Formulation In Healthy Volunteers Research Articles

Relative bioavailability, immunogenicity, and safety of two adalimumab-adbm formulations in healthy volunteers: a double-blind, randomized, single-dose, parallel-arm Phase I trial (VOLTAIRE-HCLF)

ABSTRACT Objective VOLTAIRE-HCLF compared the relative bioavailability of citrate-free high-concentration and reference formulations of the biosimilar adalimumab-adbm (Cyltezo®), including pharmacokinetic (PK) profiles, immunogenicity, and safety profiles in healthy volunteers. Methods Healthy volunteers (N = 200) aged 18–55 years and with body mass index of 18.5–29.9 kg/m2 and no prior exposure to adalimumab were randomized in a 1:1 ratio to receive a single subcutaneous injection of either adalimumab-adbm 40 mg/0.4 mL (high-concentration formulation) or 40 mg/0.8 mL (reference formulation). Participants completed 13 follow-up visits over 57 days, followed by a safety follow-up period of up to 70 days. Results The main PK parameters were similar for the high-concentration and reference groups. For all primary endpoints, the geometric mean ratios and 90% confidence intervals of AUC0–1344, AUC0–∞, and Cmax for both groups were entirely within the standard 80–125% bioequivalence acceptance range at 101.88% (93.31–111.23%), 105.38% (95.06–116.81%), and 91.29% (84.38–98.76%), respectively. There were no differences in the proportion of anti-drug antibody-positive participants or in the distribution of anti-drug antibody titers between the two formulations at any time point after drug dosing. Participants who were given the high-concentration formulation of adalimumab-adbm experienced a lower incidence of adverse events and local reactions than those who were given the reference formulation. Conclusions Overall, the high-concentration and reference adalimumab-adbm formulations had highly similar PK and immunogenicity profiles and were safe and well tolerated. Clinical trial registration NCT05203289

Clinical pharmacokinetics of atropine oral gel formulation in healthy volunteers.

Sialorrhea or drooling is a common problem in children and adults with neurodevelopmental disorders. It can negatively impact the quality of life due to its physical and psychological manifestations. Providers commonly prescribe atropine eye drops for topical administration to the oral mucosa, as an off-label treatment to manage sialorrhea. However, the off-label use of atropine eye drops can be associated with medication and dosing errors and systemic side effects. To address these limitations of treatment, we developed a mucoadhesive topical oral gel formulation of atropine as an alternative route to off-label administration of atropine eye drops. In this clinical pharmacokinetic (PK) study, we evaluated the safety and PK of atropine gel (0.01% w/w) formulation after single-dose administration to the oral mucosa in 10 healthy volunteers. The PK data showed that after topical administration to the oral mucosa, atropine followed a two-compartment PK profile. The maximum plasma concentration and area under the curve extrapolated to infinite time were 0.14 ng/mL and 0.74 h·ng·mL-1 , respectively. The absorption rate constant calculated by the compartmental analysis was 0.4 h-1 . Safety parameters, such as heart rate, blood pressure, and oxygen saturation, did not significantly change before and after administration of the gel formulation, and no adverse events were observed in all participants who received atropine gel. These data indicate that atropine gel formulation has a satisfactory PK profile, is well-tolerated at the dose studied, and can be further considered for clinical development as a drug product to treat sialorrhea.

