Two-period Crossover Study Research Articles

Respiratory safety of lemborexant in adult and elderly subjects with moderate-to-severe chronic obstructive pulmonary disease.

Because some hypnotics worsen respiratory conditions, it was important to determine the respiratory safety of lemborexant, a competitive dual orexin-receptor antagonist approved to treat adults with insomnia, in subjects with moderate-to-severe chronic obstructive pulmonary disease. E2006-A001-113 (Study 113; NCT04647383) was a multicentre, multiple-dose, randomised, double-blind, placebo-controlled, two-period crossover study in adult subjects with moderate or severe chronic obstructive pulmonary disease (per spirometry-based Global Initiative for Chronic Obstructive Lung Disease [GOLD] criteria). Subjects (N = 30) were randomised to two treatment sequences comprising 8-night treatment periods (washout ≥ 14 days) with lemborexant 10 mg or placebo. Peripheral oxygen saturation (SpO2; primary endpoint), apnea-hypopnea index, objective sleep parameters and sleep architecture measures were assessed after single (Day 1) and multiple (Day 8) doses. There was no significant difference in least-squares mean SpO2 after a single dose of lemborexant (91.1%) versus placebo (91.5%). Although a statistically significant difference in SpO2 was observed after multiple doses (least-squares mean: lemborexant, 91.3%; placebo, 90.8%) favouring lemborexant, this was not considered clinically meaningful. Apnea-hypopnea index was not significantly different between treatments after single or multiple doses. Total sleep time and total rapid eye movement sleep were significantly greater on Days 1 and 8 with lemborexant versus placebo. Treatment-emergent adverse events were reported in five (16.7%) subjects when taking lemborexant and four (13.3%) subjects when taking placebo; treatment-emergent adverse events were mostly mild. Lemborexant was well tolerated and did not adversely impact SpO2 or apnea-hypopnea index after single and multiple doses relative to placebo in subjects with moderate-to-severe chronic obstructive pulmonary disease.

Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis.

Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub-Saharan Africa. 5-flucytosine (5-FC) is a unique, brain-permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5-FC has a short plasma half-life, requiring 6-hourly oral dosing with an immediate-release (IR) formulation, a significant challenge in hospital and outpatient settings, risking a lack of compliance. We recently reported the relative bioavailability in fasting conditions of a sustained release (SR) oral pellet formulation of 5-FC. In this phase I study, we assessed the safety and pharmacokinetic profiles of the new 5-FC SR formulation in a single dose (2 × 3000 mg), relative to 5-FC IR tablets (Ancotil®; 1500 mg b.i.d.) in healthy participants in fed conditions. This randomized, two-period crossover study was conducted in South Africa to confirm the dose of the identified 5-FC SR formulation for a twice-daily 5-FC regimen in patients. Thirty-six healthy participants were included. All treatments were well tolerated and no serious adverse event was reported. Cmax and AUC(0-t) for the SR formulation (49.2 ± 10.49 μg/mL and 640.4 ± 126.4 h.μg/mL, respectively) were significantly higher than for the IR formulation (36.8 ± 7.61 μg/mL and 456.6 ± 72.8 h.μg/mL, respectively). A physiological based pharmacokinetic model (PBPK) predicted that under fasting conditions, 6000 mg SR pellets would show a good overlap with the IR product (3000 mg b.i.d), thus 6000 mg SR 5-FC b.i.d. in fasting conditions is recommended.

Comparative clinical efficacy and safety of biosimilar ABP 959 and eculizumab reference product in patients with paroxysmal nocturnal hemoglobinuria.

