Zhongfang Li

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Parathyroid Hormone (1–34) in Healthy Chinese Subjects

BACKGROUND The recombinant human parathyroid hormone (1-34) (rhPTH[1-34]) teriparatide is the first anabolic agent approved by the US Food and Drug Administration for the treatment of osteoporosis in men and women. This study was conducted to provide support for marketing authorization of an agent biosimilar to teriparatide in China. OBJECTIVE The main aim of the present study was to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic parameters of rhPTH(1-34) after single and multiple subcutaneous doses in healthy Chinese subjects. METHODS Two open-label, randomized, single-center, dose-escalation studies were performed. In study 1, subjects were randomized to receive a single dose of rhPTH(1-34) (10, 20, 30, 40, 50, or 60 μg) or a multiple dose of rhPTH(1-34) (10 and 20 μg once daily for 7 consecutive days) to determine the safety profile and tolerability, as reflected by the incidence, intensity, and seriousness of the observed adverse events. In study 2, a single dose of rhPTH(1-34) (10, 20, or 40 μg) and a multiple dose of rhPTH(1-34) (20 μg) were administrated subcutaneously to investigate the pharmacokinetic and pharmacodynamic parameters. RESULTS Forty-two subjects completed study 1, and 30 subjects completed study 2. rhPTH(1-34) was well tolerated during the investigated single (10-60 μg) and multiple (10-20 μg once daily for 7 consecutive days) dose ranges. The most generally reported adverse events were erythema at the injection site and gastrointestinal reactions. After single and multiple subcutaneous administration of rhPTH(1-34), the drug was rapidly absorbed, with a Tmax of 20 to 30 minutes, and rapidly cleared from the plasma, with a t½ of 47.2 to 60.6 minutes. The mean Cmax, AUC0-t, and AUC0-∞ increased in proportion to the doses, whereas the t½, total clearance, and Tmax values were independent of the administered dose. No significant differences in pharmacokinetic parameters were noted by sex except for Tmax in the 10-μg and 20-μg single-dose groups. Compared with the baseline levels, no significant changes or dose-related significant effects were observed in serum calcium and phosphate levels. CONCLUSIONS All rhPTH(1-34) doses appeared to be well tolerated in the population studied. Linear pharmacokinetic characteristics were displayed in the dose range studied. Chinese ClinicalTrials.gov identifier: ChiCTR-ONC-12002874.

Pharmacokinetics, pharmacodynamics, and tolerability of a generic formulation of exenatide: a randomized, open-label, single- and multiple-dose study in healthy Chinese volunteers.