The Efficacy and Safety of an Ayurvedic Petsaffa Formulation in Subjects with Constipation: An Open-Label, Non-Randomized Clinical Study

Constipation is a common gastrointestinal complaint among 16% of the world's population. Several conventional treatments are recommended; however, these sometimes do not provide satisfactory results for many patients or cause unpleasant side effects. In this context, Ayurvedic medicine can be an alternative, cost-effective and satisfactory treatment for constipation. Hence, this clinical study aimed to evaluate the efficacy and safety of an Ayurvedic PetSaffa formulation in subjects with functional constipation. Design, Setting, Participants and Intervention: This open-label, non-randomized clinical study was conducted to evaluate the safety and efficacy of an Ayurvedic PetSaffa formulation in healthy volunteers with functional constipation. Subjects were selected based on inclusion and exclusion criteria. Participants received PetSaffa granules for 21 days. Outcome parameters of the study, including frequency of bowel movements, constipation score, constipation symptoms, gas, acidity, and serum level of SGPT, were evaluated at screening and after 21 days of treatment. Results: A total of 120 participants completed the 21-day treatment. At the end of the treatment period, all clinical outcomes, including frequency of bowel movement and constipation score, were significantly (p<0.001) improved. The analysis of constipation symptoms' frequencies and severity also significantly (p<0.001) improved without any significant adverse effects. Additionally, PetSaffa granules also reduced gas and acid symptoms. As part of the safety study, serum levels of SGPT were within the normal range before and after treatment. Conclusion: The study intervention, PetSaffa granules, significantly improved bowel movements, gas and acidity symptoms without causing any adverse effects. Therefore, the Ayurvedic PetSaffa granules are a clinically effective and safe alternative for the treatment of functional constipation.

An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers.

Posaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed. This study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers. Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested. A two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2-80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2-59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose. For both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.

Plant formulation ATRICOV 452 in improving the level of COVID-19 specific inflammatory markers in patients

ImportanceDue to the huge demand for healthcare facilities, there is a need for safe therapeutic intervention which can reduce the need for extensive healthcare support. ObjectiveIn phase 1, to determine the safety of plant formulation in healthy volunteers and in phase 2, to validate its potential to improve the level of COVID-19 specific inflammatory markers. DesignSetting, and Participants: The phase 1 single fasting dose study was conducted on 24 healthy adult human volunteers to evaluate the safety and tolerability of plant formulation. The usage of plant formulation in humans was found safe and encouraged conducting Phase 2 clinical trial to evaluate the efficacy in 100 COVID-19 patients along with the standard of care. InterventionsPhase 1: plant formulation capsule of 500 mg single dose; Phase 2: plant formulation 1 gm thrice a day for 14 days. ResultsDuring the Phase 1 trial no adverse event was observed and all organ systems were normal in function. During the Phase 2 trial, 100 patients underwent randomization, 50 were assigned to receive plant formulation, and 50 to receive placebo. Three patients in the placebo and two patients in the plant formulation group had dropped out of the study. Hence, the primary analysis population included 95 patients (48 allocated to plant formulation and 47 to placebo). The COVID-19-specific inflammatory markers improved faster and became normal in the plant formulation treatment group. No one needed hospital care or oxygen. Conclusionsand Relevance: The investigational product, plant formulation (ATRICOV 452) has been found to be safe in phases 1 and 2. Further, in the phase 2 trial, ATRICOV 452 was effective at the dose of 1 mg, three times a day dose frequency to improve the level of COVID-19 specific inflammatory markers. Trial registrationPhase 1: CTRI Registration number: CTRI 2020/09/027660 Phase 2: CTRI Registration number: CTRI/2021/01/030795.

Comparative, Single-Dose, 2-Way Cross-Over Bioavailability Study of Two Olanzapine 10 Mg Tablet Formulations in Healthy Volunteers Under Fasting Conditions.

