Model informed drug development: HSK21542 PBPK model supporting dose decisions in specific populations.

HKS21542, a highly selective activator of peripheral kappa opioid receptor agonists, plays a critical role in antinociception and itch inhibition during clinical development. Due to its indication population and elimination characteristics, it is imperative to evaluate the potential HSK21542 systemic exposure in individuals with renal impairment, hepatic impairment, the elderly, and the geriatric population. Here, a physiologically-based pharmacokinetic (PBPK) model for HSK21542 was developed based on in vitro metabolism and transport characteristics and in vivo elimination mechanism. Meanwhile, the potential systemic exposure of HSK21542 in specific populations was evaluated. The predicted results indicated increased systemic exposure in patients with renal impairment, hepatic impairment and in the elderly. Compared to the healthy volunteers aged 20-60 years, the AUC0-24h increased by 52 %-71 % in population with moderate to severe renal impairment, by 46 %-77 % in those with mild to severe hepatic impairment, and by 45 %-85 % in the elderly population aged 65-95-years. Conversely, the pediatric population demonstrated a potential decrease in systemic exposure, ranging from 20 % to 37 % in patients aged 0-17 years due to the physiological characteristics. Combined with the predicted results and the exposure-response relationship observed for HSK21542 and its analog (CR845), dosage regimens were designed for the target population with renal and hepatic impairment, supporting the successfully conducted trials (CTR20201702 and CTR20211940). Moreover, the observed exposure of HSK21542 in the elderly closely matched the predicted results within the same age group. Additionally, based on the predicted results, potential reductions in systemic exposure in pediatric patients should be carefully considered to avoid potential treatment failure in future clinical trials.

Pharmacokinetics and exposure-safety relationship of ciprofol for sedation in mechanically ventilated patients in the intensive care unit.

Ciprofol (HSK3486) is a newly developed, highly selective γ-aminobutyric acid-A (GABAA ) receptor potentiator that is recently approved for a new indication of sedation for patients in the intensive care unit (ICU) in China. This analysis aimed to characterize the population pharmacokinetics (PopPKs) of ciprofol and evaluate the relationship of exposure with hypotension in mechanically ventilated patients in the ICU. A total of 462 subjects with 3918 concentration measurements from two clinical trials of mechanically ventilated patients in the ICU, four clinical trials of elective surgical patients, and six clinical trials of healthy subjects were used in the PopPK analysis. Exposure-safety relationship for hypotension was evaluated based on the data gathered from 112 subjects in two clinical trials of mechanically ventilated patients in the ICU. Ciprofol pharmacokinetics (PKs) was adequately described by a three-compartment linear disposition model with first-order elimination. Body weight, age, sex, blood sampling site (vein vs. arterial), study design (long-term infusion vs. short-term infusion), and patient population (ICU vs. non-ICU) were identified as statistically significant covariates on the PKs of ciprofol. Within the exposure range of the mechanically ventilated ICU patient population, no meaningful association was observed between ciprofol exposure and the incidence of hypotension. These results support the dosing regimen currently used in mechanically ventilated patients in the ICU.

Comparison of the Efficacy of HSK3486 and Propofol for Induction of General Anesthesia in Adults: A Multicenter, Randomized, Double-blind, Controlled, Phase 3 Noninferiority Trial.