A randomized, open-label, dose-escalating study was designed to assess the pharmacokinetics, pharmacodynamics and tolerability of single and multiple subcutaneous administrations of exenatide in 24 healthy Chinese volunteers. The effects of gender on the pharmacokinetics of exenatide were also evaluated. Subjects were randomized to receive a single and multiple subcutaneous doses of 5 or 10 μg of exenatide. Following the single dose subjects received exenatide twice daily on days 2-4 and once on day 5. Sequential blood samples were collected at regular intervals from 0 to 8 h after single administration. Concomitantly the serum glucose concentrations were measured in each sample. Tolerability was assessed using physical examination, vital signs, laboratory analysis, and by interview of subjects. Pharmacokinetic parameters for exenatide after subcutaneous administration of a single dose of 5-10 μg were as follows: Cmax=77.7 (13.9) and 136.1 (15.2) pg/mL; AUC0-t=184.2 (49.7) and 309.7 (52.3) pg·h/mL; AUC0-∞=225.8 (77.4) and 365.4 (68.8) pg·h/mL; tmax (median [range])=1.00 (0.75-1.50) and 1.00 (0.75-1.50) h; t1/2 (mean [range])=1.4 (0.7-3.2) and 1.8 (1.0-2.5) h, respectively. Because of its short t1/2, Css, min could not be detected in any plasma samples prior to daily dosing on days 3-5. Pharmacokinetic parameters for exenatide after administration of multiple doses of 5 or 10 μg were as follows: Cmax=81.2 (12.2) and 144.5 (13.3) pg/mL; AUC0-t=181.1 (39.4) and 275.6 (45.0) pg·h/mL; AUC0-∞=217.2 (44.8) and 313.3 (48.4) pg·h/mL; tmax=1.10 (0.75-1.25) and 1.00 (1.00-1.25) h; t1/2=1.6 (0.8-2.2) and 1.4 (0.9-2.7) h, respectively. Both doses of exenatide were associated with significant reductions in serum glucose concentrations (P<0.001) when compared to baseline levels. Mean percentage of maximal decline for serum glucose concentrations after single and multiple doses were 15.6% and 19.9% for 5 μg, respectively; as well as 26.3% and 28.7% for 10 μg, respectively. 12 of the 24 subjects reported a total of 75 adverse events. The rate increased with higher doses of exenatide: after 5 μg only one subject experienced at least 1 adverse event but following 10 μg 11 subjects were affected. 2 subjects receiving the higher dose of 10 μg exenatide dropped out because of adverse events (nausea and vomiting). The most common adverse events were of gastrointestinal origin (e. g. decreased appetite, nausea and vomiting) and of mild severity. In conclusion, in healthy Chinese subjects, AUC and Cmax increased in proportion to the dose, whereas t1/2 was independent of dose. The pharmacokinetic parameters after multiple dosing were consistent with those after single doses. No significant gender differences were noted for pharmacokinetic variables. Both exenatide doses were associated with significant reductions in serum glucose levels. Adverse events were mainly of gastrointestinal origin and their incidence was dose-dependent.

The pair of soliton-like distortions in organic ferromagnetic conjugated polymers

We study a soliton-like distortion in a quasi-one-dimensional conjugated carbon chain with a single side radical, which contains an unpaired electron, by taking into account the electron–phonon interaction, an extended Hubbard term due to on-site electron–electron interactions and intersite e–e interactions, and the ferromagnetic correlation between itinerant π-electrons and the unpaired radical electron. It is shown that a critical value of hopping integral exists between the side radical and the main chain, at which a transition from a single soliton-like distorted structure to a pair of soliton-like distortions occurs along the main chain. In addition, the spin density at the dangling site is transferred to the main chain due to the hopping interaction between the main chain and the side radical, and the spin density at the side radical is decreased to zero when the hopping integral is larger than the critical value.

Tolerability and Pharmacokinetics of Biapenem Following Single and Multiple Intravenous Administrations in Healthy Chinese Subjects: An Open-Label, Randomized, Single-Center Study

This study was designed to evaluate the tolerability and pharmacokinetics of biapenem after single and multiple intravenous administrations in healthy Chinese subjects. Subjects were randomly allocated to receive a single 0.15, 0.3, or 0.6 g dose of biapenem. Subjects assigned to the 0.3 g single dose group continued into the multiple-dose phase. Blood samples were collected over 6 h and plasma biapenem concentrations were determined by a validated HPLC method. Tolerability was assessed by monitoring vital signs, laboratory parameters, physical examinations, electrocardiogram, and adverse events collected by non-directive questioning/spontaneous reporting. Pharmacokinetic parameters for biapenem after intravenous administration of a single dose of 0.15, 0.3, or 0.6 g were as follows: Cmax=7.06 (1.30), 15.59 (1.33), and 29.12 (1.22) mg/L; AUC0-6 h=8.95 (1.33), 22.62 (1.25), and 42.05 (1.19) mg · h/L; t1/2=0.97 (0.13), 1.04 (0.08), and 1.12 (0.08) h; CL=15.78 (1.32), 12.91 (1.24), and 13.95 (1.19) L/h; Vd=21.87 (1.25), 19.31 (1.25), and 22.41 (1.23) L, respectively. Pharmacokinetic parameters for biapenem after intravenous administration of multiple 0.3 g doses were as follows: Cmax=18.50 (1.16) mg/L; AUC0-6 h=26.45 (1.15) mg · h/L; t1/2=1.06 (0.15) h; CL=11.06 (1.16) L/h; Vd=16.78 (1.19) L. The incidence of reported AEs was as follows: phlebitis (2/10), nausea (1/10), and diarrhea (1/10). All of the AEs were mild in intensity. The pharmacokinetic properties of biapenem were linear at dose of 0.15-0.6 g. All biapenem doses appeared to be well tolerated.