Objectives: Olanzapine is an atypical antipsychotic that is approved across Europe, the USA, and in many other countries for oral treatment of schizophrenia and acute manic episodes in patients with bipolar disorder as well as for maintenance therapy to prevent recurrence in responders. The objective of the present study was to compare the pharmacokinetics of two 10 mg tablet formulations of Olanzapine following a single oral dose in healthy volunteers under fasting conditions, as per the European Medicine Agency (EMA) guidelines to grant marketing authorization. Methods: This study was a randomized, open-label, two-treatment, two-period, two-sequences, single-dose, cross-over design with a washout period of 14 days. Both the test and the reference products were administered as 10 mg tablets with 240 mL of water after an overnight fast in each study period. A total of twenty blood samples were collected before dosing and within 144 hours after drug administration. Adverse events were monitored, recorded, and evaluated by investigators throughout the study. Results: Of the 24 healthy adult male subjects enrolled, all of them completed both study periods. The geometric mean ratio 90% confidence intervals (CI) for fasting Cmax, AUC0-t, and AUC0-infinity were 94.83-113.71%, 95.04-105.69% and 95.94-107.00%, respectively. The 90% CI for the ratios of the three primary pharmacokinetic parameters (using log-transformed data) were within the range of 80-125%, meeting the regulatory criteria for bioequivalence. Conclusions: The generic Olanzapine was bioequivalent to the reference formulation. It was well tolerated and provides an acceptable alternative to the reference drug.

OP27 A Phase 1 Study Evaluating the Bioequivalence of the Proposed Commercial and Clinical Formulations of Etrasimod 2mg, and the Effect of Food on the Pharmacokinetics of the Proposed Commercial Formulation in Healthy Volunteers

Abstract Background Etrasimod (ETR) is a once-daily, oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders including ulcerative colitis, Crohn’s disease, eosinophilic esophagitis, and atopic dermatitis. This study evaluated the single-dose bioequivalence of the proposed commercial and clinical formulations of ETR 2mg in the fasted state, and the effect of food on the pharmacokinetics of the proposed commercial formulation. Methods This 3-treatment, 3-period crossover Phase 1 study enrolled 18 healthy adults (18–55 years: 10 males/8 females). Participants were randomized to 6 treatment sequences (3 participants/sequence: ABC, BCA, CAB, ACB, BAC, CBA) consisting of Treatment A (single-dose ETR 2mg clinical formulation, fasted), Treatment B (single-dose ETR 2mg proposed commercial formulation, fasted), and Treatment C (single-dose ETR 2mg proposed commercial formulation, fed). Treatments were administered on Days 1, 10, and 19 to allow 8-day washout periods between treatments. In the fed state (Treatment C), all participants received an FDA-standard high-fat, high-calorie meal. Blood samples for determination of ETR concentration were collected at prespecified timepoints to 168 hours post dose. Analysis of variance was performed on log-transformed Cmax, AUC0-last, and AUC0-∞ values to determine geometric least squares mean ratios (GLSMR) of Test/Reference and associated 90% confidence intervals (CI) to assess bioequivalence and food effects. Safety and tolerability of ETR were also evaluated. Results Bioequivalence: The 90% CI for the GLSMR of ETR Cmax and AUC plasma exposure measures, comparing the proposed commercial vs clinical formulations, were within the accepted 80%–125% range (GLSMR and 90% CI) for establishing bioequivalence (Table 1). Median Tmax for Treatments A and B were both 4 hours. Food Effect: The 90% CI for the GLSMR of ETR Cmax and AUC plasma exposure measures, comparing the proposed commercial formulation under fed vs fasted conditions, were within the accepted 80%–125% range for establishing no food effect (Table 2). Median Tmax for Treatment C was 6 hours. Safety and Tolerability: All treatment-emergent adverse events (AEs) were mild (except 1 moderate AE [headache]). One participant had an AE leading to study drug discontinuation. There were no serious AEs or deaths. Conclusion Based on results from this study, the proposed commercial and clinical formulations of ETR 2mg were bioequivalent in terms of rate and extent of absorption. No significant differences were demonstrated in ETR exposure for the proposed commercial formulation under fed and fasted conditions. All treatments were generally safe and well tolerated.

