Relative Bioavailability Study Research Articles

P1112 Pharmacokinetic comparability and safety between original and citrate-free mirikizumab formulations for subcutaneous injections: Results from three clinical trials in healthy participants

Abstract Background Mirikizumab (miri), a humanized IgG4 monoclonal antibody which selectively binds to the p19 subunit of human IL-23, is administered via subcutaneous (SC) injection. Since injection site pain (ISP) may be negatively affected by formulation buffer excipients such as citrate1, a citrate-free (CF) formulation of miri has been developed. We assessed the bioequivalence, ISP, and overall safety of the CF formulation of miri. Methods Three phase 1, two-arm, randomised, single-dose, subject-blind, parallel design studies were conducted in healthy subjects: one pilot relative bioavailability (RBA) study A (NCT04548219), and two bioequivalence (BE) studies B (NCT05515601) and C (NCT05644353). Subjects were randomised 1:1 to CF or original miri in all studies. The primary endpoint in all studies was to assess the comparability between CF and original formulations via Cmax, area under the concentration versus time curve (AUC) (0-∞), and AUC(0-tlast). Study A assessed the RBA of a single 200 mg SC dose, Study B assessed the BE of a single 200 mg SC dose, and Study C assessed the BE of a single 300 mg SC dose. The 200 mg and 300 mg doses are proposed for ulcerative colitis and Crohn’s disease, respectively. The secondary endpoint was safety assessment by spontaneous treatment-emergent adverse events and serious adverse events. In addition, in Study A, ISP was also quantified prospectively using the 100-mm validated visual analogue scale (VAS) assessment form2. Injection site reactions (ISRs) were prospectively assessed in Study A. Results The number of subjects who received miri were 60 in Study A, 396 in Study B, and 450 in Study C. Baseline characteristics were similar across studies and treatment groups. There was no statistically significant difference in exposure between the formulations in Study A. Figure 1 shows that the CF formulation demonstrated BE in Studies B and C, with the 90% confidence intervals (CIs) of the ratios of geometric least squares means (LSM) within the pre-specified equivalence limits. Figure 2 shows a statistically significant difference of 13.43 in the VAS Pain Score LSM at 1-minute post-dose for Study A, which is also considered clinically relevant3. Overall, CF and original miri demonstrated an acceptable safety profile consistent with previous work in healthy participants. Conclusion The CF formulation of mirikizumab is bioequivalent to the original formulation and is associated with a lower VAS pain score which may positively affect treatment experience.

Relative Bioavailability Studies With Mitapivat: Formulation and Food Effect Assessments in Healthy Subjects.

Pyruvate kinase (PK) deficiency is a rare, hereditary, hemolytic anemia caused by mutations in the PKLR gene encoding the PK enzyme. Mitapivat (previously designated AG-348) is a first-in-class, oral, allosteric activator of PK. We report results from 5 Phase 1 trials in healthy adults to characterize and compare mitapivat pharmacokinetics across different formulations and analyze food effects on mitapivat bioavailability (Studies 1-5). Pharmacokinetic assessments were peak exposure, total exposure, time to maximum plasma concentration of mitapivat, and relative bioavailability (where appropriate). Plasma total exposure of mitapivat was similar in the fasted and fed (high-fat meal or different soft foods) states after capsule, tablet, and pediatric granule formulations. Although mitapivat administration with food reduced the rate of mitapivat absorption (delay in time to maximum plasma concentration; reduction in maximum concentration) versus dosing under fasted conditions, this was not considered clinically relevant, given the lack of effect on total mitapivat exposure. Consequently, the administration instructions for mitapivat relating to food state that "patients may take mitapivat tablets with or without food." These findings will continue to inform clinical studies and development of mitapivat in adult and pediatric patients with hemolytic anemias and may help inform healthcare professionals on mitapivat dosing/administration recommendations in clinical practice.

Cholic Acid-Grafted Thiolated Chitosan-Enveloped Nanoliposomes for Enhanced Oral Bioavailability of Azathioprine: In Vitro and In Vivo Evaluation.

