A First-in-Human Safety, Tolerability, and Pharmacokinetics Study of Benapenem in Healthy Chinese Volunteers.

The objective of this trial was to investigate the safety, tolerability, and pharmacokinetics (PK) of benapenem administered by single or multiple intravenous infusions in healthy Chinese volunteers. The trial was divided into 3 parts. In part A, 94 subjects were enrolled in a double-blind, placebo-controlled, sequential-ascending-single-dose study. The subjects were randomly assigned to groups receiving placebo or benapenem for injection at doses of 62.5, 125, 250, 500, 1,000, 2,000, or 3,000 mg. The effects of intravenous infusion time on the subjects of 250-, 500-, and 1,000-mg groups were explored. In part B, 12 subjects were enrolled in a single-dose PK study under fasting conditions and received 250, 500, or 1,000 mg of benapenem for injection. In part C, 36 subjects were given 250, 500, and 1,000 mg of benapenem for injection once daily for 7 consecutive days. The results showed that benapenem for injection was well tolerated during the studies. The major observed adverse events were mild, and all were resolved spontaneously without any medical intervention. Benapenem was mainly excreted through the kidneys in the form of parent molecule and metabolites. The PK and safety profiles of benapenem in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (Part A, part B, and part C have been registered at ClinicalTrials.gov under identifiers NCT03588156, NCT03578588, and NCT03570970, respectively.).

Effects of functional CYP2C8,CYP2C9,CYP3A5,and ABCB1 genetic variants on the pharmacokinetics of insulin sensitizer pioglitazone in Chinese Han individuals.

BACKGROUND AND OBJECTIVES: Pioglitazone is a thiazolidinedione antihyperglycemic drug with insulin-sensitizing properties. We investigated whether the variant genotypes of cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP3A5 and transporter ABCB1 influence the pharmacokinetic phenotype of the substrate pioglitazone in Chinese individuals. PARTICIPANTS AND METHODS: Single-nucleotide polymorphisms were determined by the PCR-restriction fragment length polymorphism method in 244 (CYP2C8 and CYP2C9) healthy Chinese Han individuals. After a single oral dose of 30 mg pioglitazone, the plasma concentrations of the parent drug and of two major active metabolites M-III and M-IV were measured using a validated LC-MS/MS in 21 (genotyping CYP3A5 and ABCB1) of these 244 volunteers. RESULTS: The results confirmed that the unique frequencies of CYP2C8*2 (0.0%), CYP2C8*3 (0.0%), and CYP2C9*2 (0.0%) alleles were significantly different from those reported in Whites and Africans, and there were only 10 variant CYP2C9*1/*3 heterozygous (CYP2C9*3 carriers) among 244 Chinese individuals. These results were similar to those reported in Asian ethnic populations, including the Chinese. Unexpectedly, the pioglitazone AUC0-48 in CYP2C9*3 carriers was lower (50.8%), whereas the AUC0-48 ratios of metabolites M-III/pioglitazone and M-IV/pioglitazone increased to 134.3 and 155.8%, respectively, compared with the wild-type CYP2C9*1/*1 homozygous. Moreover, this phenomenon was not observed in individuals with genetic variants of CYP3A5*3 and ABCB1 (C1236T). CONCLUSION: The present research suggests that the CYP2C8, CYP3A5, and ABCB1 genes play no significant role in the interindividual variation of pioglitazone pharmacokinetics, whereas CYP2C9*3 carriers are likely to accelerate the metabolism of this antidiabetic drug in the Chinese Han ethnic population.

Population pharmacokinetics modeling of levetiracetam in Chinese children with epilepsy.

AIM: To establish a population pharmacokinetics (PPK) model of levetiracetam in Chinese children with epilepsy. METHODS: A total of 418 samples from 361 epileptic children in Peking University First Hospital were analyzed. These patients were divided into two groups: the PPK model group (n=311) and the PPK validation group (n=50). Levetiracetam concentrations were determined by HPLC. The PPK model of levetiracetam was established using NONMEM, according to a one-compartment model with first-order absorption and elimination. To validate the model, the mean prediction error (MPE), mean squared prediction error (MSPE), root mean-squared prediction error (RMSPE), weight residues (WRES), and the 95% confidence intervals (95% CI) were calculated. RESULTS: A regression equation of the basic model of levetiracetam was obtained, with clearance (CL/F)=0.988 L/h, volume of distribution (V/F)=12.3 L, and K(a)=1.95 h(-1). The final model was as follows: K(a)=1.56 h(-1), V/F=12.1 (L), CL/F=1.04×(WEIG/25)(0.583) (L/h). For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95%CI were 9.834 (-0.587-197.720), 50.919 (0.012-1286.429), 1.680 (0.021-34.184), and 0.0621 (-1.100-1.980). For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were 0.199 (-0.369-0.563), 0.002082 (0.00001-0.01054), 0.0293 (0.001-0.110), and 0.153 (-0.030-1.950). CONCLUSION: A one-compartment model with first-order absorption adequately described the levetiracetam concentrations. Body weight was identified as a significant covariate for levetiracetam clearance in this study. This model will be valuable to facilitate individualized dosage regimens.