A phase 1, dose-ranging trial to assess the safety and psychoactive effects of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation in healthy volunteers

A phase 1, dose-ranging trial to assess the safety and psychoactive effects of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation in healthy volunteers

Prediction of pharmacokinetic parameters of inhaled indacaterol formulation in healthy volunteers using physiologically-based pharmacokinetic (PBPK) model

BackgroundInhaled formulations are the first choices for treating asthma and chronic obstructive pulmonary disease (COPD), attracting the increasing investment and development in the pharmaceutical industry. Both the equivalence of local and systemic exposures need to be considered when assessing the equivalence of generic inhaled drugs, which has become a dilemma in the development of generic inhaled drugs. There is an urgent need for reliable methods such as physiologically-based pharmacokinetic (PBPK) model to assist in the development of inhaled drugs. MethodTo test the strategy that in silico simulation is an effective tool in developing inhaled products and further assessing their clinically feasibility, a long-acting beta2-adrenergic agonists indacaterol, which was referred as the first-line therapy for patient with COPD, was selected as a tool drug. The PBPK model was established and the predicted plasma concentration curve was obtained by inputting the physicochemical properties of indacaterol and adjusting model parameters. The accuracy of simulation was verified by an alignment with the actual data. The main factor affecting PK in vivo was investigated by parameter sensitivity analysis. The biological equivalent size of indacaterol was investigated by virtual bioequivalence analysis. ResultsThe models of indacaterol after intravenous and oral administration were established and confirmed, and used as a background for PBPK model of inhaled administration. All those models showed favorable stability and applicability. Appropriate lung deposition was generated in the PBPK model, and the predicted plasma profile of indacaterol was consistent with the clinical actual observation values. Particle size is the most important factor affecting the PK of indacaterol in vivo. Furthermore, virtual bioequivalence simulation exhibited statistically comparable results between the particle size fluctuates in the range of 3.5–6.5 μm and baseline levels (D90 = 5 μm). ConclusionsThe PBPK model can simulate the pharmacokinetics and lung deposition of indacaterol, which will be a powerful tool to assist the development of inhaled drugs.

Population Pharmacokinetic Modelling of the Complex Release Kinetics of Octreotide LAR: Defining Sub-Populations by Cluster Analysis.

The aim of the study is to develop a population pharmacokinetic (PPK) model, of Octreotide long acting repeatable (LAR) formulation in healthy volunteers, which describes the highly variable, multiple peak absorption pattern of the pharmacokinetics of the drug, in individual and population levels. An empirical absorption model, coupled with a one-compartment distribution model with linear elimination was found to describe the data well. Absorption was modelled as a weighted sum of a first order and three transit compartment absorption processes, with delays and appropriately constrained model parameters. Identifiability analysis verified that all twelve parameters of the structural model are identifiable. A machine learning method, i.e., cluster analysis, was performed as pre-processing of the PK profiles, to define subpopulations, before PPK modelling. It revealed that 13% of the patients deviated considerably from the typical absorption pattern and allowed better characterization of the observed heterogeneity and variability of the study, while the approach may have wider applicability in building PPK models. The final model was evaluated by goodness of fit plots, Visual Predictive Check plots and bootstrap. The present model is the first to describe the multiple-peak absorption pattern observed after octreotide LAR administration and may be useful to provide insights and validate hypotheses regarding release from PLGA-based formulations.

Safety, Pharmacokinetics, Pharmacodynamics, and Formulation of Liver‐Distributed Farnesoid X‐Receptor Agonist TERN‐101 in Healthy Volunteers