ABP 959 is a biosimilar to the eculizumab reference product (RP), which is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). This multicenter, randomized, double-blind, active-controlled, two-period crossover study randomized eculizumab RP-treated patients with PNH to one of two treatment sequences (ABP 959/eculizumab RP or eculizumab RP/ABP 959) to evaluate the clinical similarity of ABP 959 when compared with eculizumab RP. This study evaluated the efficacy of ABP 959 when compared with eculizumab RP based on control of intravascular hemolysis as measured by lactate dehydrogenase (LDH) and by the time-adjusted area under the effect curve of LDH. Secondary outcomes included safety, pharmacokinetics, and immunogenicity. Forty-two patients were randomized (20 in the ABP 959/eculizumab RP group and 22 in the eculizumab RP/ABP 959 group) across 25 centers. Similarity of efficacy was established by a ratio of geometric least squares means of LDH (ABP 959/eculizumab RP) of 1.0628, with a one-sided 97.5% upper CI of 1.1576 at week 27, and a geometric means ratio of time-adjusted area under the effect curve (ABP 959 vs. eculizumab RP) of LDH of 0.981, with a 90% CI of 0.9403-1.0239 from week 13 to 27, week 39 to 53, and week 65 to 79. All secondary efficacy endpoints were comparable between treatment groups. No new safety concerns were identified. The results of this study in patients with PNH, along with previously demonstrated similarity of analytical, nonclinical, and clinical pharmacokinetics and pharmacodynamics in healthy volunteers support a demonstration of no clinically meaningful differences between ABP 959 and eculizumab RP. Clinical Trial Registration: NCT03818607.

Bioequivalence and Safety of Bilastine 20 mg Orodispersible Tablets and Conventional Tablets: A Randomized, Single-Dose, Two-Period Crossover Study in Healthy Volunteers Under Fasting Conditions.

Orodispersible tablets (ODT) rapidly dissolve in the oral cavity and can improve patient's convenience. This pharmacokinetic study assessed the bioequivalence of a novel 20 mg ODT formulation of bilastine compared with bilastine 20 mg tablets in healthy volunteers under fasting conditions. A phase I, single-center, open-label, two-period, two-sequence crossover randomized clinical trial was conducted. The study comprised two periods, in which participants were administered a single oral dose of bilastine 20 mg in the form of ODT as the test product, or conventional tablets as the reference product, and a washout of 7 days between each period. Blood samples were collected for up to 72 h. Bioequivalence was established if the 90% confidence intervals of the Cmax and AUC0-t were within the acceptance range (80-125%). Safety was evaluated at the follow-up visit (days 4-7 after the second dose) and throughout the study. A total of 42 healthy volunteers were randomized, and 41 completed the study. Pharmacokinetic parameters were comparable for both formulations after a single dose of 20 mg. Bilastine ODT and conventional tablets were bioequivalent as the 90% confidence intervals of the test over reference ratios were within the predefined range (80-125%). Both formulations were well tolerated and showed a similar safety profile. Bilastine ODT was bioequivalent to the reference treatment formulated as conventional tablets when administered as a single oral dose of 20 mg under fasting conditions. Both formulations showed a similar tolerability and safety profile, with no serious adverse events or significant analytical alterations reported. 2019-004071-39. Date of authorization: 10 December 2019.

Bioequivalence and Food Effect Assessment of Eltrombopag Olamine Tablets in Healthy Chinese Subjects: An Open, Randomized, Single-Dose, and Two-Period Crossover Study.

Eltrombopag, a nonpeptide thrombopoietin receptor agonist, is primarily used for treating immune thrombocytopenic purpura. The aim of this study was to investigate the pharmacokinetic profile and food-drug interaction of test and reference eltrombopag olamine tablets among healthy Chinese volunteers. An open, randomized, single-dose, 2-period crossover design was employed, involving fasting and fed conditions with a 10-day washout period. Ninety-six healthy volunteers received a single oral dose of 25mg of the 2 eltrombopag formulations, with 48 participants in each group: fasting volunteers and those consuming a high-fat, low-calcium meal. Plasma eltrombopag concentrations were analyzed using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were derived from the concentration-time profiles. The geometric mean ratios, with 90% confidence intervals, for the maximum plasma concentration, area under the concentration-time curve from time 0 to the last measurable concentration, and area under the concentration-time curve from time 0 to infinity fell within the bioequivalence acceptance criteria (80%-125%) under both fasting and fed conditions, indicating bioequivalence between the test and reference formulations. Administration of eltrombopag with a high-fat, low-calcium diet reduced the net systemic exposure by approximately 40%. Adverse events were recorded, and no serious adverse events were observed in either fasting or fed conditions. In conclusion, eltrombopag is well tolerated and exhibits a favorable safety profile in the Chinese population. The achievement of bioequivalence under fasting and fed conditions supports the demonstration of biosimilarity between the test and reference formulations.