The purpose of the present study was to develop a cholic acid-grafted thiolated chitosan (CA-CS-TGA) polymeric biomaterial for attaining improved permeation via attaching thiol groups and cholic acid moieties. For this purpose, a CA-CS-TGA graft was prepared, and modification was confirmed via FTIR analysis. The prepared CA-CS-TGA graft was used to coat the azathioprine-loaded nanoliposomes (ENLs), with subsequent characterization in terms of zeta size, zeta potential, and SEM analysis. Pharmaceutical evaluation was carried out in terms of drug release studies, and ex vivo permeation and in vivo oral bioavailability were studied. The particle size and zeta potential of CA-CS-TGA coated nanoliposomal formulation CA-CS-TGA-NLs were found to be 245 ± 15.6 and +22.4 ± 0.58, respectively, compared to that of nonenveloped nanoliposomal formulation 165.7 ± 12.3 and -21.8 ± 0.14, respectively, indicating successful coating. CA-CS-TGA-NLs indicated 64% of drug release in 24 h at pH 7.4. Ex vivo permeation enhancement and relative oral bioavailability studies indicated a 2.84-fold enhanced permeation and 6-fold enhanced oral bioavailability of CA-CS-TGA-NLs compared to Azathioprine suspension. Based on the results, it can be concluded that grafting the CA-CS-TGA polymer onto nanoliposomes seems to be a promising strategy to enhance the oral bioavailability of Azathioprine.

Physiologically Based Biopharmaceutics Modeling for Gefapixant IR Formulation Development and Defining the Bioequivalence Dissolution Safe Space.

Gefapixant is a weakly basic drug which has been formulated as an immediate release tablet for oral administration. A physiologically based biopharmaceutics model (PBBM) was developed based on gefapixant physicochemical properties and clinical pharmacokinetics to aid formulation selection, bioequivalence safe space assessment and dissolution specification settings. In vitro dissolution profiles of different free base and citrate salt formulations were used as an input to the model. The model was validated against the results of independent studies, which included a bioequivalence and a relative bioavailability study, as well as a human ADME study, all meeting acceptance criteria of prediction errors ≤ 20% for both Cmax and AUC. PBBM was also applied to evaluate gastric pH-mediated drug-drug-interaction potential with co-administration of a proton pump inhibitor (PPI), omeprazole. Model results showed good agreement with clinical data in which omeprazole lowered gefapixant exposure for the free base formulation but did not significantly alter gefapixant pharmacokinetics for the citrate based commercial drug product. An extended virtual dissolution bioequivalence safe space was established. Gefapixant drug product batches are anticipated to be bioequivalent with the clinical reference batch when their dissolution is > 80% in 60 minutes. PBBM established a wide dissolution bioequivalence space as part of assuring product quality.

Relative Bioavailability Study of Midazolam Intramuscularly Administered with the Needle-Free Auto-Injector ZENEO® in Healthy Adults.

Intramuscular (IM) midazolam is indicated for the treatment of status epilepticus. Administration must be efficient to rapidly terminate prolonged seizures and prevent complications. The objective of this study was to compare, in terms of relative bioavailability and bioequivalence, IM midazolam injection by needle-free auto-injector, in different settings, to IM midazolam injection by a conventional syringe and needle. In this open-label, randomized, four-period crossover study, healthy adults received single doses of midazolam (10mg) under fasting conditions. The reference treatment (conventional syringe) was administered once, on bare skin in the thigh. The tested treatment (the needle-free auto-injector ZENEO®) was administered three times: on bare skin in the thigh, on bare skin in the ventrogluteal area, and through clothing in the thigh. Repeated plasma samples were collected to obtain 36-h pharmacokinetic (PK) profiles. Primary PK parameters were area under the plasma concentration-time curve, from time zero to the last measurable time point (AUC0-t) and from time zero to infinity (AUC0-∞), and the maximum observed plasma concentration (Cmax). Forty adults were enrolled and included in the PK analysis set. In all comparisons, the 90% confidence interval (CI) of the least-squares geometric mean ratios for AUC0-t and AUC0-∞ were within the bioequivalence range of 80-125%, with low intra-individual coefficients of variation (< 20.5% for all parameters in all comparisons). Bioequivalence was also met for Cmax in all comparisons except when comparing the tested treatment through clothing versus the reference treatment, where the 90% CI lower limit was slightly outside the bioequivalence range (78.8%). With all tested treatments Cmax was slightly lower, but early mean plasma concentrations (first 10min post-dosing) were higher when compared to the reference treatment. In general, all treatments were well tolerated, with maximum sedation 0.5-1h post-injection. This study establishes that IM midazolam injection on bare skin in the thigh with the ZENEO® is bioequivalent to IM midazolam injection with a syringe and needle. An acceptable relative bioavailability, compatible with emergency practice, was also shown in multiple settings. Higher mean concentrations within the first 10min with the ZENEO® device, and quicker two-step injection suggest a faster onset of action, and thereby an earlier seizure termination, thus preventing the occurrence of prolonged seizure and neurological complications. ClinicalTrials.gov identifier: NCT05026567. Registration first posted August 30, 2021, first patient enrolled May 9, 2022.