TERN-101 is a nonsteroidal farnesoid X-receptor agonist being developed for the treatment of nonalcoholic steatohepatitis (NASH). We assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TERN-101 capsule and tablet formulations in healthy volunteers. In a randomized, double-blind, placebo-controlled study, 38 participants were enrolled and randomized to receive placebo or 25-, 75-, or 150-mg TERN-101 capsules orally once daily for 7 days. In a separate open-label PK and formulation-bridging study, 16 participants received single doses of TERN-101 tablets (5 and 25 mg) or capsules (25 mg). TERN-101 was overall well-tolerated in this healthy volunteer population; no pruritus was reported. TERN-101 capsule administration over 7 days resulted in decreases in serum 7α-hydroxy-4-cholesten-3-one that were sustained for 24 hours after the last dose (maximum suppression 91% from baseline), indicating target engagement in the liver. TERN-101 capsules exhibited less than dose-proportional PK. Relative to capsules, TERN-101 tablets showed increased bioavailability, with 24-hour plasma exposure of the 5-mg tablet similar to that of the 25-mg capsule. There was no significant effect of food on exposure. The overall safety, PK, and PD profiles of TERN-101 support its further evaluation for the treatment of NASH.

Effect of Food on MDM2 Inhibitor KRT-232 Pharmacokinetics and Macrophage Inhibitory Cytokine-1 (MIC-1) Response in Healthy Volunteers

Background: KRT-232 is a potent, selective, orally available, small-molecule drug that binds to mouse double minute 2 homolog (MDM2) and inhibits its interactions with tumor suppressor protein p53. KRT-232 is under development for treatment of myeloproliferative neoplasms, acute myeloid leukemia, and Merkel cell carcinoma. Increased serum MIC-1 (pg/mL) is a pharmacodynamic (PD) marker of p53-mediated activity in patients treated with KRT-232 (Allard,HemaSphere, 2020;4:S1, Abstract EP519). The aim of this study was to assess the safety and effect of a high-fat meal on KRT-232 pharmacokinetics (PK) and MIC-1 PD of a new tablet formulation in healthy volunteers. This is the first characterization of a MDM2-inhibitor-induced MIC-1 response in healthy volunteers. Methods: KRT-232-105 was a single-center, open-label, 60-mg single-dose, 3-treatment, 4-period, and 3-sequence study with a partial replicate crossover design. Volunteers (N=30) were randomized to three treatment groups: A: new tablet, fasted (reference, dosed twice in Periods 2-4); B: new tablet, 30 min after a high-fat, high-calorie meal (test 1, dosed once in periods 2-4); C: current tablet, fasted (test 2, period 1 only). Plasma KRT-232, its acyl glucuronide metabolite (M1) and serum MIC-1 concentrations were measured over 0-96 h. Urine from group C was collected over 0-48 h. Doses were one week apart. All volunteers had aH pyloribreath test and were genotyped for UGT1A1*28 polymorphisms. Results: Volunteers were 43% female, 7% African American and 77% Hispanic/Latino. Mean age was 38.1 y (range, 18-54), and mean body mass index was 26.9 kg/m2 (range, 21.4-30.9). No deaths, serious adverse events (SAEs), or discontinuations were reported. Twenty-one treatment-emergent AEs (TEAEs) were observed in 13 (43%) volunteers; constipation was the most frequent AE, followed by headache. All TEAEs were grade 1 (n=17) or grade 2 (n=4: 1 headache event [possibly study drug-related] and 3 events of headache, influenza-like illness, and pharyngitis). Mean (SD) concentration-time plots of KRT-232 and M1 were similar across the 3 groups (Figure 1a and b). A second peak was observed, consistent with enterohepatic recirculation. With a meal (test 1), KRT-232 geometric least-squares mean (GLSM) maximum concentration (Cmax) was similar (431 and 442 ng/mL (GLSM ratio [90% CI], 103% [87.4-121]) and KRT-232 GLSM area under the curve (AUC0-t) decreased from 2858 to 2325 ng∙h/mL (GLSM ratio [90% CI], 81.4 [76.2-86.9]). Median time of Cmax (Tmax) was 2 h fasted and 3 h fed. Geometric mean half life (t1/2) was unchanged (17.0 vs 17.1 h). Under fasting conditions, the current tablet (C, test 2) vs new tablet (A, reference), KRT-232 GLSM Cmax decreased from 431 to 337 ng/mL (GLSM ratio [90% CI], 78.4% [72.0-85.3]) and KRT-232 GLSM AUC0-t had a possible small decrease (2858 and 2455 ng∙h/mL, GLSM ratio [90% CI], 85.9 [80.5-91.7]). Median Tmax (~2 h) and geometric mean t1/2 (17 h) were unchanged. The fraction of the KRT-232 dose in urine as KRT-232 and M1 was negligible at 0.0201% and 0.0220% of dose, respectively. KRT-232 is a carboxylic acid with pH-dependent solubility that increases with increasing pH.H pyloriinfection, which can increase stomach pH, did not have any discernable impact on KRT-232 PK. KRT-232 and M1 exposure in heterozygous UGT1A1*28 poor metabolizers (6/7 TA repeats, N=16) was generally comparable to exposure in wild-type (WT) UGT1A1*28 (6/6 TA repeats, N=12) subjects. MIC-1 concentrations in serum were variable and followed the PK time course with a median Tmax lag of ~8-12 h. Group A: Mean Cmax 2115 pg/mL, C0 (Baseline) 170 pg/mL, AUC0-T 89267 pg*h/mL and mean t1/2 27 h. MIC-1 Cmax and AUC were generally comparable over 96 h across groups (Figure 1c).Figure 1dshows the statistically significant correlation between KRT-232 AUC0-t and MIC-1 AUC0-t. Conclusions: Based on generally comparable PK, KRT-232 can be administered with or without food, and no dose adjustment is warranted with a new tablet formulation. KRT-232 PK was not affected byH pylori, inferring that higher gastric pH did not alter absorption of KRT-232. KRT-232 exposure in UGT1A1*28 heterozygous poor metabolizers was generally comparable to WT UGT1A1*28 wild type healthy volunteers. The 60-mg KRT-232 dose elicited a reproducible and robust MIC-1 response that correlated with KRT-232 exposure, indicating MDM2-p53 target engagement. Disclosures Wong: Kartos Therapeutics:Current Employment;AbbVie Biotherapeutics:Ended employment in the past 24 months.Krejsa:Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company;Seattle Genetics:Current equity holder in publicly-traded company;Acerta Pharma:Current equity holder in private company.Lee:Kartos Therapeutics:Current Employment.Harris:Gilead Sciences:Current equity holder in publicly-traded company;Kartos Therapeutics:Current Employment, Current equity holder in private company;BeiGene:Ended employment in the past 24 months;Clovis:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Simard:Certara:Current Employment;AltaScience:Ended employment in the past 24 months.Wang:Certara:Current Employment.Rubets:Certara:Current Employment.Allard:Certara:Consultancy, Ended employment in the past 24 months;CytomX Therapeutics:Ended employment in the past 24 months;Telios Pharma:Current Employment, Current equity holder in private company.Podoll:IV/PO, LLC:Consultancy.O'Reilly:Celerion:Current Employment.Slatter:Amgen:Divested equity in a private or publicly-traded company in the past 24 months;Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor.