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Recombinant Human Parathyroid Hormone after Single‐ and Multiple‐Dose Subcutaneous Administration in Healthy Chinese Volunteers

Recombinant human parathyroid hormone [rhPTH(1-84)] represents a new class of anabolic agents for the treatment of osteoporosis. The present study was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of rhPTH(1-84) after single- and multiple-dose subcutaneous administration in healthy Chinese volunteers. Six cohorts of 32 volunteers received a single dose of rhPTH(1-84) at 0.5-5.0 μg/kg, and two cohorts of 12 volunteers received 2.0 and 3.0 μg/kg of rhPTH(1-84) once daily for 7 consecutive days to assess its safety and tolerability. The results indicated that rhPTH(1-84) appeared to be safe and well tolerated. Additionally, pharmacokinetics of rhPTH(1-84) and its active N-terminal fragment rhPTH(1-34) were investigated after administration of single 1.0, 2.0 and 4.0 μg/kg doses of rhPTH(1-84) in 30 other volunteers and after multiple doses of 2.0 μg/kg once daily for 7 consecutive days. The pharmacokinetic parameters for rhPTH(1-84) and rhPTH(1-34) after subcutaneous administration of a single dose of 1.0, 2.0 and 4.0 μg/kg were as follows: Cmax = (110.54 ± 59.18), (149.70 ± 50.61) and (372.52± 94.96) pg/mL; (53.93±6.27), (61.12±11.28) and (89.04 ± 7.08) pg/mL, respectively. AUC0-10  =  (268.87 ± 47.72), (538.93 ± 146.89) and (1364.11 ± 176.82) pg hr/mL; (197.20 ± 50.78), (207.15 ± 72.08) and (344.05 ± 77.06) pg hr/mL, respectively. t1/2  =  (2.34 ± 1.93), (2.58 ± 1.18) and (2.74 ± 1.31) hr; (3.37 ± 1.82), (4.39 ± 3.79), and (3.99 ± 1.85) hr, respectively. Plasma Cmax and AUC values of rhPTH(1-84) and rhPTH(1-34) were found to be dose proportional. The pharmacokinetic parameters for rhPTH(1-84) and rhPTH(1-34) after administration of multiple doses of 2.0 μg/kg were as follows: Css_max  = (164.96 ± 52.61) and (75.05 ± 7.31) pg/mL; Css_min  = (6.99 ± 7.73) and (2.05 ± 2.82) pg/mL; AUCss  = (567.26 ± 118.41) and (306.02 ± 77.55) pg hr/mL; t1/2  =  (1.81 ± 0.89) and (2.27 ± 1.11) hr; DF = (6.93 ± 2.64) and (6.00 ± 1.37), respectively. After multiple doses, the pharmacokinetic parameters for rhPTH(1-84) were consistent with those after single dose. However, the mean Cmax and AUC0-10 of rhPTH(1-34) after multiple dosing were significantly higher than the corresponding values obtained after single-dose administration. Serum total calcium and phosphate concentrations increased and decreased significantly at 4 hr post-dosing, respectively.

Comparative bioavailability and tolerability of a single 20-mg dose of two fluoxetine hydrochloride dispersible tablet formulations in fasting, healthy Chinese male volunteers: an open-label, randomized-sequence, two-period crossover study.