In Vitro/In Vivo Correlation of Two Extended-Release Cilostazol Formulations.

This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using the paddle and basket USP release apparatus. A single-dose, two-period crossover study design in beagle dogs was applied for the pharmacokinetic study. The fed and fast effects were considered for evaluation. Pseudo gastric release medium transfer setup study from pH 1.2 to pH 6.8 (+0.5% SLS) and pH 1.2 to pH 6.8 (+1.0% SLS) demonstrated that Pletaal® SR 200 mg capsules have higher drug release rates than Cilostan® CR 200 mg tablets. Similarly, in vivo study showed Cilostazol concentration in plasma and AUC was lower under the fast state than the fed state. The ratio of least squared geometric mean values, Cmax, AUC0-t, and AUC0-inf of Cilostazol were 2.53-fold, 2.89-fold, and 2.87-fold higher for Pletaal® SR 200 mg capsules compared with Cilostan® CR 200 mg tablets, respectively. Correlation of in vitro/in vivo data indicated that Pletal® SR 200 mg capsules have better release and pharmacodynamic effect than Cilostan® CR 200 mg tablets.

The effect of food on the pharmacokinetics of Sutetinib maleate capsule, an irreversible EGFR tyrosine kinase inhibitor, in healthy Chinese subjects.

Sutetinib is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and showed favorable efficacy and safety in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring nondrug-resistant rare EGFR mutations. To evaluate the potential food effect, eighteen healthy Chinese subjects were enrolled in a single-centre, randomized, open-label, two-sequence, two-period crossover study. Sutetinib was administered as a single oral 100mg under fasting or fed conditions, and pharmacokinetic sampling was performed following each dose and analysed by a validated liquid chromatography/mass spectrometry method. Safety and tolerability were also evaluated. Food intake slightly decreased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC0 - inf) of sutetinib (geometric least-squares mean [GLSM] ratio, 80.94% and 86.11%; 90% confidence interval [CI], 68.43-95.72 and 75.88-97.73) and its active metabolite sutetinib N-Oxide (GLSM ratio, 75.58% and 84.00%; 90% CI, 65.69-86.95 and 75.42-93.56), respectively. In addition, the time to maximum plasma concentration (Tmax) of both sutetinib and its metabolite has been prolonged by 2h under fed conditions. A total of 31 adverse events (AEs) occurred during the study, with no serious adverse events (SAE) reported, and no obvious difference was observed between the fasting and fed groups. Our results demonstrated that a high-fat and high-calorie diet caused a significant delay in drug absorption and a marginal reduction in drug exposure. Sutetinib was generally well tolerated in healthy Chinese subjects. (This trial was registered at http://www.chinadrugtrials.org.cn . The registration No. is CTR20201933, and the date of registration is 2020-10-16).

A Crossover Trial Evaluating Coconut Oil as an Alternative to Commercial Ultrasound Gel in Obstetrical Ultrasounds.

Our objective was to evaluate the quality of obstetrical ultrasound images obtained with coconut oil compared with commercial ultrasound gel and to assess patient acceptability. This was a randomized two-period crossover study in which 40 pregnant patients had standard biometry images obtained with both coconut oil and commercial ultrasound gel during their growth or anatomy ultrasound. All images were then rated by two blinded maternal-fetal medicine physicians on quality, resolution, and detail using a 0 to 100 scale. Contrasts obtained from linear mixed models were used to estimate the differences in image parameters between the agents. Participant experience was evaluated with an acceptability survey which included five items measured on a five-point Likert scale. Image quality, as rated by physicians, was found to be equivalent between commercial ultrasound gel and coconut oil. Additionally, there was not a statistically significant difference in image resolution or detail between the two coupling agents. The overall patient experience was significantly lower for commercial ultrasound gel when compared with coconut oil (mean difference = - 5.48, 95% confidence interval = [-6.89, -4.06]). Ultrasound images collected with coconut oil as the coupling agent are equivalent in quality to those collected using commercial ultrasound gel. Patients also preferred the use of coconut oil during their ultrasound, making its use a possible way to improve the patient ultrasound experience. Coconut oil has the potential as an alternative coupling agent that could significantly increase access to ultrasound use in resource-limited settings. · Coconut oil produces quality images during obstetrical ultrasounds.. · Patients prefer the use of coconut oil to standard ultrasound gel during obstetrical ultrasounds.. · Coconut oil is a coupling agent that could increase ultrasound use in resource-limited settings..

