Clinical Pharmacology in Drug Development最新文献

Deutetrabenazine, a deuterated vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved for the treatment of Huntington's disease (HD)-related chorea and tardive dyskinesia (TD). However, pharmacokinetics (PK) and bioequivalence (BE) evidence in the Chinese population has been lacking. This single-center, randomized, open-label, single-dose, two-formulation, four-period, fully replicated crossover study evaluated the PK, BE, and safety of test and reference deutetrabenazine 12 mg tablets under fasting and fed conditions in healthy Chinese volunteers. A total of 90 subjects were enrolled (40 fasting; 50 fed), and 88 completed the study. Plasma concentrations of deutetrabenazine and its active metabolites d6-α-dihydrotetrabenazine (d6-α-HTBZ) and d6-β-dihydrotetrabenazine (d6-β-HTBZ) were quantified using a validated liquid chromatography-tandem mass spectrometry method. BE was assessed using average bioequivalence (ABE) or reference-scaled average bioequivalence (RSABE) according to within-subject variability. Under fasting conditions, RSABE was applied for maximum plasma concentration (C_max) and met equivalence criteria (point estimate within 80%-125%, upper confidence interval bound ≤ 0); under fed conditions, as well as for all remaining PK parameters, ABE criteria were met with the 90% confidence interval within the 80%-125% range. Both formulations were well tolerated, with only mild and transient adverse events and no serious safety findings. These results demonstrate that the test and reference deutetrabenazine tablets are bioequivalent in healthy Chinese adults under both nutritional states.

Co-administration of atorvastatin and fenofibrate has demonstrated clinical benefits in patients with dyslipidemia. To improve convenience and adherence, a fixed-dose combination (FDC) of the two agents has gained interest. This study aimed to compare the pharmacokinetics (PKs) and safety of an FDC of atorvastatin/fenofibrate 20/145 mg with the corresponding individual components. A randomized, open-label, single-dose, two-sequence, two-treatment, four-period full replicated crossover study was conducted. Participants were randomly assigned to one of the two sequences and received FDC or individual components. PK parameters were estimated using a non-compartmental method. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the individual components were calculated using mixed effect model. A total of 36 participants completed the study. The GMRs (90% CIs) for maximum plasma concentration and area under the time-concentration curve from zero to the last measurable point were 1.1038 (0.9985-1.2202) and 1.0148 (0.9745-1.0567) for atorvastatin, 1.0032 (0.9261-1.0867) and 0.9882 (0.9520-1.0258) for 2-OH atorvastatin. For fenofibric acid, the corresponding values were 0.9896 (0.8810-1.1116) and 0.9871 (0.8869-1.0986), respectively. The FDC of atorvastatin/fenofibrate 20/145 mg showed comparable PK profiles to the corresponding individual components, supporting its potential as an alternative therapeutic option for dyslipidemia with convenience.

CIN-102 is a deuterated form of domperidone in development for the treatment of acute, recurrent gastroparesis. This thorough QT study assessed the effects of CIN-102 on cardiac repolarization in 62 healthy volunteers. In this 4-period randomized crossover study, participants were administered single doses of 30-mg CIN-102 (representing therapeutic exposures), 100-mg CIN-102 (representing supratherapeutic exposures), placebo, and moxifloxacin (positive control). Continuous 12-lead electrocardiograms (ECGs) and time-matched blood samples were collected to determine plasma levels of deuterated domperidone and its major metabolites. The primary endpoint was placebo-corrected change-from-baseline QTc corrected by Fridericia's formula (ΔΔQTcF). By-time-point and concentration-QTc analyses excluded an effect on ΔΔQTcF exceeding 10 ms for both doses of CIN-102 at all time points up to deuterated domperidone plasma concentrations of ≈92  ng/mL (≈6 times the therapeutic steady-state concentration). There were no clinically relevant effects of CIN-102 on heart rate or cardiac conduction, and no deaths or serious adverse events occurred. This thorough QT study demonstrated that at doses producing therapeutic and supratherapeutic exposures, CIN-102 does not have a clinically meaningful effect on ECG parameters, including QT interval. This modified formulation of domperidone provides a potential gastroparesis treatment while decreasing the risk of QT prolongation associated with the traditional formulation of domperidone.