BACKGROUND The proprietary formulation of fluoxetine hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. Pharmacokinetic studies investigating the bioequivalence of generic and branded formulations are needed to market generic fluoxetine in China. OBJECTIVE The aim of this study was to compare the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of fluoxetine hydrochloride 20 mg in a fasting, healthy Chinese male population. METHODS This 10-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 20-mg dose of the test or reference formulation, followed by a 35-day washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties (including C(max), T(max), AUC(0-t), AUC(0-∞), and t(½)), blood samples were obtained over a 672-hour period after dosing. Plasma concentrations of fluoxetine and its active metabolite, norfluoxetine, were analyzed using a validated LC-MS/MS method. The formulations were to be considered bioequivalent if the ln-transformed ratios (test/ reference) of C(max) and AUC were within the predetermined bioequivalence range of 80% to 125%, as established by the US Food and Drug Administration, and if the P values were <0.05 for the 90% CIs. Signs and symptoms of adverse effects of fluoxetine hydrochloride such as nausea, vomiting, insomnia, somnolence, anxiety, and nervousness, as well as any untoward effects, were collected using a daily written questionnaire and recorded by the study physicians. Tolerability was assessed using monitoring of vital signs, physical ex- amination, ECG, and routine blood and urine tests, along with blood biochemical tests, at the start as well as at the end of the study. RESULTS Twenty-four subjects were enrolled and completed the study (mean [SD] age, 24.4 [2.3] years [range, 20-30 years]; weight, 63.6 [8.5] kg [range, 51.2-86.8 kg]; height, 1.72 [0.07] m [range, 1.57-1.91 m]). The AUC values for fluoxetine were not consistent with a normal distribution, reflecting the existence of 2 different populations (poor and extensive metabolizers). Data from the one poor metabolizer were excluded from the pharmacokinetics data summarized. In extensive metabolizers, the mean (SD) C(max) for fluoxetine with the test formulation was 11.786 (3.459) ng/mL and T(max) was 5.48 (2.06) hours. With the reference formulation, the corresponding values were 11.754 (3.292) ng/mL and 6.26 (5.77) hours, respectively. The t(½) values with the test and reference formulations were 30.86 (7.61) and 30.96 (6.91) hours, respectively. For norfluoxetine, mean C(max) with the test formulation was 14.177 (4.957) ng/mL and T(max) was 58.48 (31.67) hours; the corresponding values for the reference formulation were 13.828 (4.838) ng/mL and 57.91 (25.75) hours. The t(½) values with the test and reference formulations were 130.91 (42.04) and 128.79 (52.72) hours, respectively. For fluoxetine, the 90% CIs (in extensive metabolizers only) for the In-transformed C(max), AUC(0-168), and AUC(0-∞) were 92.0% to 108.4%, 95.7% to 110.3%, and 97.4% to 111.3%, respectively (all, P < 0.001). For norfluoxetine, the 90% CIs for the ln-transformed C(max), AUC(0-672), and AUC(0-∞) were 93.7% to 110.7%, 98.9% to 111.4%, and 98.8% to 110.9% (all, P < 0.001). No period or sequence effects were observed for any pharmacokinetic variable in the extensive metabolizers. No adverse events were reported by the volunteers or found with results of clinical laboratory testing. CONCLUSIONS This single-dose study found that the test and reference formulations of fluoxetine hydro- chloride met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated.

Development and validation of an LC-MS method with electrospray ionization for quantitation of digoxin in human plasma and urine: application to a pharmacokinetic study.

A highly sensitive and specific LC-MS method was developed and validated for the quantification of digoxin in human plasma and urine using d5-dihydrodigoxin as internal standard (IS). The assay procedure involved extraction of digoxin and IS from human plasma with chloroform-isopropanol (95:5, v/v). Chromatogrphic separation was achieved on a Spherisorb ODS2 column using a gradient mobile phase with 5 mmol/L ammonium acetate in water with 1% acetic acid and acetonitrile. The mass spectrometer was operated in the selected ion monitoring mode using the respective [M+K](+) ions, m/z 819.4 for digoxin and m/z 826.4 for IS. The method was proved to be accurate and precise at linearity range of 0.12-19.60 ng/mL in plasma with a correlation coefficient (r(2)) of >or=0.9968 and 1.2-196.0 ng/mL in urine. The limit of quantification achieved with this method was 0.12 ng/mL in plasma and 1.2 ng/mL in urine. The intra- and inter-assay precision and accuracy values were found to be within the assay variability limits as per the FDA guidelines. The developed assay method was successfully applied to a pharmacokinetic study in human volunteers following intravenous administration of digoxin.