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.

Pharmacokinetics, Safety, and Tolerability of Once-Daily Darunavir With Cobicistat and Weekly Isoniazid/Rifapentine.

Once-weekly isoniazid with rifapentine (HP) for 3 months is a recommended treatment for latent tuberculosis infection in persons with HIV. HP reduces exposures of certain antiretroviral medications, resulting in limited options for the concomitant use of these therapies. Here, we examined the pharmacokinetics (PK), safety, and tolerability of darunavir/cobicistat with HP. This was an open-label, fixed sequence, two-period crossover study in persons without HIV. Participants received darunavir 800 mg/cobicistat 150 mg once-daily alone for 4 days, then continued darunavir/cobicistat once-daily for days 5-19 with HP coadministration on days 5, 12, and 19. Intensive PK assessments were performed on days 4, 14, and 19. PK parameters were determined using noncompartmental methods. Geometric mean ratios with 90% confidence intervals (CIs) were calculated and compared between phases using mixed-effects models. Thirteen participants were enrolled. Two withdrew after day 4, and one withdrew after day 14. Of the 3 withdrawals, 2 were attributed to drug-related adverse events. Darunavir area under the concentration-time curve, maximum concentrations (Cmax), and concentrations at 24 hours postdose (C24h) were reduced by 71%, 41%, and 96% ∼48-72 hours after HP administration (day 14), respectively, and 36%, 17%, and 89% with simultaneous HP administration (day 19), respectively. On day 14, 45% of the predose and 73% of C24h concentrations were below the darunavir EC50 (0.055 µg/mL). Darunavir exposures were significantly decreased with HP coadministration. Temporal relationships between HP coadministration and the extent of induction or mixed inhibition/induction of darunavir metabolism were apparent. Coadministration of darunavir/cobicistat with 3HP should be avoided.

Development and Validation a UPLC-MS/MS Method for Quantification of Pentoxifylline in Beagle Plasma: Application for Pharmacokinetic Study of Food Effect.

To develop an UPLC-MS/MS method for the quantitative analysis of pentoxifylline in beagle dog plasma and apply it to a pharmacokinetic study of food effect. Sample separation was achieved using a Kinetex Phenyl-Hexyl column (50 × 2.1 mm, 1.7 μm) with a gradient elution program in 5.5 min after a simple protein precipitation with methanol. Using the mobile phase that made up by 0.2% formic acid and 5mM ammonium formate water (A) and methanol (B). Quantitation was carried out using the positive ionization mode with multiple reaction monitoring (MRM). A randomized, single-dose, two-period crossover study was conducted insix fasted or fed beagles that received 400 mg pentoxifylline sustained-release tablets (Brand name: Shuanling™, CSPC Pharmaceutical Group). WinNonlin® software was used to calculate pharmacokinetic parameters. The linear calibration range was 2-1000 ng/mL (r2> 0.99). Both intra- and inter-batch precision were less than 6.27%, and the accuracy ranged from 88.65% to 97.18%. Pentoxifylline was readily absorbed in fasted and fed dogs administered a dose of 400 mg (tmax:1.54h vs 1.83h). Compared to the fasted group, the AUC0→t and Cmax in the fed group increased by 1.71-fold and 1.30-fold, respectively. In the fasted group, the AUC0→t and Cmax values were 4684.08 h•ng/mL and 2402.33 ng/mL, respectively. In the fed group, these values were 8027.75 h•ng/mL and 3119.67 ng/mL. The difference in AUC0-t between the fed and fasted group was statistically significant. The novel optimized UPLC-MS/MS assay is an effective tool for the determination of pentoxifylline and has been successfully applied in pharmacokinetic studies of pentoxifylline in beagle dogs. The administration of pentoxifylline sustained-release tablets with food significantly increased the area under the time curve, and it is recommended that they should be administered during or shortly after feeding.