Lercanidipine hydrochloride is a third-generation dihydropyridine calcium channel blocker used to treat mild-to-moderate hypertension. The aim of this study is to compare the pharmacokinetic characteristics of lercanidipine hydrochloride tablets (10 mg) in healthy Chinese volunteers after oral administration under fasting conditions with those of a reference formulation, and to evaluate the bioequivalence and safety of the two formulations. A validated liquid chromatography-tandem mass spectrometry method was established to determine the plasma concentration of lercanidipine. Phoenix WinNonlin software (version 7.0) was used to calculate pharmacokinetic parameters based on plasma drug concentration-time data. The geometric mean ratios and 90% confidence intervals of C_max, AUC_0-t, and AUC_0-∞ for the test formulation relative to the reference formulation were 110.37% (99.96%-121.86%), 106.81% (99.65%-114.49%), and 106.91% (99.86%-114.45%), respectively, all within the range of 80.00%-125.00%. The test formulation met the bioequivalence acceptance criteria and was well tolerated by healthy Chinese volunteers under fasting conditions.

DW-1021 is a novel fixed-dose combination salt formulation containing pelubiprofen 45 mg and tramadol hydrochloride 45.9 mg (equivalent to 40.3 mg tramadol free base). Two open-label, phase I clinical studies were conducted in healthy Vietnamese male volunteers to characterize the pharmacokinetics of DW-1021. The relative bioavailability study employed a randomized, single-dose, two-period, two-sequence crossover design (n = 14) comparing DW-1021 with co-administration of Pelubi CR (pelubiprofen 45 mg) and Zytram CR (tramadol hydrochloride 75 mg, equivalent to 65.9 mg tramadol base) under fasting conditions. The food effect study used a fixed-sequence, two-period design (n = 14) to evaluate DW-1021 under fasting and fed (high-fat, high-calorie) conditions. In the relative bioavailability study, DW-1021 resulted in lower exposure to pelubiprofen (AUC_0-t GMR: 86.68%) and generally comparable exposure to trans-OH-pelubiprofen (AUC_0-t GMR: 108.74%) compared with the reference treatment. For tramadol, unadjusted comparisons showed a higher peak concentration (C_max GMR: 192.17%) but lower overall exposure (AUC_0-t GMR: 79.30%). After dose normalization, tramadol exposure per unit dose was higher (AUC_0-t/Dose GMR: 129.58%). In the food effect study, fasting conditions were associated with higher C_max and AUC_0-t of pelubiprofen (GMRs: 109.92% and 140.48%, respectively). Food increased tramadol C_max, while AUC_0-t remained largely comparable between conditions. All adverse events were mild to moderate, and no serious adverse events were reported. In conclusion, DW-1021 exhibited analyte-dependent pharmacokinetic differences relative to the reference treatment. Food intake primarily reduced pelubiprofen exposure, while tramadol AUC_0-t was minimally affected, with a modest increase in C_max under fed conditions.

Daily oral cyclobenzaprine hydrochloride (HCl) has provided transient benefits in fibromyalgia, a chronic pain condition. To improve this effect, we evaluated sublingual formulations designed to drive transmucosal absorption. Two open-label studies evaluated the pharmacokinetics (PK), tolerability, and relative bioavailability of sublingual cyclobenzaprine HCl in healthy adults. In Study 1 (n = 24), three 2.8 mg sublingual formulations of cyclobenzaprine HCl containing potassium phosphate dibasic (A), sodium phosphate dibasic (B), or trisodium citrate (C) were compared to immediate release (IR) cyclobenzaprine HCl 5 mg. All sublingual formulations showed increased bioavailability (154% [A], 126% [B], and 125% [C]) and rapid absorption. Formulation A demonstrated the most favorable PK, with a ∼3 min absorption lag versus ∼37 min for oral IR, and a 783% higher dose-normalized AUC_0-1. Formulation A was designated TNX-102 SL for further development. In Study 2 (n = 16), TNX-102 SL 2.8 and 5.6 mg exhibited dose proportionality and no food effect. Furthermore, this is the first report describing the active metabolite norcyclobenzaprine in clinical studies, showing an elimination half-life of ∼60 h. Oral hypoesthesia and abnormal taste were the most common adverse events. These findings support TNX-102 SL as a rapidly absorbed and efficient sublingual tablet formulation of cyclobenzaprine HCl, providing effective transmucosal delivery.

This Phase 1, open-label, 2-part, single-dose study aimed to investigate the pharmacokinetics, metabolism, and excretion of xevinapant, a small molecule inhibitor of apoptosis proteins (IAPs), in healthy male subjects. Part 1 focused on determining the mass balance recovery, pharmacokinetics, and metabolic profile of [¹⁴C]xevinapant following a single oral dose of 200 mg. Part 2 aimed to determine the absolute oral bioavailability of xevinapant by evaluating the pharmacokinetics of an oral dose of 200 mg xevinapant in comparison to an intravenous microtracer dose of [¹⁴C]xevinapant using accelerator mass spectrometry. After oral administration, xevinapant was rapidly absorbed, with a median time to maximum concentration of 0.5 h and a geometric mean half-life of 13.2 h. The principal route of excretion of drug-related material was fecal, accounting for 60.2% of the administered dose, while 33.3% was excreted in urine. Renal clearance accounted for 18.4% of total clearance. In addition to xevinapant, seven metabolites were structurally characterized in the samples analyzed. The principal route of metabolism was dealkylation to form metabolite D-1143-MET1, with secondary metabolism by oxidation. The major circulating components in plasma were xevinapant and D-1143-MET1 (inactive on IAPs), which represented 28% and 42% of the total drug-related exposure, respectively. The absolute oral bioavailability of xevinapant was determined to be 57.8%. The clearance of [¹⁴C]xevinapant was 12.2 L/h and the volume of distribution at steady-state was 75.3 L. Xevinapant was well tolerated in healthy male subjects, with no clinically significant findings in clinical laboratory evaluations, vital signs, ECG, or physical examinations.