Relative bioavailability study of ticagrelor in healthy subjects under fasting conditions

Objectives: This is a randomized, single-dose, two-period, two-sequence, and crossover study to evaluate the bioequivalence (BE) profiles of two formulations of ticagrelor 90 mg, under fasting conditions. Materials and Methods: The plasma concentrations of ticagrelor were measured using a validated liquid chromatography mass spectrometry method. Enrolled for the study were 30 healthy adult volunteers (21 males and 9 females). All completed the study. The two formulations of ticagrelor were considered bioequivalent if a 90% confidence interval (CI) fell within 80.00–125.00% for Cmax and AUC0-t. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) Clenosan® and reference product (R) Brilinta® under fasting conditions (90% CI for all PK parameters fell within 80.00–125.00%). The 90% CI of the test/reference ratios of log-transformed PK parameter point estimates were Cmax: 95.49% (87.99– 103.62%) and AUC0-t: 103.20% (97.52–109.21%), respectively. Conclusion: Our results demonstrated BE between the test and reference drug products of oral ticagrelor in healthy subjects under fasting conditions.

Pharmacokinetics and relative bioavailability study of two cefquinome sulfate intramammary infusions in cow milk.

In this study, two intramammary infusions of cefquinome sulfate were investigated for pharmacokinetics and bioavailability. Twelve lactating cows for each group were administered an effective dose of 75 mg/gland for cefquinome, with milk samples collected at various time intervals. The concentrations of cefquinome in milk at different times were determined by the UPLC-MS/MS method. Analyses of noncompartmental pharmacokinetics were conducted on the concentration of cefquinome in milk. Mean pharmacokinetic parameters of group A and group B following intramammary administration were as follows: AUClast 300558.57 ± 25052.78 ng/mL and 266551.3 ± 50654.85 ng/mL, Cmax 51786.35 ± 11948.4 ng/mL and 59763.7 ± 8403.2 ng/mL, T1/2 5.69 ± 0.62 h and 5.25 ± 1.62 h, MRT 7.43 ± 0.79 h and 4.8 ± 0.78 h, respectively. Pharmacokinetic experiments showed that the relative bioavailability of group B was 88.69% that of group A. From our findings, group B (3 g: 75 mg) shows a quicker drug elimination process than group A (8 g: 75 mg), which suggests that the withdrawal period for the new formulation may be shorter.

Formulation, pharmacokinetics, and antibacterial activity of florfenicol-loaded niosome

The growing interest in employing nano-sized pharmaceutical formulations in veterinary medicine has prompted the exploration of the novel nanocarriers’ ability to augment the therapeutic outcome. In this study, we harnessed niosomes, spherical nanocarriers formed through non-ionic surfactant self-assembly, to enhance the therapeutic efficacy of the broad-spectrum antibiotic florfenicol. Pre-formulation studies were conducted to identify the optimal parameters for preparing florfenicol-loaded niosomes (FLNs). These studies revealed that the formulation that consisted of Span 60, cholesterol, and dihexadecyl phosphate (DDP) at a molar ratio of 1:1:0.1 exhibited the highest entrapment efficiency (%EE) and uniform size distribution. In vitro antibacterial testing demonstrated the niosomal capacity to significantly reduce florfenicol minimum inhibitory concentration (MIC) against E. coli and S. aureus. Pharmacokinetic profiles of free florfenicol and FLN were assessed following oral administration of 30 mg florfenicol/kg body weight to healthy or E. coli–infected chickens. FLN exhibited a substantially higher maximum plasma concentration (Cmax) of florfenicol compared to free florfenicol. Furthermore, FLN showed significantly higher area under the curve (AUC0–t) than free florfenicol as revealed from the relative bioavailability studies. Lethal dose (LD) 50 values for both free florfenicol and FLN exceeded 5 g/kg of body weight, indicating high safety profile. Assessment of mortality protection in mice against lethal E. coli infections showed the significantly higher capability of FLN to improve the survival rate (75%) than free florfenicol (25%). Collectively, these findings demonstrate the niosomal ability to improve the oral bioavailability as well as the antibacterial activity of the incorporated veterinary antibiotic florfenicol.Graphical abstract