Safety, Pharmacokinetics and Pharmacodynamics of Multiple Escalating Doses of PEGylated Exenatide (PB-119) in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: At present, the deficiency of ß-cell function is progressive in patients with type 2 diabetes mellitus. Exenatide cannot only control blood glucose well, but also promotes the regeneration and proliferation of islet ß-cells and improves the function of ß cells. However, it needs to be given twice a day, and there are many adverse reactions such as nausea. PEGylated exenatide (study code: PB-119) needs to be administered only once a week. The purpose of this experiment was to evaluate the safety, pharmacokinetics and pharmacodynamics of an escalating dose regimen of subcutaneous PEGylated exenatide injections in healthy subjects. METHODS: Twelve healthy young adult subjects in each group received once-weekly subcutaneous injections of 165 µg, 330 µg, and 660 µg PEGylated exenatide for 6 weeks. Plasma drug concentration was determined in venous blood collected across selected time points. Safety and tolerability were evaluated by monitoring adverse events, laboratory parameters, and electrocardiogram. Blood glucose, insulin,  glucagon and C peptide were monitored at different time points to evaluate the pharmacodynamics of PEGylated exenatide. RESULTS: A total of 11, 10, and 12 subjects completed the study in 165 µg, 330 µg, and 660 µg dose groups, respectively. After 6 consecutive weeks of administration, the t1/2 in the 165 µg, 330 µg, and 660 µg dose groups was 55.67 ± 11.03 h, 56.99 ± 21.37 h, and 54.81 ± 13.87 h, respectively. The Cavg was 4.22 ± 0.78 ng/ml, 6.03 ± 1.43 ng/ml, and 10.50 ± 3.06 ng/ml, respectively. AUCss was 708.59 ± 131.87 h•ng/ml, 1012.63 ± 240.79 h•ng/ml, and 1763.81 ± 514.50 h•ng/ml, respectively. The accumulation index was 1.15 ± 0.07, 1.17 ± 0.11, and 1.14 ± 0.07. The CLss/F was 241.25 ± 51.13 ml/h, 341.53 ± 73.62 ml/h, and 450.06 ± 313.76 ml/h, respectively. A total of 10 of 36 (27.78%) subjects in the three dose groups developed specific antibodies after consecutive subcutaneous injections of PEGylated exenatide. The Cavg and Cmax were higher than those of antibody-negative subjects. Furthermore, in antibody-positive subjects, CLss/F, t1/2, AUCτ, accumulation index, MRT(0-inf) and other parameters were lower than those of antibody-negative subjects. In the 165 µg dose group, two subjects (16.67%) experienced 4 adverse events. In the 330 µg dose group, no subjects reported adverse events. In the 660 µg dose group, 8 subjects (66.67%) reported 16 adverse events, which were mostly gastrointestinal. There were no significant changes in the pharmacodynamic parameters except the glucagon level at day 36 in the 660 µg dose group, the 2h postprandial insulin and C peptide levels at day 36 and day 50 in the 165 µg dose group compared with baseline (- 1 day). CONCLUSION: A once-weekly subcutaneous injection of 165 µg and 330 µg PEGylated exenatide is safe. No significant effects on blood glucose or pancreatic hormone levels were observed in the subjects within these dose groups. The pharmacokinetic parameters of PEGylated exenatide may be affected by immunogenicity. CLINICAL TRIALS REGISTRATION: The study is registered at clinicaltrials.gov (No. NCT03062774).

Correction to: Safety, Tolerability and Pharmacokinetics of Single Dose Polyethylene Glycolated Exenatide Injection (PB-119) in Healthy Volunteers.

The original version of this article unfortunately contained a mistake.