BACKGROUND: Propofol is an intravenous anesthetic associated with hypotension, respiratory depression, and injection-site pain. HSK3486 injectable emulsion (ciprofol) is a 2,6-disubstituted phenol derivative with fast onset and quick, stable recovery. Previous studies support HSK3486 as an effective, safe anesthetic with substantially less injection-site pain than propofol. The primary objective of this study was to investigate the noninferiority of HSK3486 compared with propofol in successful general anesthesia induction. METHODS: Two hundred fifty-five participants were enrolled in HSK3486-304, a multicenter, randomized (2:1), double-blind, propofol-controlled, phase 3 study evaluating HSK3486 for general anesthesia induction in adults undergoing elective surgery with tracheal intubation. The primary endpoint was successful anesthesia induction, defined as 1 or less on the Modified Observer's Assessment of Alertness/Sedation scale. Key secondary endpoints were proportion of participants with injection-site pain on the Numerical Rating Scale of 1 or greater and a composite endpoint, including the proportion of participants successfully induced while maintaining the desired anesthetic depth and without substantial cardiac and respiratory events. Safety endpoints included adverse events, abnormal vital signs, and injection-site pain. RESULTS: Two hundred fifty-one participants (HSK3486, n = 168; propofol, n = 83) were included in the analyses. General anesthesia was successfully induced in 97.0% versus 97.6% of participants with HSK3486 and propofol, respectively. The difference in success rate was -0.57% (95% CI, -5.4 to 4.2%); the noninferiority boundary of -8% was not crossed. Thirty participants (18.0%) had injection-site pain with HSK3486 versus 64 (77.1%) with propofol (P < 0.0001). Eighty-one participants (48.2%) with HSK3486 versus 42 (50.6%) with propofol (P = 0.8780) satisfied the composite endpoint. When injection-site pain was excluded, the incidence of treatment-emergent adverse events related to study drug was 17.9% for HSK3486 and 14.5% for propofol. CONCLUSIONS: The study met its primary objective and endpoint, demonstrating noninferiority of HSK3486 compared with propofol in successful anesthetic induction. Substantially less injection-site pain was associated with HSK3486 than with propofol.

Population pharmacokinetic/pharmacodynamic modeling and exposure-response analysis of ciprofol in the induction and maintenance of general anesthesia in patients undergoing elective surgery: A prospective dose optimization study.

AIM: This study aimed to establish a population pharmacokinetic and pharmacodynamic (PK-PD) model to explore the optimal maintenance dose and appropriate starting time of maintenance dose after induction of ciprofol and investigate the efficacy and safety of ciprofol for general anesthesia induction and maintenance in patients undergoing elective surgery. METHOD: A total of 334 subjects with 3092 concentration measurements from nine clinical trials and 115 subjects with 5640 bispectral index (BIS) measurements from two clinical trials were used in the population PK-PD analysis. Exposure-response relationships for both efficacy endpoints (duration of anesthesia successful induction, time to recovery from anesthesia, time to respiratory recovery, and time from discontinuation to the 1st/3rd consecutive Aldrete score ≥ 9) and safety variables (hypotension, bradycardia, and injection site pain) were evaluated based on the data gathered from 115 subjects in two clinical trials. RESULT: Ciprofol pharmacokinetics (PK) were adequately described by a three-compartment model with first-order elimination from the central compartment and redistribution from the deep and shallow peripheral compartments. An inhibitory sigmoidal Emax model best described the relationship between ciprofol effect-site concentrations and BIS measurements. Body weight, age, sex, blood sampling site, and study type (short-term infusion vs long-term infusion) were identified as statistically significant covariates on the PK of ciprofol. No covariates were found to have a significant effect on the pharmacodynamic (PD) parameters. The PK-PD simulation results showed that the optimal maintenance dose was 0.8 mg/kg/h and the appropriate time to start the maintenance dose was 4-5 mins after the induction dose of ciprofol. Within the exposure range of this study, no meaningful correlations between ciprofol exposures and efficacy or safety endpoints were observed. CONCLUSION: A population PK-PD model was successfully developed to describe the ciprofol PK and BIS changes. Efficacy was consistent across the exposure range with a well-tolerated safety profile indicating no maintenance dose adjustment is required for patients undergoing elective surgery.

Pharmacokinetics, pharmacodynamics, and safety of ciprofol emulsion in Chinese subjects with normal or impaired renal function.

