Prediction of human pharmacokinetics of typical compounds by a physiologically based method using chimeric mice with humanized liver

<p></p><p>In this study, total body clearance (CL_t), volume of distribution at steady state (<i>V</i>_ss) and plasma concentration–time profiles in humans of model compounds were predicted using chimeric mice with humanized livers.</p><p>On the basis of assumption that unbound intrinsic clearance (CL_Uint) per liver weight in chimeric mice was equal to those in humans, CL_t were predicted by substituting human liver blood flow and liver weights in well-stirred model. <i>V</i>_ss were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SF_Kp) in chimeric mice estimated from a difference between the observed and predicted <i>V</i>_ss. These physiological approaches showed high prediction accuracy for CL_t and <i>V</i>_ss values in humans.</p><p>We compared the predictability of CL_t and <i>V</i>_ss determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method.</p><p>Simulation of human plasma concentration–time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CL_Uint and SF_Kp obtained from chimeric mice.</p><p>Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds.</p><p></p> <p>In this study, total body clearance (CL_t), volume of distribution at steady state (<i>V</i>_ss) and plasma concentration–time profiles in humans of model compounds were predicted using chimeric mice with humanized livers.</p> <p>On the basis of assumption that unbound intrinsic clearance (CL_Uint) per liver weight in chimeric mice was equal to those in humans, CL_t were predicted by substituting human liver blood flow and liver weights in well-stirred model. <i>V</i>_ss were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SF_Kp) in chimeric mice estimated from a difference between the observed and predicted <i>V</i>_ss. These physiological approaches showed high prediction accuracy for CL_t and <i>V</i>_ss values in humans.</p> <p>We compared the predictability of CL_t and <i>V</i>_ss determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method.</p> <p>Simulation of human plasma concentration–time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CL_Uint and SF_Kp obtained from chimeric mice.</p> <p>Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds.</p

Synthesis of ¹¹C‑Labeled Thiamine and Fursultiamine for in Vivo Molecular Imaging of Vitamin B₁ and Its Prodrug Using Positron Emission Tomography

To enable in vivo analysis of the kinetics of vitamin B₁ (thiamine) and its derivatives by positron emission tomography (PET), ¹¹C-labeled thiamine ([¹¹C]-<b>1</b>) has been synthesized. This was carried out via a rapid, multistep synthesis consisting of Pd⁰-mediated <i>C</i>-[¹¹C]­methylation of a thiazole ring for 3 min and benzylation with 5-(bromomethyl)­pyrimidine for 7 min. The [¹¹C]-<b>1</b> was also converted to ¹¹C-labeled fursultiamine ([¹¹C]-<b>2</b>), a prodrug of vitamin B₁, by disulfide formation with <i>S</i>-tetrahydrofurfurylthiosulfuric acid sodium salt. Characterization of [¹¹C]-<b>1</b> and [¹¹C]-<b>2</b> showed them to be suitable for use as PET probes for in vivo pharmacokinetic and medical studies. The total durations of the preparations of [¹¹C]-<b>1</b> and [¹¹C]-<b>2</b> were shorter than 60 and 70 min, respectively. The [¹¹C]­CH₃I-based decay-corrected radiochemical yields of [¹¹C]-<b>1</b> and [¹¹C]-<b>2</b> were 9–16% and 4–10%, respectively. The radioactivities of the final injectable solutions of [¹¹C]-<b>1</b> and [¹¹C]-<b>2</b> were 400–700 and 100–250 MBq, respectively. The radiochemical purity of both [¹¹C]-<b>1</b> and [¹¹C]-<b>2</b> was 99%, and the chemical purities of [¹¹C]-<b>1</b> and [¹¹C]-<b>2</b> were 99% and 97–99%, respectively. In vivo PET imaging of normal rats was illustrated by the distribution of [¹¹C]-<b>1</b> and [¹¹C]-<b>2</b> following intravenous injection

SAR Exploration Guided by LE and Fsp³: Discovery of a Selective and Orally Efficacious RORγ Inhibitor

A novel series of RORγ inhibitors was identified starting with the HTS hit <b>1</b>. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp³ carbon atoms (Fsp³), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor <b>3z</b>