A Comparison of Efficacy among Syrian diabetic patients treated with Empagliflozin versus Dapagliflozin, a Randomized, Triple-blind, Two-period crossover study

A Comparison of Efficacy among Syrian diabetic patients treated with Empagliflozin versus Dapagliflozin, a Randomized, Triple-blind, Two-period crossover study

Dermal effects and pharmacokinetic evaluation of the lidocaine/prilocaine cream in healthy Chinese volunteers

BackgroundEMLA cream is a local anesthetic. The pharmacokinetics and dermal effects of a topical anesthetic formulation has not been evaluated in healthy Chinese volunteers.Materials and methodsThe Pharmacokinetics of the lidocaine/prilocaine test (T) or reference (R, EMLA) cream were evaluated in a fasting, single-dose, two-period crossover bioequivalent study conducted in 40 healthy Chinese volunteers. Meanwhile, the dermal effects including blanching, erythema, temperature sensation, edema, and skin rash were also evaluated during the study.ResultsAfter applied 15 g of the cream for 4 h to a 100 cm2 area under plastic occlusive film on the skin of the thigh of healthy volunteers, the results of the pharmacokinetic study showed that the active components absorbed in skin from topical products was relatively low compared with most system absorption drugs. After the removal of the residual anesthetic cream, there was a vascular biphasic response with initial transient blanching which reaches a peak at 4.5 h and later more persisting period erythema. The change of temperature sensory sensitivity reached the peak value at 4.5-6 h.There was no statistically significant difference of the changes after application the lidocaine/prilocaine T or R cream in subjects. In general, the lidocaine/prilocaine T or R cream was well tolerated.ConclusionThe method described a model for investigations of pharmacokinetics and pharmacodynamics of topical lidocaine/prilocaine cream. Except the plasma drug level indicator, these pharmacodynamics data should also be evaluated in the anesthetic transdermal pharmacokinetics study.Clinical Trial RegistrationCTR20211544; registered in http://www.chinadrugtrials.org.cn/ at September 2021.

Physiologically based pharmacokinetic modeling to characterize enterohepatic recirculation and predict food effect on the pharmacokinetics of hyzetimibe

Background and ObjectiveHyzetimibe is a cholesterol absorption inhibitor indicated for the treatment of hypercholesterolemia. This study aims to describe the multiple-peak pharmacokinetics (PK) of hyzetimibe and its active metabolite M1 through physiologically-based pharmacokinetic (PBPK) modeling, and to compare the model predictions of a virtual food effect study with the results of a clinical food effect study. MethodsThe plasma concentration data used for PBPK modeling were obtained from a single-dose, two-period crossover bioequivalence study in the fasted state. Advanced Compartmental Absorption and Transit model was used for absorption. Enterohepatic recirculation process was modeled by changing the gut physiological state from fasted to fed at meal time. Based on the established PBPK models, a virtual food effect study was simulated. A clinical food effect study was used for model external validation. ResultsPK profiles of hyzetimibe and M1 under fasting condition could be well described by the PBPK model, and the errors of Cmax, AUC0-∞, and AUC0-t were within the two-fold range. Simulated geometric mean ratios (GMRs, fed/fasted) showed that a high-fat breakfast slightly affected the PK of hyzetimibe, expressed as increased Cmax of hyzetimibe (130.6%). Simulated GMRs and 90% confidence intervals of AUC were within the preset bioequivalent range. The results of the simulated virtual food effect trial were consistent with those of the clinical food effect trial. ConclusionsThe established PBPK model could describe the concentration-time profiles of hyzetimibe and M1 well with good prediction performance. A fully mechanistic model of enterohepatic recirculation warrants further investigation.