Background: Ciprofol, a novel sedative-hypnotic drug, has been approved for its use in inducing and maintaining general anesthesia, as well as for providing sedation. Methods: In this phase I, single-center, parallel, controlled, open-label clinical trial, our objective was to analyze the pharmacokinetics (PK), pharmacodynamics (PD), and safety of ciprofol emulsion in 24 participants with mild and moderate renal impairment (n = 8 per group) and matched healthy participants (n = 8). An initial loading infusion of ciprofol was administered at 0.4 mg/kg for 1 min, followed by a maintenance infusion at a rate of 0.4 mg/kg/h for 30 min. We collected plasma and urine samples from the participants to assess the PK of ciprofol and its metabolite M4. The evaluation of PD involved using a modified observer's alertness/sedation scale (MOAA/S) in combination with bispectral index (BIS) monitoring. Safety assessments were conducted throughout the trial process. Results: The plasma concentration-time curve of ciprofol in participants with renal impairment was similar to that in participants with normal kidney function. The area under the curve (AUC) and maximum concentration (Cmax) of total and unbound ciprofol in plasma for participants with renal impairment were only slightly higher (0.7-1.2-fold) than those in participants with normal renal function. In contrast, for the metabolite M4, AUC values were 1.3- and 2.1-fold greater in participants with mild and moderate renal impairment, respectively, than in healthy controls. However, renal impairment had no significant impact on the PD parameters. The study found that ciprofol was well-tolerated, with all adverse events (AEs) reported being mild or moderate in severity. Conclusion: Based on these findings, we can conclude that no dosage adjustment of ciprofol is necessary for patients with mild-moderate renal impairment who receive the injection. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT04142970.

Dose decision of HSK7653 oral immediate release tablets in specific populations clinical trials based on mechanistic physiologically-based pharmacokinetic model.

HSK7653, an oral dipeptidyl peptidase-4 inhibitor administered every 2 weeks, is a candidate for the treatment of type 2 diabetes mellitus. The major elimination pathway of HSK7653 in vivo is renal excretion, and hepatic metabolism and fecal excretion of unchanged compound contribute less to the systemic clearance of HSK7653. Considering the disposition characteristics and the potential indication population of HSK7653, evaluating the HSK7653 exposure in patients with renal impairment and geriatric populations is a prerequisite for bringing more benefits to the patients. Here, a PBPK model was developed based on in vitro experimental results, such as dissolution, permeability, and metabolism, and the in vivo renal clearance, to evaluate the effects of physiological factors and food on HSK7653 exposure in specific populations, including adult and elder individuals with renal impairment and geriatric populations. Simulation results showed that the AUC of HSK7653 increased by 46%, 82%, and 129% in adult patients with mild, moderate, and severe renal impairment, and by 56%, 78%, and 101% in patients aged 65-75, 75-85 and 85-95 years, respectively. The AUC increased in the range of 62%-83%, 98%-133%, and 153%-195% in elderly patients (65-95 years) with mild, moderate, and severe renal impairment, respectively. Moreover, two different absorption model development methods (dissolution profile method and the diffusion layer model method) predicted that food had no effect on the exposure of the same simulated population. Since the predicted AUC of HSK7653 at the 10 mg dose in various specific populations was still within the relatively flat results of the exposure-response analysis, the 10 mg dose of HSK7653 was first used to explore the exposure in the renal impairment population (CTR20221952).

Population total and unbound pharmacokinetics and pharmacodynamics of ciprofol and M4 in subjects with various renal functions.

AIMS: The aim of this study was to develop a population pharmacokinetic (PK) model to simultaneously describe both total and unbound concentrations of ciprofol and its major glucuronide metabolite, M4, and to link it to the population pharmacodynamics (PD) model in subjects with various renal functions. METHODS: A total of 401 and 459 pairs of total and unbound plasma concentrations of ciprofol and M4, respectively, as well as 2190 bispectral index (BIS) data from 24 Chinese subjects with various renal functions were available. Covariates that may potentially contribute to the PK and PD variability of ciprofol were screened using a stepwise procedure. The optimal ciprofol induction dosing regimen was determined by model-based simulations. RESULTS: The PK of unbound ciprofol could best be described by a three-compartment model, while a two-compartment model could adequately describe unbound M4 PK. The concentrations of total and unbound ciprofol and M4 were linked using a linear protein binding model. The relationship between plasma concentrations of ciprofol and BIS data was best described by an inhibitory sigmoidal Emax model with a two-compartment biophase distribution compartment. Hemoglobin was the identified covariate determining the central compartment clearance of ciprofol; uric acid was a covariate affecting the central compartment clearance of M4 and protein binding rate, kB . The included covariates had no effect on the PD of ciprofol. Simulation results indicated that the label-recommended dose regimen was adequate for anaesthesia induction. CONCLUSIONS: The developed model fully characterized the population PK and PD profiles of ciprofol. No dose adjustment is required in patients with mild and moderate renal impairment.

Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment.

BACKGROUND: The primary objective of this study was to investigate if hepatic impairment alters the safety, pharmacokinetics, and pharmacodynamics of HSK3486. RESEARCH DESIGN AND METHODS: This was a clinical trial of HSK3486 in subjects with normal hepatic function (n = 8), and mild (Child-Pugh A; n = 8), or moderate (Child-Pugh B; n = 8) hepatic impairment. Each subject received an IV bolus dose of 0.4 mg/kg HSK3486 for 1 min, immediately followed by a maintenance infusion of 0.4 mg/kg/h HSK3486 for 30 min. RESULTS: In total, 24 subjects were enrolled and completed the study. HSK3486 was generally well tolerated by all subjects. There were no serious AEs and no deaths reported during the study. The incidence of AEs was numerically highest in subjects with moderate hepatic impairment. The exposure (AUC) of HSK3486 increased gradually with the decrease in hepatic function; however, degree of hepatic impairment had little effect on HSK3486 PD (MOAA/S and BIS). CONCLUSIONS: Overall, there were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to normal control. These data imply that HSK3486 dose adjustment is not warranted in subjects with mild or moderate hepatic impairment. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04145596).Key MessageHSK3486 at an IV bolus dose of 0.4 mg/kg and a maintenance infusion of 0.4 mg/kg/h was safe and well tolerated by all mild or moderate hepatic impairment subjects and normal hepatic function subjects.There were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function.HSK3486 dose adjustment is not required in subjects with mild or moderate hepatic impairment.

Safety, Pharmacokinetics, and Pharmacodynamics of a Single Bolus of the γ-aminobutyric Acid (GABA) Receptor Potentiator HSK3486 in Healthy Chinese Elderly and Non-elderly.

Background: The present clinical trial investigated the potential influences of dosage and age on the pharmacokinetic properties and safety profile of HSK3486, and whether any adjustment in dosing regimen is necessary in elderly patients. Methods: Twenty-four elderly participants (65-73 years) were apportioned to three equal cohorts to receive a single IV bolus of 0.2, 0.3, and 0.4 mg/kg HSK3486, respectively. An additional control group comprised eight non-elderly participants (21-44 years), who each received a single IV bolus dose of 0.4 mg/kg. Safety was assessed throughout the study, and the clinical effects were assessed based on modified observer's assessment of alertness/sedation and bispectral index (BIS) monitor. Pharmacokinetic parameters were calculated. Results: The rates of drug-related adverse reactions among the elderly groups were a little higher than that of the non-elderly, and were slightly higher in the elderly receiving 0.4 mg/kg compared with the elderly given lower doses. The pharmacokinetic characteristics of 0.4 mg/kg HSK3486 in the elderly and non-elderly were comparable. The time to recovery was similar in elderly 0.3 mg/kg, elderly 0.4 mg/kg and non-elderly 0.4 mg/kg groups. In the elderly 0.2 mg/kg group, the time to loss of consciousness was a little longer, and the time to recovery was shorter, relative to the other three groups. Conclusions: Administration of 0.3 mg/kg to the elderly and 0.4 mg/kg to the non-elderly were similarly efficacious. A dose of HSK3486 of 0.3 mg/kg may be chosen for clinical use in elderly patients.

Mass balance, pharmacokinetics and pharmacodynamics of intravenous HSK3486, a novel anaesthetic, administered to healthy subjects.

