A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects.

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.

A first-in-human phase I study of SHR-1906, a humanized monoclonal antibody against connective tissue growth factor, in healthy participants.

New therapeutic targets and drugs are urgently needed to halt the fibrosing process in idiopathic pulmonary fibrosis (IPF). SHR-1906 is a novel fully humanized monoclonal antibody against the connective tissue growth factor, which plays an essential role in the genesis of IPF. We assessed the safety, tolerability, pharmacokinetics (PKs), and immunogenicity of single dose SHR-1906 in healthy participants. This was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Twelve healthy participants for each dose level were enrolled to receive single ascending doses of SHR-1906 intravenously (1.5, 6, 12, 20, 30, and 45 mg/kg) or placebo and followed for 71 days. The primary end points were safety and tolerability. Treatment-related treatment-emergent adverse events occurred in 25 participants (46.3%) in the SHR-1906 group and 11 (61.1%) in the placebo group. No serious adverse events occurred. Over the dose range investigated, the geometric mean clearance was 0.14-0.63 mL/h/kg, the geometric mean volume of distribution at steady-state was 47.4-75.5 mL/kg, and the terminal elimination half-life was 51.9-349 h. SHR-1906 showed nonlinear PKs. The peak concentration increased in a dose-proportional manner, whereas the area under the concentration-time curve showed a greater than dose-proportional increase. Anti-drug antibodies of SHR-1906 were detected in nine of 54 participants (16.7%). A single dose of SHR-1906 up to 45 mg/kg demonstrated a favorable tolerability profile in healthy participants. The PKs and immunogenicity of SHR-1906 were evaluated, supporting further clinical development.

Population pharmacokinetics and pharmacogenetics of apatinib in adult cancer patients.

AIMS: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment. METHODS: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations. RESULTS: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers. CONCLUSIONS: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.

Pharmacokinetics and bioavailability of a new long-acting insulin analog in healthy Chinese volunteers: an open, randomized, single-dose, two-period and two-sequence cross-over study.

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T). Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t and AUC0-∞) were used to evaluate relative bioavailability. Results: After a single dose at 0.4 U/kg, the median Tmax of INS068 was 12 h for both formulations, and the mean t1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of Cmax and AUC0-∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of Cmax, AUC0-t and AUC0-∞ of T over R were 98.7% (90% CI: 92.7%-105.2%), 102.6% (90% CI: 100.0%-105.3%) and 102.8% (90% CI: 100.1%-105.5%). Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT05336071.

LPS-Induced Inflammation Affects Midazolam Clearance in Juvenile Mice in an Age-Dependent Manner.

PURPOSE: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis. METHODS: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9-42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2. RESULTS: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age. CONCLUSION: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age.

Population Pharmacokinetics and Dosing Optimization of Vancomycin in Infants, Children, and Adolescents with Augmented Renal Clearance.

Augmented renal clearance (ARC) can cause underexposure to vancomycin, thereby increasing the risk of treatment failure. Our objective was to evaluate population pharmacokinetics and optimize the dosing regimen of vancomycin in a pediatric population with ARC. Sparse pharmacokinetic sampling and therapeutic drug monitoring (TDM) data were collected from pediatric patients with ARC treated with vancomycin. A pharmacokinetic model was developed using NONMEM 7.2. The dosing regimen was optimized using Monte Carlo dose simulations. A total of 242 vancomycin serum concentrations from 113 patients (age range, 0.4 to 14.9 years; 49 females and 64 males) were available. The mean vancomycin dose was 58.8 mg/kg body weight/day (13.6 mg/kg/dose), and the mean vancomycin serum trough concentration was 6.5 mg/liter. A one-compartment pharmacokinetic model with first-order elimination was developed. Body weight and age were the most significant and positive covariates for clearance and volume of distribution. For the pediatric population with ARC, the current recommended vancomycin dose of 60 mg/kg/day was associated with a high risk of underdosing. To reach the target area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC) ratio of 400 to 700 in these pediatric patients, the vancomycin dose should be increased to 75 mg/kg/day for infants and children between 1 month and 12 years of age and 70 mg/kg/day for adolescents between 12 and 18 years of age. In conclusion, a one-compartment pharmacokinetic model with first-order elimination was established with body weight and age as significant covariates. An optimal dosing regimen was developed in pediatric patients with ARC aged 1 month to 18 years.

Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration.

PURPOSE: Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters. METHODS: ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively. CONCLUSIONS: The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

First dose in neonates: pharmacokinetic bridging study from juvenile mice to neonates for drugs metabolized by CYP3A.

First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A. We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK parameters in neonates using different correction methods. The bridging results were evaluated by the fold-error of 0.5- to 1.5-fold. Simple allometry with and without a correction factor for maximum lifespan potential could be used for a bridging of clearance (CL) and volume of distribution (Vd), respectively, from juvenile mice to neonates. Simulation results demonstrated that for midazolam, 100% of clinical studies for which both the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. For clindamycin, 75% and 100% of clinical studies for which the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. A PK bridging of drugs metabolized by CYP3A is feasible from juvenile mice to neonates. It could be a complement to the ADE and PBPK models to support the first dose in neonates.

COMPARISON OF PROJECTION-RESOLVED OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY-BASED METRICS FOR THE EARLY DETECTION OF RETINAL MICROVASCULAR IMPAIRMENTS IN DIABETES MELLITUS.

PURPOSE: To determine the ability of nonperfusion, vessel density, and morphologic measurements using projection-resolved optical coherence tomography angiography to detect early retinal microvasculature impairments in diabetes mellitus. METHODS: A retrospective review was performed on Type 2 diabetes mellitus patients with no diabetic retinopathy (DR) or mild nonproliferative DR and age-matched controls imaged with optical coherence tomography angiography. Foveal avascular zone-related metrics and extrafoveal avascular area were measured in optical coherence tomography angiography images. Vessel density and fractal dimension were calculated with and without a skeletonization process. The vessel diameter index and vessel tortuosity were computed. The area under the receiver operating characteristic curve (AUC) estimated diagnostic performances. RESULTS: Dilated capillary diameter was observed in the deep capillary plexus in the diabetic groups. Vessel density and fractal dimension of skeletonized deep capillary plexus significantly and progressively decreased in the no DR and mild nonproliferative DR groups compared with controls. Superficial extrafoveal avascular area, vessel density, and fractal dimension of the skeletonized deep capillary plexus had the highest diagnostic performance to differentiate mild nonproliferative DR from control eyes, with AUCs of 0.885, 0.876, and 0.876, respectively. CONCLUSION: Vessel density and fractal dimension from the skeletonized deep capillary network may be the most sensitive for detecting early retinal capillary loss in diabetes mellitus.

Visual outcome and optical quality after bilateral implantation of aspheric diffractive multifocal, aspheric monofocal and spherical monofocal intraocular lenses: a prospective comparison.

AIM: To evaluate the visual function after bilateral implantation of aspheric diffractive multifocal Tecnis ZMA00, aspheric monofocal ZA9003 versus spherical monofocal Akreos Adapt intraocular lenses (IOLs). METHODS: Tecnis ZMA00, Tecnis ZA9003 or Akreos Adapt IOLs were bilaterally implanted in 180 eyes from 90 patients. The following parameters were assessed 3 months postoperatively: monocular and binocular uncorrected visual acuity (UCVA) and distance-corrected visual acuity (DCVA) for distance, intermediate and near, spherical aberration (SA), contrast and glare sensitivity, near point refractive power, uncorrected and best-corrected near stereoscopic acuity (NSA). Patient satisfaction was assessed by a questionnaire. RESULTS: Three months postoperatively, the monocular and binocular UCVA and DCVA at near of Tecnis ZMA00 were significantly better than other two groups. The mean SA for 5.0mm optical zone in Tecnis ZMA00 and Tecnis ZA9003 was significantly lower than that in Akreos Adapt. Mean contrast sensitivity and glare sensitivity were better for Tecnis ZA9003 group than for other two groups. Patients with Tecnis ZMA00 had higher monocular and binocular near point refractive power and uncorrected NSA than monofocal groups. The patients in Tecnis ZMA00 had higher mean values for halo compared with other two groups. CONCLUSION: Tecnis ZMA00 provided better near VA and uncorrected NSA and higher near point refractive power than monofocal IOLs and patients were spectacle independent. The IOLs with Tecnis aspheric design improved contrast and glare sensitivity. Patients with Tecnis ZMA00 reported more disturbances on visual phenomena of halo.

