of decreased renal function, uremic solutes circulate at high levels in the maternal circulation. This study aimed to acquire more knowledge about the placental transfer of uremic solutes across the human placenta. METHODS: Placental transfer was studied in healthy term placentas, via the ex vivo dual-side human cotyledon perfusion technique (closed-closed set-up for both maternal and fetal circulations). Uremic solute concentrations in maternal and fetal perfusates were measured via LC-MS/MS over 180 min of perfusion. RESULTS: We found that the studied compounds demonstrated different degrees of placental transfer. Fetal-to-maternal perfusate ratios at t = 180 min were for anthranilic acid 1.00 ± 0.02, indole-3-acetic acid 0.47 ± 0.08, hippuric acid 0.36 ± 0.18, l-arabinitol 0.33 ± 0.04, indoxyl sulfate 0.33 ± 0.11, neopterin 0.28 ± 0.14 and kynurenic acid 0.13 ± 0.03. All uremic solutes studied also emerged in the perfusates when cotyledons were perfused in the absence of uremic solute concentrations added to the maternal reservoir. For kynurenin these concentrations were so high, it complicated the calculation of a transfer ratio for the exogenously administered compound. DISCUSSION: After 180 min of exposure the extent of placental transfer differs substantially for the solutes studied, reflecting different transfer rates. Future studies should investigate to what extent specific uremic solutes reach the fetal circulation in vivo and how they may interfere with organ function and development of the unborn child.

Experimental study of diclofenac and its biliary metabolites on anastomotic healing.

BACKGROUND: Diclofenac increases the risk of anastomotic leakage, but the underlying mechanism is unknown. As diclofenac is excreted largely as biliary metabolites, the aim of this study was to determine the effect of these metabolites on intestinal anastomoses. METHODS: This was a randomized controlled blinded experiment using 210 male Wistar rats to assess the effect of 'diclofenac bile' on the anastomotic complication score, leak rate and anastomotic strength following oral and parenteral administration of diclofenac. Bile duct and duodenal catheterization techniques were used for diversion and replacement of bile, and biliary diclofenac metabolites were determined. RESULTS: Replacement of control bile with diclofenac bile resulted in higher anastomotic complication scores (P = 0·006) and leakage in five of 18 animals, compared with one of 18 controls (P = 0·089). In turn, following oral diclofenac administration, replacement of diclofenac bile with control bile reduced anastomotic complications (P = 0·016). The leak rate was seven of 15 versus 13 of 17 without replacement (P = 0·127). After intramuscular administration of diclofenac, the reduction in anastomotic complications was not significant when bile was replaced with control bile (P = 0·283), but it was significant when bile was drained without replacement (P = 0·025). Diclofenac metabolites in bile peaked within 2 h after administration. Administration of diclofenac bile resulted in nearly undetectable plasma levels of diclofenac (mean(s.d.) 0·01(0·01) µg/ml) after 120 min. Following oral diclofenac, bile replacement with control bile did not affect the plasma concentration of diclofenac (0·12(0·08) µg/ml versus 0·10(0·05) µg/ml with diclofenac bile; P = 0·869). CONCLUSION: Altered bile composition as a result of diclofenac administration increases the ileal anastomotic complication rate in rats.

Placental disposition of the immunosuppressive drug tacrolimus in renal transplant recipients and in ex vivo perfused placental tissue.

Currently, tacrolimus is the most potent immunosuppressive agent for renal transplant recipients and is commonly prescribed during pregnancy. As data on placental exposure and transfer are limited, we studied tacrolimus placental handling in samples obtained from renal transplant recipients. We found transfer to venous umbilical cord blood, but particularly noted a strong placental accumulation. In patient samples, tissue concentrations in a range of 55-82 ng/g were found. More detailed ex vivo dual-side perfusions of term placentas from healthy women revealed a tissue-to-maternal perfusate concentration ratio of 113 ±â€¯49 (mean ±â€¯SEM), underlining the placental accumulation found in vivo. During the 3 h ex vivo perfusion interval no placental transfer to the fetal circulation was observed. In addition, we found a non-homogeneous distribution of tacrolimus across the perfused cotyledons. In conclusion, we observed extensive accumulation of tacrolimus in placental tissue. This warrants further studies into potential effects on placental function and immune cells of the placenta.

Drug-drug interactions between rosuvastatin and oral antidiabetic drugs occurring at the level of OATP1B1.

Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with oral antidiabetics in the clinic. The aim of this study was to investigate possible drug-drug interactions between these drugs at the level of OATP1B1 and OATP1B1*15. We generated human embryonic kidney (HEK)293 cells stably overexpressing OATP1B1 or OATP1B1*15 that showed similar protein expression levels of OATP1B1 and OATP1B1*15 at the cell membrane as measured by liquid chromatography-tandem mass spectrometry. In HEK-OATP1B1*15 cells, the V(max) for OATP1B1-mediated transport of E(2)17ß-G (estradiol 17ß-d-glucuronide) was decreased >60%, whereas K(m) values (Michaelis constant) were comparable. Uptake of rosuvastatin in HEK-OATP1B1 cells (K(m) 13.1 ± 0.43 µM) was nearly absent in HEK-OATP1B1*15 cells. Interestingly, several oral antidiabetics (glyburide, glimepiride, troglitazone, pioglitazone, glipizide, gliclazide, and tolbutamide), but not metformin, were identified as significant inhibitors of the OATP1B1-mediated transport of rosuvastatin. The IC(50) values for inhibition of E(2)17ß-G uptake were similar between OATP1B1 and OATP1B1*15. In conclusion, these studies indicate that several oral antidiabetic drugs affect the OATP1B1-mediated uptake of rosuvastatin in vitro. The next step will be to translate these data to the clinical situation, as it remains to be established whether the studied oral antidiabetics indeed affect the clinical pharmacokinetic profile of rosuvastatin in patients.