Qiang Fu

Physiologically‐based pharmacokinetic (PBPK) modeling offers a viable approach to predict induction drug–drug interactions (DDIs) with the potential to streamline or reduce clinical trial burden if predictions can be made with sufficient confidence. In the current work, the ability to predict the effect of rifampin, a well‐characterized strong CYP3A4 inducer, on 20 CYP3A probes with publicly available PBPK models (often developed using a workflow with optimization following a strong inhibitor DDI study to gain confidence in fraction metabolized by CYP3A4, f_m,CYP3A4, and fraction available after intestinal metabolism, Fg), was assessed. Substrates with a range of f_m,CYP3A4 (0.086–1.0), Fg (0.11–1.0) and hepatic availability (0.09–0.96) were included. Predictions were most often accurate for compounds that are not P‐gp substrates or that are P‐gp substrates but that have high permeability. Case studies for three challenging DDI predictions (i.e., for eliglustat, tofacitinib, and ribociclib) are presented. Along with parameter sensitivity analysis to understand key parameters impacting DDI simulations, alternative model structures should be considered, for example, a mechanistic absorption model instead of a first‐order absorption model might be more appropriate for a P‐gp substrate with low permeability. Any mechanisms pertinent to the CYP3A substrate that rifampin might impact (e.g., induction of other enzymes or P‐gp) should be considered for inclusion in the model. PBPK modeling was shown to be an effective tool to predict induction DDIs with rifampin for CYP3A substrates with limited mechanistic complications, increasing confidence in the rifampin model. While this analysis focused on rifampin, the learnings may apply to other inducers.

危重症患者的高病死率是世界范围内重症监护医师面临的重大挑战，有效的抗生素治疗是挽救患者生命的关键因素。危重症患者病理生理学改变导致抗生素药代动力学（pharmacokinetics，PK）/药效动力学（pharmacodynamics，PD）发生改变，优化抗生素给药方案是重要的应对策略。本文对常见抗生素的PD特征、在危重症患者体内PK潜在改变，及PK/PD在危重症患者抗生素治疗方案优化中的应用研究进展进行综述。

Background and Objectives Lenabasum is a synthetic agonist of the cannabinoid receptor type 2 (CB2) with anti-inflammatory and antifibrotic properties. Utilizing Simcyp, we developed a physiologically based pharmacokinetic (PBPK) model based on physicochemical properties, cell culture data, and cytochrome P450 (CYP) phenotyping, inhibition, and induction data. Methods Clinical data from healthy volunteers treated with 20 mg of lenabasum in a single ascending dose (SAD) study were used for model development. The model was verified using lenabasum SAD (10 and 40 mg) data as well as multiple dose (20 mg three times per day) data. Lenabasum is a CYP substrate, and the model predicted lenabasum clearance of 51% by CYP2C9, 37% by CYP2C8, and 12% by CYP3A4. Lenabasum is also an inhibitor of these isozymes. Results The model accurately described the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) for lenabasum within 1.19-fold and 1.25-fold accuracy, respectively, of the observed clinical values. The simulations of CYP inducers predicted that the strongest interaction would occur with rifampin, with the AUC decreasing to 0.36 of the control value, whereas the simulations of CYP inhibitors predicted that the greatest effect would occur with fluconazole, with a 1.43-fold increase in AUC. Conclusions Our model is a useful tool for predicting the pharmacokinetics of lenabasum and adjustments to its dosing in possible drug–drug interaction scenarios.