Development of a pharmacokinetic and pharmacodynamic model for intranasal administration of midazolam in older adults: a single-site two-period crossover study

BackgroundIntranasal midazolam can produce procedural sedation in frail older patients with dementia who are unable to tolerate necessary medical or dental procedures during domiciliary medical care. Little is known about the pharmacokinetics and pharmacodynamics of intranasal midazolam in older (>65 yr old) people. The aim of this study was to understand the pharmacokinetic/pharmacodynamic properties of intranasal midazolam in older people with the primary goal of developing a pharmacokinetic/pharmacodynamic model to facilitate safer domiciliary sedation care. MethodsWe recruited 12 volunteers: ASA physical status 1–2, aged 65–80 yr, and received midazolam 5 mg intravenously and 5 mg intranasally on two study days separated by a 6 day washout period. Concentrations of venous midazolam and 1ʹ–OH–midazolam, Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score, bispectral index (BIS), arterial pressure, ECG, and respiratory parameters were measured for 10 h. ResultsTime to peak effect of intranasal midazolam for BIS, MAP, and SpO2 were 31.9 (6.2), 41.0 (7.6), and 23.1 (3.0) min, respectively. Intranasal bioavailability was lower compared with intravenous administration (Fabs 95%; 95% confidence interval: 89–100%). A three-compartment model best described midazolam pharmacokinetics following intranasal administration. A separate effect compartment linked to the dose compartment best described an observed time-varying drug-effect difference between intranasal and intravenous midazolam, suggesting direct nose-to-brain transport. ConclusionsIntranasal bioavailability was high and sedation onset was rapid, with maximum sedative effects after 32 min. We developed a pharmacokinetic/pharmacodynamic model for intranasal midazolam for older persons and an online tool to simulate changes in MOAA/S, BIS, MAP, and SpO2 after single and additional intranasal boluses. Clinical trial registrationEudraCT (2019-004806-90).

Bioequivalence study of generic nirmatrelvir in healthy volunteers

Nirmatrelvir is an antiviral drug that, in combination with ritonavir, is an effective agent for the etiotropic therapy of patients with mild to moderate COVID-19.The aim of the study was to evaluate bioequivalence of the generic drug nirmatrelvir Аrpaxel in combination with ritonavir and the original drug Paxlovid, which is a combination of nirmatrelvir/ritonavir, in a single dose administration to healthy volunteers.Materials and methods. This research was an open-label, randomized, two-period crossover bioequivalence study. It included 2 periods, in each of which the volunteers received either a test drug (nirmatrelvir at the dose of 300 mg) in combination with ritonavir (100 mg), or a reference drug (a combination of nirmatrelvir 300 mg and ritonavir 100 mg), given as a single dose. A wash-out period between each of the administrations was 7 days. The blood sampling to determine the concentration of nirmatrelvir was carried out in the range from 0 to 36 h in each of the study periods. A nirmatrelvir concentration was determined by a validated HPLC-MS/MS method with a lower quantitation limit of 10 ng/mL. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC(0–16) and Cmax of the test drug and reference drugs with the established equivalence limits of 80.00–125.00%.Results. In the study were included 68 healthy volunteers, 67 participants of which were included in the bioequivalence population. The pharmacokinetic parameters of the drugs were comparable to each other. The 90% confidence interval for the ratio of the geometric mean of the maximum drug concentration in the blood plasma and the area under the pharmacokinetic curve «concentration-time» from zero to the last blood draw within 36 hours of nirmatrelvir was 87.26–100.83 and 93.27–103.74%, which meets the criteria for assessing bioequivalence. The test drugs were well tolerated by the volunteers. The incidence of adverse events was similar for the test and reference drugs. No serious adverse events were recorded during the entire study.Conclusion. As a result of this study, bioequivalence of the test and reference drugs has been established.

Pharmacokinetics and bioequivalence study of esomeprazole magnesium enteric-coated tablets 20mg in healthy Chinese subjects under fasting and fed conditions.