Coenzyme Q10 (CoQ10) is a naturally occurring biochemical cofactor found in all human cell membranes in two interconvertible forms: oxidized ubiquinone and reduced ubiquinol. Clinical studies indicate that different CoQ10 formulations have different absorption rates, highlighting research comparing their systemic bioavailability. This study compared the oral bioavailability of cocrystal formulation soft gels (test product), a novel ubiquinol formulation, and ubiquinone formulation (reference product) in a randomized, double-blind, two-period crossover study with 12 healthy subjects under fasting conditions. The secondary objective of this study was to evaluate the safety and tolerability of the ubiquinol formulation. The pharmacokinetic analyses indicated that the test ubiquinol formulation demonstrated substantially higher relative systemic bioavailability compared with the ubiquinone reference. The geometric mean ratios (test/reference) for baseline-corrected peak plasma concentration (C_max) and area under the curve from zero to last quantifiable time (AUC_0-t) were 2.20 and 2.01, respectively, with 90% confidence intervals of 1.59-3.04 and 1.51-2.70. The geometric mean ratio for AUC from time zero to infinity (AUC_0-∞) was 3.43 (90% CI: 1.47-8.00). No adverse events were reported in this small pilot study for either of the formulations. These findings demonstrate that ubiquinol has a better systemic bioavailability than ubiquinone, supporting the novel formulation's potential as a promising alternative to traditional CoQ10 supplements.

Olopatadine hydrochloride, a second-generation selective histamine H1 receptor antagonist, is an effective anti-allergic agent. This study evaluated the pharmacokinetics and bioequivalence of two olopatadine hydrochloride tablet formulations in healthy Chinese subjects under fasting (n = 24) and fed (n = 24) conditions. A single-center, randomized, open-label, single-dose, two-way crossover study was conducted, in which 48 subjects were randomized to receive 5 mg of the test or reference formulation, followed by a 7-day washout period. Blood samples were collected at predefined intervals up to 24 h post-dose, and olopatadine plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. The results demonstrated no significant differences in the pharmacokinetic profiles between the test and reference formulations under fasting or fed conditions. The 90% confidence intervals (CIs) for the ratio of geometric means of C_max, AUC_0-t, and AUC_0-∞ of olopatadine hydrochloride under both conditions were within the bioequivalence range of 0.80-1.25. A high-fat diet delayed olopatadine hydrochloride absorption, leading to a reduction in C_max to approximately 60% of the fasting value and a decrease in AUC to 85%-90%. No serious adverse events occurred, and safety profiles were comparable between formulations. This research confirmed the bioequivalence and similar safety of the generic olopatadine hydrochloride tablets to the reference formulation.

The effects of food on the pharmacokinetics (PKs) and safety of 1 mg Tacrolimus sustained-release Tacrolimus capsules in healthy Chinese subjects were investigated from one bioequivalence trial. The bioequivalence trial was designed as single-center, openlabel, randomized, single-dose, two-sequence, four-period crossover under both fasted and fed conditions. A total of 80 healthy subjects were enrolled. These subjects received a single oral 1 mg dose of Tacrolimus with a 14-day washout between four periods. Serial PK samples were collected and blood concentrations were analyzed using validated high-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental methods. The BE module of WinNonLin was used for statistical analysis of the maximum concentration (C_max), the area under the concentration-time curve from zero to the final measurable concentration (AUC_0-t), and the area under the concentration-time curve from time zero to infinity (AUC_0-∞) of Tacrolimus in blood. The mean values of all pharmacokinetic parameters were similar for the T and R formulations under fasting and fed conditions, and the 90% confidence intervals were inside the 80.00%-125.00% range. For both the T and R formulations, the AUC_0-t and AUC_0-∞ values were higher in the fed test than in the fasting one. The incidence of adverse events (AEs) was similar between the fasted and fed states, and no serious AEs were observed. Fasting significantly increased the exposure of Chinese subjects to 1 mg Tacrolimus.