Safety, Tolerability and Pharmacokinetics of Single Dose Polyethylene Glycolated Exenatide Injection (PB-119) in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Exenatide promotes insulin secretion and inhibits postprandial glucagon secretion. Polyethylene glycolated exenatide injection (PB-119), a derivative obtained by modification of exenatide, is more stable in metabolic behavior than exenatide in vivo. Our study aimed to evaluate the safety, tolerability and pharmacokinetic characteristics of polyethylene glycolated exenatide as a single subcutaneous injection in healthy volunteers. METHODS: Seventy subjects were randomly assigned to 8 incremental dosage groups (2, 5, 10, 25, 50, 100, 200 and 400 µg). The 2- to 50-µg groups had 8 subjects in each group (the ratio of test preparation to placebo was 3:1), and the 100- to 400-µg groups had 10 subjects in each group (the ratio of test preparation to placebo was 4:1). All the subjects received a single subcutaneous injection of polyethylene glycolated exenatide and placebo according to the dosage groups. The tolerability test was conducted in the 2- to 10-µg groups. The pharmacokinetic test was carried out in the 25- to 400-µg groups, and plasma samples were collected to determine the pharmacokinetics of polyethylene glycolated exenatide. After medication, the vital signs of the subjects were monitored, and laboratory tests and electrocardiogram tests were carried out regularly in all the subjects. RESULTS: All 70 subjects completed the experiment. Except for the 5-µg and 10-µg groups, the safety and tolerability tests showed no adverse reactions in the 2-µg to 50-µg groups. Several subjects in the 100-µg and 200-µg groups had tolerable gastrointestinal tract reactions, and all subjects in the 400-µg group experienced adverse reactions, mainly gastrointestinal tract reactions and liver dysfunction. The pharmacokinetics of polyethylene glycolated exenatide was studied in 36 subjects, which showed slow absorption, a mean peak time of 20-40 h, and a mean elimination half-life of 51-64 h. CONCLUSION: The administration of polyethylene glycolated exenatide injection at a single dose of 2-200 µg is safe and tolerable for healthy volunteers. Once-weekly polyethylene glycolated exenatide injection can be recommended. CLINICAL TRIALS REGISTRATION: The study was registered at clinicaltrials.gov (No. NCT02084251).

Determination of the inhibitory potential of 6 fluoroquinolones on CYP1A2 and CYP2C9 in human liver microsomes.

AIM: To determine the inhibitory potential of 2 new fluoroquinolones, caderofloxacin and antofloxacin, together with 4 marketed fluoroquinolones, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin, on the activity of cytochrome P450 isoforms 1A2 (CYP1A2) and 2C9 (CYP2C9). METHODS: Probe substrates, phenacetin (CYP1A2), and tolbutamide (CYP2C9) were incubated with human liver microsomes and the metabolites were analyzed by liquid chromatography/mass spectrometry using electrospray ionization in positive or negative mode. Glipizide was used as the internal standard in both modes. The inhibitory potential of fluoroquinolones on CYP1A2 and CYP2C9 was investigated. RESULTS: The IC50 values (micromol/L) determined with the cocktail were in agreement with individual probe substrates (alpha-naphthoflavone: 0.27 vs 0.26; sulfaphenazole: 0.49 vs 0.37). Ciprofloxacin showed weak inhibition on both the activity of CYP1A2 (IC50 135 micromol/L) and CYP2C9 (IC50 180 micromol/L), whereas levofloxacin inhibited only CYP2C9 (IC50 210 micromol/L). Caderofloxacin, antofloxacin, moxifloxacin, and gatifloxacin showed little or no inhibition on the activity of CYP1A2 or CYP2C9 when tested at comparable concentrations (0-200 mg/L). CONCLUSION: Caderofloxacin, antofloxacin, moxifloxacin, and gatifloxacin are negligible inhibitors to CYP1A2 and CYP2C9. The in vitro system can be used as a high-throughput model to screen similar compounds for the early identification of drug-drug interaction potential.

Effects of UGT1A1, CYP3A5 and ABCB1 Genetic Variants on Pharmacokinetics of Antihistamine Drug Mizolastine in Chinese Healthy Volunteers.