AIMS: This trial (NCT03751956) investigated the mass balance, pharmacokinetics and pharmacodynamics of HSK3486, a novel anaesthetic, in healthy subjects. METHODS: A single dose of 0.4 mg/kg [14 C]HSK3486 was administered to six healthy subjects. Blood, urine and faecal samples were collected, analysed for radioactivity, unchanged HSK3486 and profiled for metabolites. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and vital signs were closely monitored during the study. RESULTS: The mean recovery of total radioactivity in excreta was 87.3% in 240 h, including 84.6% in urine and 2.65% in faeces. The exposure (AUC0-t ) of total radioactivity was much higher than that of unchanged HSK3486 in plasma, indicating there were circulating metabolites in plasma. The glucuronide conjugate of HSK3486 (M4) was found as the only major circulating metabolite in plasma (79.3%), while unchanged HSK3486 accounted for only 3.97% of the total radiation exposure. M4 also resulted in a longer estimated elimination half-life (t1/2 ) of total radioactivity than that of unchanged HSK3486 in plasma. Fortunately, the metabolite was detected to be not specific to red blood cells and was suggested to be nonhypnotic and nontoxic. All the subjects were quickly anaesthetized (2 min) after drug administration and woke up smoothly after a short time (5.5-14.1 min) with few residual effects. The only adverse event in the study was mild (grade 1) and consisted of hypotension. CONCLUSION: HSK3486 is a promising anaesthetic candidate with rapid onset of action and clear absorption, distribution, metabolism, excretion (ADME) processes. HSK3486 showed favourable pharmacokinetic characteristics, pharmacodynamic responses and safety at the study dose.

Design, Synthesis, and Evaluation of a Series of Novel Super Long-Acting DPP-4 Inhibitors for the Treatment of Type 2 Diabetes.

In the present work, a novel series of trifluoromethyl-substituted tetrahydropyran derivatives were rationally designed and synthesized as potent DPP-4 inhibitors with significantly improved duration time of action over current commercially available DPP-4 inhibitors. The incorporation of the trifluoromethyl group on the 6-position of the tetrahydropyran ring of omarigliptin with the configuration of (2R,3S,5R,6S) not only significantly improves the overall pharmacokinetic profiles in mice but also maintains comparable DPP-4 inhibition activities. Further preclinical development of compound 2 exhibited its extraordinary efficacy in vivo and good safety profile. Clinical studies of compound 2 (Haisco HSK7653) are now ongoing in China, which revealed that inhibitor 2 could serve as an efficient candidate with a once-biweekly therapeutic regimen.

Oral Delivery of Propofol with Methoxymethylphosphonic Acid as the Delivery Vehicle.

Phosphonamidate 3a of methoxymethylphosphonic acid (MMPA) with propofol (1) and l-alanine ethyl ester was found to be an efficient scaffold for the oral delivery of compound 1. The synthesis and evaluation of MMPA based phosphonamidates of compound 1, HSK3486 (2), and other phenolic drugs revealed the general application of MMPA as the effective delivery vehicle for phenolic drugs. On the basis of plasma concentrations of compound 1 and SN38 (14), the oral bioavailability of compound 3a and 15 in beagle dogs was found to be 97.6% and 34.1%, respectively.

SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models.

AIM: The sodium glucose cotransporter 2 (SGLT2) plays an important role in renal glucose reabsorption, thus serves as a new target for the treatment of diabetes. The purpose of this study was to evaluate SHR3824 as a novel selective SGLT2 inhibitor and to characterize its in vivo effects on glucose homeostasis. The effects of chronic administration of SHR3824 on peripheral insulin sensitivity and pancreatic ß-cell function were also investigated. METHODS: The in vitro potency and selectivity of SHR3824 were assessed in HEK293 cells transfected with human SGLT2 or SGLT1. Acute and multi-dose studies were performed on ICR mice, GK rats and db/db mice to assess the ability of SHR3824 to enhance urinary glucose excretion and improve blood glucose levels. 2-Deoxyglucose uptake and insulin immunohistochemical staining were performed in the soleus muscle and pancreas, respectively, of db/db mice. A selective SGLT2 inhibitor BMS512148 (dapagliflozin) was taken as positive control. RESULTS: SHR3824 potently inhibited human SGLT2 in vitro, but exerted much weak inhibition on human SGLT1 (the IC50 values of SHR3824 against human SGLT2 and SGLT1 were 2.38 and 4324 nmol/L, respectively). Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg·kg(-1)·d(-1)) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice. CONCLUSION: SHR3824 is a potent and selective SGLT2 inhibitor and exhibits antidiabetic efficacy in several rodent models, suggesting its potential as a new therapeutic agent for the treatment of type 2 diabetes.