Objective: The main purpose of this study was to evaluate the pharmacokinetics, bioequivalence, and safety properties between a new generic and a brand reference formulation of esomeprazole enteric-coated tablets 20mg in healthy Chinese subjects under fasting and fed conditions. Methods: The fasting study was an open-label, randomized, two-period crossover study conducted in 32 healthy Chinese volunteers, and the fed study was a four-period crossover study conducted in 40 healthy Chinese volunteers. Blood samples were collected at the specified time points and determined to obtain the plasma concentrations of esomeprazole. The primary pharmacokinetic parameters were calculated using the non-compartment method. Bioequivalence was analyzed by the geometric mean ratios (GMRs) of the two formulations and the corresponding 90% confidence intervals (CIs). The safety of the two formulations was assessed. Results: The fasting and fed study showed that the pharmacokinetics of the two formulations was similar. Under the fasting condition, the 90% CIs of GMRs of the test-to-reference formulation were 87.92%-104.36% for Cmax, 87.82%-101.45% for AUC0-t, and 87.99%-101.54% for AUC0-∞; under the fed condition, the 90% CIs of GMRs of the test-to-reference formulation were 80.53%-94.95% for Cmax, 87.46%-97.26% for AUC0-t, and 87.46%-97.16% for AUC0-∞. The 90% CIs of GMRs fall within the bioequivalence range of 80.00%-125.00%. The two formulations had good safety and were well-tolerated, and no serious adverse events occurred. Conclusion: According to relevant regulatory standards, esomeprazole enteric-coated generic and reference products exhibited bioequivalence and good safety in healthy Chinese subjects. Clinical Trials Registration: http://www.chinadrugtrials.org.cn/index.html, identifier CTR20171347 and CTR20171484.

Pen-administered low-dose dasiglucagon vs usual care for prevention and treatment of non-severe hypoglycaemia in people with type 1 diabetes during free-living conditions: a Phase II, randomised, open-label, two-period crossover trial

Aims/hypothesisConsumption of excess carbohydrates to manage hypoglycaemia can lead to rebound hyperglycaemia and promote weight gain. The objective of this trial was to evaluate the efficacy, safety and feasibility of pen-administered low-dose dasiglucagon for prevention and treatment of non-severe hypoglycaemia in people with type 1 diabetes during free-living conditions.MethodsTwenty-four adults with insulin pump-treated type 1 diabetes (HbA1c ≤70 mmol/mol [8.5%]) completed a randomised, open-label, two-period crossover study with 2 week periods. During the usual care and dasiglucagon intervention (DASI) periods, participants managed impending and manifested episodes of hypoglycaemia with regular carbohydrate consumption or pen-administered low-dose (80 μg) s.c. dasiglucagon, respectively. Glycaemic control was evaluated using continuous glucose monitoring (Dexcom G6) and event registration of prevention and treatment episodes.ResultsCompared with usual care, the mean difference (95% CI) in the DASI period for time in (3.9–10.0 mmol/l) and below (<3.9 mmol/l) range was 2.4 %-points (−0.7, 5.5) and −0.5 %-points (−1.2, 0.2), respectively. In the DASI period, recovery rate (time from hypoglycaemia treatment to euglycaemia) was 44% (11, 87) faster while total daily carbohydrate intake was reduced by 11% (−18, −3). Dasiglucagon use was safe and well tolerated with mild nausea being the most frequent adverse effect. Among the participants, 96% (p<0.0001) were likely to include dasiglucagon in their future routine management of hypoglycaemia.Conclusions/interpretationUse of low-dose dasiglucagon to prevent and treat non-severe hypoglycaemia during free-living conditions was safe, fast and efficacious while significantly reducing the total daily carbohydrate intake and yielding high treatment satisfaction.Trial registrationClinicalTrials.gov NCT04764968FundingThe study was an investigator-initiated trial. Zealand Pharma supplied the investigational drug and device and provided financial support for the conduct of the trial.Graphical abstract

