Revisiting Nonlinear Bosentan Pharmacokinetics by Physiologically Based Pharmacokinetic Modeling: Target Binding, Albeit Not a Major Contributor to Nonlinearity, Can Offer Prediction of Target Occupancy.

Bosentan is a high-affinity antagonist of endothelin receptors and one of the earliest examples for target-mediated drug disposition [a type of nonlinear pharmacokinetics (PKs) caused by saturable target binding]. The previous physiologically based PK (PBPK) modeling indicated that the nonlinear PKs of bosentan was explainable by considering saturable hepatic uptake. However, it remained unexamined to what extent the saturable target binding contributes to the nonlinear PKs of bosentan. Here, we developed a PBPK model incorporating saturable target binding and hepatic uptake and analyzed the clinical bosentan PK data using the cluster Gauss-Newton method (CGNM). The PBPK model without target binding fell short in capturing the bosentan concentrations below 100 nM, based on the PK profiles and the goodness-of-fit plot. Both global and local identifiability analyses (using the CGNM and Fisher information matrix, respectively) informed that the target binding parameters were identifiable only if the observations from the lowest dose (10 mg) were included. By analyzing blood PK profiles alone, the PBPK model with target binding yielded practically identifiable target binding parameters and predicted the maximum target occupancies of 0.6-0.8 at clinical bosentan doses. Our results indicate that target binding, albeit not a major contributor to the nonlinear bosentan PKs, may offer a prediction of target occupancy from blood PK profiles alone and potential guidance on achieving optimal efficacy outcomes, under the condition when the high-affinity drug target is responsible for the efficacy of interest and when the dose ranges cover varying degrees of target binding. SIGNIFICANCE STATEMENT: By incorporating saturable target binding, our physiologically based pharmacokinetic (PBPK) model predicted in vivo target occupancy of bosentan based only on the blood concentration-time profiles obtained from a wide range of doses. Our analysis highlights the potential utility of PBPK models that incorporate target binding in predicting target occupancy in vivo.

Oral drugs used to treat persistent pulmonary hypertension of the newborn.

Introduction:Persistent Pulmonary Hypertension of the Newborn (PPHN) is a life-threatening neonatal condition, mostly treated with inhaled nitric oxide (iNO), intravenous prostaglandins, oral bosentan, sildenafil and tadalafil. However, the utility of non-oral agents is limited in PPHN for their side effects and inconvenient deliveries. Therefore, oral agents such as bosentan, sildenafil and tadalafil are becoming appealing for their satisfactory efficacy, easy mode of administration and acceptable side effects. Areas covered: We conducted a comprehensive search on Pubmed, Scopus, Web of Sciences concerning the use of bosentan, sildenafil and tadalafil to treat PPHN and summarized their efficacy, safety and pharmacokinetics. Expert opinion: Current randomized controlled trials (RCTs) have demonstrated the favorable responses and tolerable side effects of bosentan and sildenafil. Nevertheless, those RCTs are small and only one study has described the pharmacokinetics of sildenafil in neonates. Accordingly, bosentan, sildenafil and tadalafil remain off-label in clinical use. More well-designed RCTs with large samples and long-term follow-up and pharmacometrics studies are needed to demonstrate the efficacy, safety and pharmacokinetics of bosentan, sildenafil and tadalafil in PPHN.

Predictive model of bosentan-induced liver toxicity in Japanese patients with pulmonary arterial hypertension.

Bosentan, an endothelin receptor antagonist, has been widely used as a first-line medication for the treatment of pulmonary arterial hypertension (PAH). It has been shown to improve symptoms of hypertension, exercise capacity, and hemodynamics and prolong time to clinical worsening. However, liver dysfunction is a major side effect of bosentan treatment that could hamper the optimal management of patients with PAH. Previously, we demonstrated, using drug metabolism enzymes and transporters analysis, that the carbohydrate sulfotransferase 3 (CHST3) and CHST13 alleles are significantly more frequent in patients with elevated aminotransferases during therapy with bosentan than they are in patients without liver toxicity. In addition, we constructed a pharmacogenomics model to predict bosentan-induced liver injury in patients with PAH using two single-nucleotide polymorphisms and two nongenetic factors. The purpose of the present study was to externally validate the predictive model of bosentan-induced liver toxicity in Japanese patients. We evaluated five cases of patients treated with bosentan, and one presented with liver dysfunction. We applied mutation alleles of CHST3 and CHST13, serum creatinine, and age to our model to predict liver dysfunction. The sensitivity and specificity were calculated as 100% and 50%, respectively. Considering that PAH is a rare disease, multicenter collaboration would be necessary to validate our model.

Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling.

Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 and 6, is metabolized mainly by cytochrome P450 (CYP)3A4. Clinical studies were performed to assess the impact of strong inhibitor (clarithromycin) and inducer (rifampin) on the exposure of abemaciclib and active metabolites. A physiologically based pharmacokinetic (PBPK) model incorporating the metabolites was developed to predict the effect of other strong and moderate CYP3A4 inhibitors and inducers. Clarithromycin increased the area under the plasma concentration-time curve (AUC) of abemaciclib and potency-adjusted unbound active species 3.4-fold and 2.5-fold, respectively. Rifampin decreased corresponding exposures 95% and 77%, respectively. These changes influenced the fraction metabolized via CYP3A4 in the model. An absolute bioavailability study informed the hepatic and gastric availability. In vitro data and a human radiolabel study determined the fraction and rate of formation of the active metabolites as well as absorption-related parameters. The predicted AUC ratios of potency-adjusted unbound active species with rifampin and clarithromycin were within 0.7- and 1.25-fold of those observed. The PBPK model predicted 3.78- and 7.15-fold increases in the AUC of the potency-adjusted unbound active species with strong CYP3A4 inhibitors itraconazole and ketoconazole, respectively; and 1.62- and 2.37-fold increases with the concomitant use of moderate CYP3A4 inhibitors verapamil and diltiazem, respectively. The model predicted modafinil, bosentan, and efavirenz would decrease the AUC of the potency-adjusted unbound active species by 29%, 42%, and 52%, respectively. The current PBPK model, which considers changes in unbound potency-adjusted active species, can be used to inform dosing recommendations when abemaciclib is coadministered with CYP3A4 perpetrators.

Target-Mediated Population Pharmacokinetic Modeling of Endothelin Receptor Antagonists.

PURPOSE: Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. METHODS: PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects modeling approach. RESULTS: Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. CONCLUSION: The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.

Preparation and characterization of bosentan monohydrate/ε-polycaprolactone nanoparticles obtained by electrospraying.

The electrospraying technique provides nano and microparticles that can be used as drug delivery systems. The aims of this study were, firstly, to optimize the influent parameters of electrospraying for the manufacture of a Bosentan (BOS) nanoparticulate platform, and secondly, to evaluate its physicochemical properties and in vitro biopharmaceutical behavior. Particles were characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetry (TG) and Fourier transformed Infrared spectroscopy (FTIR). Drug loading, encapsulation efficiency and kinetic dissolution were determined. Additionally, Bosentan release assays at 24 and 72 h were performed in vitro to evaluate biopharmaceutical properties of nano-scaffolds by diffusion technique through dialysis bag. The nanostructures had heterogeneous sizes predominantly smaller than 550 nm and they were semicrystalline according to PXRD, indicating a partial amorphization of BOS during the encapsulation in the polymer matrix. FT-IR and DSC showed an absence of chemical interactions between BOS and ε-Polycaprolactone (PCL), suggesting that both components behaved as a physical mixture in these particles. The drug loading was 25.98%, and the encapsulation efficiency was 58.51%. Additionally, the release assays showed an extended and controlled release of BOS, in comparison to non-encapsulated BOS. These data also showed to fit with the Cubic Root kinetic dissolution. As a conclusion, we demonstrate that the use of electrospraying for the manufacture of BOS (or similar drugs) controlled release nanoplatforms would represent an interesting contribution in the development of new therapeutic alternatives for the treatment of pathologies such as pulmonary hypertension and other related diseases. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 35: e2748, 2019.