Co-existent choroidal neovascular membrane and macular hole in pathologic myopia: a long follow-up clinical outcome and literature review.

Choroidal neovascularization (CNV) is an uncommon complication associated with a macular hole. In this case report of a rare condition, we present a pathologic myopia patient with a co-existent macular hole and choroidal neovascular membrane. The patient was treated with photodynamic therapy for CNV, and then vitreous surgery for the retinal detachment and macular hole. At the end of 4 years follow-up, her visual acuity was improved to 0.1 while the macular hole remained open. Optical coherence tomography is a useful inspection method of the diagnosis of CNV and macular hole.

Conductive keratoplasty: an approach for the correction of residual hyperopia in post-lasik pseudophakia.

Although there are many formulae for the calculation of intraocular lens power in the eyes with previous kerato-refractive surgeries, unexpected refractive bias still exists. Hyperopic bias is particularly disliked because it affects both uncorrected distance and near visual acuity. Surgical treatment of the residual hyperopia for the eyes with both laser in situ keratomileusis and cataract surgery remains to be a big problem. Conductive keratoplasty has been shown to be an effective, safe and predictable method for low and moderate hyperopia in the pseudophakic eyes or in the eyes with kerato-refractive surgeries. However, the efficacy and safety of conductive keratoplasty in the correction of residual hyperopia after both corneal and lens refractive surgeries has not been reported. Herein, we reported the surgical correction with conductive keratoplasty for cases of residual hyperopia with/without astigmatism after previous laser in situ keratomileusis for high myopia and following phacoemulsification combined with posterior intraocular lens implantation for complicated cataract.

[Conductive keratoplasty for presbyopia and two years follow-up].

OBJECTIVE: To investigate the effect of conductive keratoplasty (CK) for presbyopia and 2 years follow-up. METHODS: This study is prospective clinical trial. CK was performed on 34 patients for presbyopia, in which 26 hyperopic patients underwent binocular operations and 8 emmetropic patients underwent monocular operation. The following-up time was 24 months. RESULTS: At 24 months postoperatively, for the hyperopia group, binocular uncorrected near visual acuity (33 cm) (5-logMAR) (4.63 ± 0.12) was increased significantly (t = 9.237, P < 0.001) compared pre-operatively (4.06 ± 0.15); binocular uncorrected distance visual acuity (4.99 ± 0.02) was significantly increased (t = 6.718, P < 0.05) compared pre-operatively (4.82 ± 0.21); for the emmetropia group, binocular uncorrected near visual acuity (33 cm) (5-logMAR) (4.68 ± 0.16) was increased significantly (t = 10.413, P < 0.001) compared pre-operatively (4.13 ± 0.18); binocular uncorrected distance visual acuity was same as pre-operative one; compared pre-operatively (+0.97 ± 0.63D), manifest refractive spherical equivalent was decreased significantly (P < 0.001) to peak value (-1.21 ± 1.00) D at 1 week, and then regressed to a relative plateau (-0.40 ± 0.70) D at 24 months; the regressive rate was decreased from (+0.35 ± 0.44) D/month at 1 month postoperatively to (+0.01 ± 0.01) D/months at 24 months postoperatively. Contrast sensitivity and glare sensitivity, intraocular pressure, tear break-up time, endothelial cell count, central corneal thickness, stereopsis function and best corrected visual acuity were not significantly changed. CONCLUSIONS: For treatment of presbyopia, CK appeared to be safe, effective, refractive-predictable and controllable, and relatively stable at 24 months post-operatively. More long-time follow-up is necessary for further evaluation.