Pharmacokinetic investigation of synthetic cannabidiol oral formulations in healthy volunteers

Recent advances in the research of medicinal cannabis has placed the non-intoxicating cannabinoid cannabidiol (CBD) at the front of scientific research. The reasons behind this popularity is the compound’s therapeutic properties, alongside a safe profile of administration lacking addictive properties such as euphoric state of mind and a wide dosing range. Oral administration of CBD is challenging due to poor solubility in the gastro-intestinal system and susceptibility to extensive first pass metabolism. As a result, the practice in clinic and investigational trials is to administer cannabinoids in edible oils or oil-based solutions. Nonetheless, reported pharmacokinetics of cannabinoids and CBD in particular are not uniform among research groups and are affected by the vehicle of administration.The purpose of the work presented here is to investigate oral absorption processes of synthetic CBD when given in different oral formulations in healthy volunteers.The study design was a three way, blind, cross-over single administration study of 12 healthy male volunteers. CBD was administered in powder form, dissolved in sesame oil and in self-nano-emulsifying drug delivery system (SNEDDS).Administration of CBD in lipid-based vehicles resulted in a significant increase in Cmax and AUC of CBD, as compared to powder form. Overall plasma exposure of CBD did not differ between sesame oil vehicle and the SNEDDS formulation. However, administration of CBD in pure oil resulted in two absorption behaviors of early and delayed absorption among subjects, as opposed to SNEDDS platform that resulted in a uniform early absorption profile.Results of this trial demonstrate the importance of solubilization process of lipophilic drugs such as CBD and demonstrated the ability of the nano formulation to achieve a reliable, predictable PK profile of the drug. These findings offer a standardized oral formulation for the delivery of cannabinoids and contribute data for the growing field of cannabinoid pharmacokinetics.