Background: Ibrutinib (Imbruvica; PCI‐32765), an orally administered inhibitor of Bruton’s tyrosine kinase, is considered a breakthrough targeted therapy that is approved as frontline therapy in chronic lymphocytic leukemia (CLL). Ibrutinib has an average oral bioavailability in humans of in vivo PK studies were performed in wild‐type (WT) male and female FVB mice treated with CYP3A inhibitors including ketoconazole (50 mg/kg p.o.) and cobicistat (30 mg/kg; p.o.) or the respective vehicle controls (PEG400 or corn oil p.o.) thirty minutes prior to dosing with ibrutinib (10 mg/kg p.o.). Based on these results, CYP3A ^(−/−) female FVB mice were treated with ibrutinib (10 mg/kg p.o. or 1 mg/kg i.v.) alone or thirty minutes after administration of cobicistat (30 mg/kg; p.o.). Concentrations of ibrutinib and PCI‐45227 in plasma were determined by a validated method based on liquid chromatography‐tandem mass spectrometry, and PK parameter estimates were calculated with the software package Phoenix WinNonlin (Version 8.1). Student t‐tests comparing mean AUC values between groups were used to determine significance. Results: The peak plasma concentration (C _max ) and area under the concentration‐time curve (AUC) of ibrutinib were ~10‐fold higher in mice administered pharmacologic CYP3A inhibitors prior to ibrutinib ( P < 0.0001) with a substantial decrease in the PCI‐45227 to ibrutinib AUC ratio. As expected, when ibrutinib was administered orally to CYP3A ^(−/−) mice, the AUC of ibrutinib in CYP3A ^(−/−) mice was increased ~10‐fold ( P < 0.0001) with almost no formation of the PCI‐45227 metabolite compared with WT mice. Cobicistat did not impact ibrutinib AUC in CYP3A ^(−/−) mice ( P > 0.9), which suggests that CYP3A inhibition is the major mechanism for cobicistat‐induced increases in ibrutinib exposure. Conclusions: Previously obtained data with other kinase inhibitors indicate that patients with high CYP3A4 activity may benefit from an increased dose to achieve drug concentrations required to interact with kinase targets; a strategy by which enzyme activity is inhibited could achieve similar results. In view of the established inverse‐correlation between absolute bioavailability and inter‐individual PK variability, the current data provide a rationale for the development of exploratory clinical studies aimed at decreasing the variability in ibrutinib exposure by concomitant administration of CYP3A4 inhibitors. Future preclinical efficacy studies will determine the impact of this strategy on survival in mouse models of B‐cell malignancies.

Background: The human organic anion‐transporting polypeptide 2B1 (OATP2B1; SLC21A9) is localized to the basolateral membrane of hepatocytes and the brush‐border membrane of small‐intestinal enterocytes. Based on its distribution pattern and functional similarity to OATP1B‐type transporters, it has been hypothesized that OATP2B1 might influence the absorption and disposition properties of a wide range of xenobiotic agents. Although several prescription drugs, including statins such as fluvastatin, have been identified as OATP2B1 substrates in vitro , the lack of a useful in vivo model system has limited our understanding of the pharmacological role of this transporter. Experimental design: OATP2B1‐overexpressing cells were generated by transfecting HEK293 cells with an empty vector (VC) or a construct containing human OATP2B1 or mouse OATP2B1 cDNA. Transporter function was evaluated in vitro by measuring the comparative cellular uptake of [ ³ H]estrone‐3‐sulfate (ES) in VC cells and OATP2B1‐overexpressing cells. Candidate substrates and inhibitors were identified based on the difference in intracellular accumulation of radioactivity. OATP2B1‐knockout (KO) mice were obtained from the Slco2b1 ^{tm1a(KOMP)Wtsi} clone, and derived chimera and subsequent progeny were mated to C57BL/6N for germline production and colony expansion. Mouse genotypes were confirmed by PCR, and OATP2B1 gene deletion was verified by qPCR on major organs. The pharmacokinetic profiles of fluvastatin, a known OATP2B1 substrate, and sorafenib, a known OATP2B1 inhibitor, were determined through serial blood collection and subsequent LC‐MS/MS analysis. Noncompartmental pharmacokinetic parameters were calculated using WinNolin 6.2 software (Pharsight). Results: An approximately four‐fold increase in intracellular accumulation of radiolabeled ES (2.5 μM) was observed in the OATP2B1 overexpressing cells compared to VC cells (34.8 ± 2.45 pmol/mg vs 8.38 ± 0.341 pmol/mg, respectively). Subsequently, we identified several drugs as candidate OATP2B1 substrates, including multiple tyrosine kinase inhibitors (TKIs). Knockout of OATP2B1 in organs from KO mice was confirmed at the gene level (PSupport or Funding Information Eli Lilly Fellowship in Pharmaceutics This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

For emergency contraceptive, the rapid delivery of levonorgestrel (LNG) to plasma is desirable, furthermore, a sustained delivery of LNG along with rapid absorption will be necessary. The pharmacokinetics and pharmacodynamics of LNG entrapped in different kinds of liposome formulations via nasal administration in rats were evaluated and compared with LNG suspension via the oral route. The relative bioavailabilities of these liposome formulations via nasal administration were 100% or higher than 100%. The Cmax and Tmax values of sterylglucoside (SG) and chitosan-contained formulations by nasal administration were 416.84 ng/mL and 1.02 hr, 227.97 ng/mL and 2.02 hr, respectively, compared with that of 334.94 ng/mL and 1.89 hr of oral suspension. Fully 100% contraception was observed for all the formulations. SG could promote the absorption of LNG via the nasal route and may provide a rapid onset of action of LNG for emergency contraception. Chitosan could retain LNG in the nasal cavity for long contact time to sustain delivery of LNG. The rapid onset and sustained delivery of LNG can be achieved via the nasal route using liposomes as the vehicle.