Correction of extreme hyperopia: artisan iris-fixated intraocular lens implantation for pseudophakia after clear lens extraction.

A 22-year-old patient suffering from both-side extreme hyperopia with amblyopia was corrected with an Artisan iris-fixated intraocular lens (IOL) implantation followed to clear lens extraction (CLE) with posterior chamber (PC)-IOL implantation. The preoperative refraction values were +17.75DS -1.50DC × 168° for the right eye and +17.25DS -0.75DC × 8° for the left eye. The uncorrected visual acuity (UCVA) was 20/200 bilaterally and the spectacle-corrected visual acuity (BSCVA) was 20/50 bilaterally. One year after Artisan iris-fixated IOL implantation, bilateral BSCVA was 20/50 with a refraction of +1.25DS -0.75DC × 13° for the right eye and +1.50DS -1.00DC × 55° for the left eye. The outcomes of an Artisan iris-fixated IOL implantation followed to CLE with PC-IOL implantation were encouraging for the correction of extreme hyperopia. Long term follow-up examinations were necessary for further determination of the efficacy and safety of this combinational procedure.

[Advances and prospects in studies of cataract in the past five years in China].

In the past five years, the cataract surgery rate increased in China. Cataract researches has made significant achievements and has gradually geared international standard. Along with the trend of increasing visual quality requirement to a higher level, studies of cataract face new opportunities and challenges. This article reviews the progress and problems of cataract studies in the past five years in China in order to make further development in this field.

[Binocular clinical comparison study of Tecnis multifocal aspheric and monofocal spherical intraocular lenses].

PURPOSE: To compare visual function in pseudophakic patients with bilateral implantation of Tecnis multifocal aspheric and conventional monofocal spherical intraocular lenses (IOL). METHODS: A prospective study of 100 consecutive cases (200 eyes) was conducted. All cataract patients underwent phacoemulsification were randomized to receive multifocal aspheric IOL (Tecnis ZM900, AMO, multifocal aspheric group) or conventional spherical IOL (Akreos Adapt, Bausch & Lomb, monofocal spherical group). The following investigations were performed to assess the uncorrected and distance-corrected visual acuity of distance, intermediate and near distances, accommodative amplitude, spherical aberrations of total eye, contrast sensitivity, glare sensitivity and near stereoacuity. Patients were surveyed for visual disturbances and lifestyle visual quality. The independent-samples t test was used to compare the measure data which met normal distribution and the Mann-Whitney U test was used to compare the measure data which didn't meet. The chi-square test was applied to compare categorical variables. RESULTS: The uncorrected and distance-corrected bilateral visual acuity of multifocal aspheric group at 30 cm and 40 cm were 0.24 ± 0.12 and 0.22 ± 0.11 (logMAR), better than monofocal spherical group (Z = -8.261, P = 0.000; Z = -5.508, P = 0.000), but the visual acuity at other distances had no statistical difference between two groups. Patients with multifocal aspheric IOL had significantly higher accommodative amplitude than those with monofocal spherical IOL, improved about 2.3 ∼ 2.8 D (Z = -10.655, P = 0.000; Z = -2.709, P = 0.007). Mean spherical aberration of multifocal aspheric group was (0.027 ± 0.160) µm and (0.006 ± 0.083) µm, significantly lower than that of monofocal spherical group (0.269 ± 0.161) µm, (0.037 ± 0.205) µm at 5 mm and 3 mm pupil diameter (Z = -8.815, P = 0.000; Z = -2.791, P = 0.005). The difference of contrast sensitivity was not significant, but glare sensitivity was higher for monofocal spherical group than for multifocal aspheric group. Multifocal aspheric group showed statistically better uncorrected stereoacuity (72.4 ± 29.9)″ than monofocal spherical group (92.8 ± 35.7)″ (Z = -3.089, P = 0.002). CONCLUSIONS: The present clinical results demonstrated that Tecnis multifocal aspheric group had better near visual acuity, accommodative amplitude and near stereoacuity as compared to conventional monofocal spherical group. The aspheric design reduced spherical aberration of total eye and improved contrast sensitivity in some way.