Mizolastine is a selective histamine H1 receptor antagonist for chronic urticaria or allergic rhinitis. We investigated whether the variant genotypes of metabolic enzymes UGT1A1, CYP3A5 and transporter ABCB1 influence pharmacokinetic phenotype of substrate mizolastine in Chinese volunteers. Genotyping of single nucleotide polymorphisms in UGT1A1*6 (G211A), CYP3A5*3 (A6986G) and ABCB1 (C3435T) was determined by the pyrosequencing method. After a single oral dose of 10 mg mizolastine, the plasma concentrations were measured using validated high-performance liquid chromatography in 24 Chinese healthy volunteers. The results showed that the distributions of wild-type homozygotes and variant allele carriers (the sum of variant heterozygotes and variant homozygotes) were as follows: 17 cases (70.8%) versus seven cases (29.2%) in UGT1A1*6 genotypes, five cases (20.8%) versus 19 cases (79.2%) in CYP3A5*3 genotypes and seven cases (29.2%) versus 17 cases (70.8%) in ABCB1 3435T genotypes, respectively. There were no significant differences in pharmacokinetic parameters of mizolastine between the variant allele UGT1A1*6, CYP3A5*3 and ABCB1 3435T carriers and the wild-type homozygotes, and the ratios were as follows: Cmax was 101.03%, 86.02% and 105.78%; Tmax was 162.35%, 98.98% and 144.90%; AUC0-28 was 113.04%, 77.35% and 112.71%; and t1/2 was 95.77%, 72.40% and 100.97%, respectively. In conclusion, these results suggested that the UGT1A1, CYP3A5 and ABCB1 genetic polymorphisms might be not contributed to the interindividual variation of mizolastine pharmacokinetic phenotype in the Chinese population.

Breast cancer treatment and sulfotransferase.

INTRODUCTION: Sustained exposure to excessive estrogen is an established risk factor for breast cancer. Sulfotransferase (SULT)-mediated sulfonation represents an effective approach for estrogen deprivation as estrogen sulfates do not bind and activate estrogen receptors (ERs). The nuclear receptor (NR) superfamily functions as a sensor for xenobiotics as well as endogenous molecules, which can regulate the expression of SULT. AREAS COVERED: In this review, we summarize the mechanisms of SULT regulation by NRs and inactivation of estrogen by SULT. Furthermore, we discuss the potential of clinical therapy targeting SULT in breast cancer treatment. Gaps in current knowledge that require further study are also highlighted. EXPERT OPINION: The prevention of estrogen binding to ER by antiestrogen and inhibition of estrogen synthesis by aromatase or sulfatase inhibitor have been used in clinical therapy for breast cancer. Although the induction of SULT has been proven effective to estrogen inactivation, reports on this method applied to breast cancer treatment are rare. Targeted activation of SULT may open up a new means of treating hormone-dependent breast cancer.

A Pharmacokinetic and Pharmacodynamic Study on Intravenous Cefazedone Sodium in Patients with Community-acquired Pneumonia.

BACKGROUND: As a time-dependent antibiotic, the time of cefazedone concentration exceeds the minimum inhibitory concentration (MIC) is the key pharmacokinetic-pharmacodynamic (PK-PD) variable associated with the killing of pathogens. The purpose of the study was to evaluate the clinical regimen rationality of intravenous cefazedone sodium in the treatment of community-acquired pneumonia (CAP) by PK/PD study. METHODS: Ten patients with mild to moderate CAP were enrolled to receive intravenous cefazedone sodium (2 g q12 h) for 7-14 days. Blood samples were collected in any day during day 5-7. Sputum specimens were collected before treatment for bacteria isolated, and susceptibility to cefazedone determined. PK-PD analysis was performed using the noncompartmental analysis of Phoenix WinNolin software (version 6.1, Pharsight Corporation, CA, USA). The maximal time above MIC (ƒT > MIC) was calculated, and its correlation with clinical efficacy was analyzed. RESULTS: All 10 patients completed the study and 8 of them were cured. Six strains were isolated from patients before treatment (one for each patient) and all susceptible to cefazedone. Five patients of six in culture positive group were cured. All pathogens were cleared at the end of therapy. The MICs were between 0.25 and 1 mg/L. The main PK parameters were C max 175.22 ± 36.28 mg/L; T½ 1.52 ± 0.23 h; AUC (0-∞) 280.51 ± 68.17 mg·L -1·h -1 ; CL 7.37 ± 1.84 L/h; Vd 16.06 ± 4.42 L. The average ƒT > MIC was 55.45 ± 8.12%. CONCLUSIONS: Intravenous injection of cefazodone sodium with 2 g q12 h dosage regimen is used in the treatment of CAP caused by sensitive bacteria, either ƒT > MIC or clinical efficacy shows that such dosing regimen is reasonable.