Development of a homogeneous calcium mobilization assay for high throughput screening of mas-related gene receptor agonists.

AIM: To develop homogeneous calcium mobilization assay for high-throughput screening (HTS) of mas-related gene (Mrg) receptor agonists. METHODS: CHO-K1 cells stably expressing the full-length MrgD receptor and a calcium-sensitive dye were used to develop an HTS assay based on intracellular calcium influx. This method was applied to large-scale screening of a library containing 8000 synthetic compounds and natural product extracts. cAMP measurements were carried out to verify the bioactivities of the hits found by the calcium mobilization assay. Similar approaches were also employed in the identification of the MrgA1 receptor agonists following HTS of 16,000 samples. RESULTS: EC(50) values of the positive control compounds (beta-alanine for MrgD receptor and dynorphin A for MrgA1 receptor) determined by the calcium mobilization assay were consistent with those reported in the literature, and the Z' factors were 0.65 and 0.50 for MrgD and MrgA1 receptor assay, respectively. About 31 compounds for the MrgD receptor and 48 compounds for the MrgA1 receptor showing > or =20% of the maximal agonist activities found in the controls were initially identified as hits. Secondary screening confirmed that 2 compounds for each receptor possessed specific agonist activities. Intracellular cAMP level measurements indicated that the 2 confirmed hits displayed the functionality of the MrgD receptor agonists. CONCLUSION: A series of validation studies demonstrated that the homogeneous calcium mobilization assay developed was highly efficient, amenable to automation and a robust tool to screen potential MrgD and MrgA1 receptor agonists. Its application may be expanded to other G-protein coupled receptors that mobilize calcium influx upon activation.

The immunosuppressant cyclosporin A antagonizes human formyl peptide receptor through inhibition of cognate ligand binding.

Cyclosporin A (CsA) is a fungus-derived cyclic undecapeptide with potent immunosuppressive activity. Its analog, cyclosporin H (CsH), lacks immunosuppressive function but can act as an antagonist for the human formyl peptide receptor (FPR). More recent studies have shown that CsA also inhibits fMLF-induced degranulation in differentiated HL-60 promyelocytic leukemia cells. However, it is unclear whether CsA interferes with ligand-receptor interaction, G protein activation, or other downstream signaling events. In this study we used human neutrophils, differentiated HL-60 cells, and rat basophilic leukemia (RBL)-2H3 cells expressing human FPR (RBL-FPR) to identify the action site of CsA. In functional assays, CsA inhibited fMLF-stimulated degranulation, chemotaxis, calcium mobilization, and phosphorylation of the MAPKs ERK 1/2 and the serine/threonine protein kinase Akt. CsA also blocked Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm)-induced functions in RBL-FPR cells. Concentrations for half-maximal inhibition with CsA are generally 6- to 50-fold higher than that of CsH. CsA was compared with another immunosuppressant, ascomycin, relative to the inhibitory effects on FPR-mediated chemotaxis, calcium mobilization, and degranulation. In these experiments, ascomycin produced no inhibitory effects at low micromolar concentrations (1-4 microM), whereas the inhibitory effects of CsA were prominent at comparable concentrations. Finally, CsA dose-dependently inhibited the uptake of fNle-Leu-Phe-Nle-Tyr-Lys-fluoresceine and [3H]fMLF or [125I]WKYMVm binding to FPR. However, CsA and CsH did not show any obvious inhibitory effect on FPR-like 1-mediated cellular functions. These results demonstrate that CsA is a selective antagonist of FPR and that its inhibition of fMLF-stimulated leukocyte activation is at the level of cognate ligand binding.