Pharmacokinetics of Ambroxol Sustained Release (Mucosolvan® Retard) Compared with Other Formulations in Healthy Volunteers.

IntroductionAmbroxol is used in the treatment of acute and chronic respiratory conditions characterized by abnormal mucus secretion and impaired mucus transport and is available in a variety of formulations. This study aimed to compare the steady-state (SS) pharmacokinetic characteristics of extended-release (ER) 75-mg retard capsules with two immediate-release (IR) formulations (60-mg effervescent tablets and 30-mg tablets) over a 24-h period.MethodsAn open-label, randomized, three-period, six-sequence crossover study was conducted in healthy volunteers aged 18–45 years who had a normal body mass index. The test (ER 75-mg retard capsule once daily) and reference treatments (half of IR 60-mg effervescent tablet twice daily or 30-mg IR tablet twice daily) were administered on days 1–5 of each treatment period. Meals were standardized and concomitant therapy was prohibited. Blood samples for pharmacokinetic assessment were collected on day 5 (SS) of each treatment period. The co-primary endpoints were exposure (AUCSS 0–24) and maximum plasma level (Cmax SS).ResultsTwenty-four participants received ambroxol (male n = 13, 54.2%; mean ± standard deviation [SD] age 25.0 ± 6.4 years) and 23 completed the study. ER retard capsules provided similar AUCSS 0–24 compared to IR tablets (geometric means ratio [GMR] 110.7%; 90% confidence interval [CI] 99.8%, 122.7%) and effervescent tablets (GMR 106.9%; 90% CI 100.3%, 114.0%). ER retard capsules provided similar Cmax SS compared to IR tablets (GMR 84.7%, 90% CI 77.0%, 93.3%), and lower Cmax SS compared to effervescent tablets (GMR 80.9%, 90% CI 73.9%, 88.6%). Time to Cmax SS (tmax SS) was longer with ER retard capsules (6.0 h) than with IR tablets (2.0 h) or effervescent tablets (1.0 h).ConclusionsER ambroxol 75-mg retard capsules given once daily showed a similar pharmacokinetic profile to IR ambroxol formulations and therefore can be used instead of these in the treatment of respiratory conditions.ClinicalTrials.gov identifierNCT02036775.Electronic supplementary materialThe online version of this article (10.1007/s41030-020-00116-7) contains supplementary material, which is available to authorized users.

Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate-release oral formulation in healthy volunteers.

Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single-center, randomized, double-blind, placebo-controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate-release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty-two healthy subjects (single ascending dose (n = 32) and multiple ascending dose (n = 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 µg (single dose), but not 200 µg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0–1.5 h post-dose and mean terminal elimination half-life values from 20.5–26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady-state plasma exposure measures were observed where evaluable, with mean steady-state peak-to-trough ratios ranging from 3.34–4.49 (QD dosing) and 1.95–2.36 (BID dosing). Mean effective half-life values ranged from 17.5–18.4 h, reflecting ∼1.7-fold (QD dosing) and ∼2.6-fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediate-release ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady-state peak-to-trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended-release formulation to facilitate QD dosing.