BIOEQUIVALENCE STUDY OF GENERIC MOLNUPIRAVIR IN HEALTHY VOLUNTEERS

Molnupiravir is one of the drugs for the etiotropic therapy of a new coronavirus infection COVID-19. It has confirmed its clinical efficacy in the treatment of patients with mild and moderate COVID-19, including those who are at high risk of progressing to severe disease.The aim of the study was to evaluate bioequivalence of the generic drug molnupiravir ALARIO-TL and the original drug Lagevrio with a single oral administration in healthy volunteers.Materials and methods. This bioequivalence study was an open, randomized, two-period crossover study. In each of the two periods, volunteers received a single dose of the test drug, or reference drug molnupiravir, in the form of capsules at the dose of 200 mg. The washout period between the doses was 3 days. To determine pharmacokinetic (PK) parameters and bioequivalence, the concentration the concentration of N-hydrozycytidine (NHC), the main molnupiravir metabolit in the blood plasma of volunteers was evaluated. The blood plasma sampling was carried out in the range from 0 to 16 hours in each of the study periods. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC(0–16) and Cmax of the test drug and reference drugs with the established equivalence limits of 80.00 – 125.00%.Results. A total of 28 healthy male volunteers were included in the study. According to the results of the statistical analysis, after the administration of the test and reference drugs, the 90% CIs for the ratio of the geometric means of AUC (0–16) and Cmax were 96.31% – 113.64% and 91.37% – 114.8%, respectively. These intervals fit within the established limits of 80.00–125.00%, which confirms the bioequivalence of the drugs. When comparing the frequency of the individual adverse events registration, no significant differences were found out after the administration of the test and reference drugs.Conclusion. Based on the results of this study, it can be concluded that the test and reference drugs of molnupiravir are bioequivalent. In addition, the data obtained indicate that the drugs have similar safety profiles.

Pharmacokinetics and bioequivalence of Ezetimibe tablet versus Ezetrol®:an open-label, randomized, two-sequence crossover study in healthy Chinese subjects

BackgroundEzetimibe is a new class of antihyperlipidemic agent indicated for the prevention of atherosclerosis disease and for the treatment of hypercholesterolemia. Information on the pharmacokinetic profiles of ezetimibe tablet in healthy Chinese volunteers are lacking, and regulatory requirements necessitate a bioequivalence study of ezetimibe tablet versus Ezetrol® in China.MethodsA single-dose randomized, open-label, two-group, two-period crossover study was conducted in 59 healthy Chinese volunteers under fasting or fed conditions to assess the bioequivalence between two preparations. Eligible participants were randomly divided into fasted and fed groups. Blood samples were collected at specified time intervals, and the plasma concentrations of ezetimibe and ezetimibe glucuronide were determined by a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method. PK and bioavailability parameters were estimated via non-compartmental methods. Adverse events were also recorded.ResultsFifty-nine healthy volunteers were enrolled in the study. The main pharmacokinetic parameters of total ezetimibe in the plasma of the ezetimibe tablet (10 mg) and the Ezetrol® (10 mg) after a single fasting administration: Cmax were (65.73 ± 47.14), (71.32 ± 51.98) ng·mL− 1; Tmax were 1.75, 1.25 h; T½ were (17.09 ± 13.22), (17.35 ± 12.14) h; AUC0-t were (643.34 ± 400.77), (668.49 ± 439.57) h·ng·mL− 1; AUC0-∞ were (706.36 ± 410.92), (734.23 ± 468.26) h·ng·mL− 1. The main pharmacokinetic parameters of total ezetimibe in plasma of ezetimibe tablet (10 mg) and Ezetrol® (10 mg) after a fed administration: Cmax were (83.38 ± 38.95), (84.74 ± 34.62) ng·mL− 1; Tmax were 2.50, 2.50 h; T½ were (22.56 ± 12.68), (19.80 ± 15.59) h; AUC0-t were (494.21 ± 208.65), (536.69 ± 209.11) h·ng·mL− 1; AUC0-∞ were (573.74 ± 252.74), (604.75 ± 247.13) h·ng·mL− 1. The main pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ of the two drugs were analyzed by variance analysis after logarithmic transformation. The total ezetimibe under fasting state with 90% confidence intervals (CIs) were 85.29 ~ 97.19, 90.41% ~ 104.38%, and 90.81 ~ 106.05%; total ezetimibe in fed state were 86.36% ~ 109.17, 84.96% ~ 96.40, and 85.32% ~ 101.0%. The 90% CIs of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ of Ezetrol® and ezetimibe tablet both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80–1.25. Both Cmax and AUC met the predetermined criteria for assuming bioequivalence. No severe adverse events were observed.ConclusionsThe test ezetimibe tablet and Ezetrol® were determined to be bioequivalent under both fasting and fed conditions in Chinese people.Trial registrationClinicaltrials, NCT05681247 (retrospectively registered in 11/01/ 2023).