A Study to Assess the Amount of Drug Levels in Blood and Safety of AZD5718 Formulations in Healthy Volunteers

A Study to Assess the Amount of Drug Levels in Blood and Safety of AZD5718 Formulations in Healthy Volunteers

6x3 Crossover, Bioavailability, Safety and Tolerability Among Different Eutropin Formulations in Healthy Volunteers

6x3 Crossover, Bioavailability, Safety and Tolerability Among Different Eutropin Formulations in Healthy Volunteers

Bioavailability and swallowability of an age-appropriate, delayed-release mesalamine formulation in healthy volunteers.

Objective: Delayed-release mesalamine 400 mg capsules containing four 100 mg tablets have been developed for children with ulcerative colitis who have difficulty swallowing. Bioavailability of the mesalamine capsules was compared with existing mesalamine tablets in healthy adults, and the effect of food on bioavailability from mesalamine capsules was determined. Tablet swallowability in healthy children was evaluated.Methods: In the open-label, replicate-treatment, single-dose, crossover, comparative bioavailability study, healthy adult volunteers were randomized to one of four treatment sequences to receive mesalamine 400 mg tablets (fasted) twice, mesalamine 400 mg capsules (fasted) twice, and a mesalamine 400 mg capsule (with food) once, with ≥7 days between treatments. Pharmacokinetic (PK) parameters were calculated and analyzed using the reference-scaled average bioequivalence procedure. In the open-label, single-dose swallowability study, healthy children aged 5–11 years were asked to swallow eight placebo tablets identical to those contained in two mesalamine capsules.Results: In the bioavailability study (n=160), mesalamine capsules and tablets in fasted volunteers exhibited similarly delayed absorption and were shown to be bioequivalent; statistical parameters calculated from PK values met the criteria for bioequivalence. A slight increase in mesalamine bioavailability was observed with food administration, but the delayed-release performance of the capsules was not affected. Overall safety profiles between capsules and tablets were similar. In the swallowability study (n=60), the majority of children swallowed eight placebo tablets, with slight variability between age groups.Conclusion: Evaluation of PK parameters confirmed mesalamine capsules are bioequivalent to mesalamine tablets. Mesalamine capsules were well tolerated, can be administered with or without food, and are an age-appropriate product for children.

Pharmacokinetic Characterization of Two Novel CG5503 Tablet Formulations in Healthy Volunteers

Pharmacokinetic Characterization of Two Novel CG5503 Tablet Formulations in Healthy Volunteers

Comparative single-dose bioavailability study of two 10 mg Zolpidem tablet formulations in healthy volunteers

Zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines or other drugs with known hypnotic properties. Zolpidem as conventional tablets is used as a hypnotic agent in the short-term management of insomnia, generally for periods not exceeding 7–10 days in duration. The objective of this study was to evaluate and compare the relative bioavailability, and therefore the bioequivalence of Zolpidem 10 mg test formulation versus a reference Zolpidem 10 mg formulation, following a single dose administration under fasting conditions The study was a single center, open, single dose, randomized, two - way crossover study in healthy male volunteers with a wash - out period of one week between study periods. Twenty-eight male healthy volunteers, aged 20-49 years were included into study. Blood samples for determination of zolpidem plasma concentrations were withdraw at 0 (pre-drug administration), 0.33, 0.66, 1, 1.33, 1.66, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-drug. The zolpidem concentrations in plasma were determined with HPLC, using fluorescence detection. The test formulation of zolpidem, dosed at 10 mg is bioequivalent for primary zolpidem parameters (Cmax, AUC0-t and AUC0-∞) to the reference formulation after a single oral administration of 10 mg zolpidem. Both medications are well tolerated with no serious adverse events. Thus, in view of the clinical use, both formulations are exchangeable without restrictions. Keywords: Zolpidem, bioavailability, bioequivalence study, single-dose