Abstract 16208: Population Pharmacokinetics of Intravenously and Orally Administered Sotalol in Patients With Cardiac Arrhythmias

Introduction: Recently, an intravenous (IV) formulation of sotalol was approved to provide a loading dose before initiating oral sotalol therapy to reduce hospitalization days. However, the population pharmacokinetics (PK) of sotalol after administration of an IV loading dose regimen in patients with atrial fibrillation were not characterized. Understanding the PK of IV sotalol loading dose in patients with atrial fibrillation is required to ensure safety and optimal therapeutic outcomes. Hypothesis: The population PK model of IV and orally administered sotalol can be developed using data from two clinical PK studies with reasonable empirical Bayes estimates (EBEs) of PK parameters absorption rate constant (Ka), clearance (CL), and volume of distribution (Vd). Methods: The PK dataset of sotalol was from: 1) Relative bioavailability study with IV and oral sotalol PK data by sponsor AltaThera Inc., 2) Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) registry study. Population PK was evaluated using NONMEM® 7.5, Perl-speaks-NONMEM (PsN®) version 5.3.0. Results: 545 sotalol concentrations in 25 patients were analyzed. A one-compartment model with a first-order elimination rate best described the data (Figure 1). The data correlated QTc interval levels within the observed sotalol concentration range (1.2 to 1900 ng/mL) were below 500 ms. In the final model, the EBE’s of sotalol PK parameters were, Ka - 1.44 hr -1 , CL 0.46 - L/h/kg, and the Vd -5.6 L/kg. Further PK/PD studies are needed to establish the correlation between sotalol PK and safety in this population. Conclusions: The PK of sotalol after IV and oral doses were adequately described using a population PK modeling approach. The QTc levels correlated to the plasma concentrations in this study were within the safety limit of 500 ms. This population PK model could be used to correlate the PK with safety (QTc interval prolongation) further to optimize the sotalol IV and oral dosing regimen.

Approaches to Account for Colon Absorption in Physiologically Based Biopharmaceutics Modeling of Extended-Release Drug Products.

The rate and extent of colon absorption are important determinants of the in vivo performance of extended-release (ER) drug products. The ability to appropriately predict this at different stages of development using mechanistic physiologically based biopharmaceutic modeling (PBBM) is highly desirable. This investigation aimed to evaluate the prediction performance of three different approaches to account for colon absorption in predictions of the in vivo performance of ER drug product variants with different in vitro release profiles. This was done by mechanistic predictions of the absorption and plasma exposure of the ER drug products using GastroPlus and GI-Sim for five drugs with different degrees of colon absorption limitations in humans. Colon absorption was accounted for in the predictions using three different approaches: (1) by an a priori approach using the default colon models, (2) by fitting the colon absorption scaling factors to the observed plasma concentration-time profiles after direct administration to the colon in humans, or (3) from the ER drug product variant with the slowest in vitro release profile. The prediction performance was evaluated based on the percentage prediction error and the average absolute prediction error (AAPE). Two levels of acceptance criteria corresponding to highly accurate (AAPE ≤ 20%) and accurate (AAPE 20-50%) predictions were defined prior to the evaluation. For the a priori approach, the relative bioavailability (Frel), AUC0-t, and Cmax of the ER drug product variants for the low to medium colon absorption limitation risk drugs was accurately predicted with an AAPE range of 11-53 and 8-59% for GastroPlus and GI-Sim, respectively. However, the prediction performance was poor for the high colon absorption limitation risk drugs. Moreover, accounting for the human regional colon absorption data in the models did not improve the prediction performance. In contrast, using the colon absorption scaling factors derived from the slowest ER variant significantly improved the prediction performance regardless of colon absorption limitation, with a majority of the predictions meeting the high accuracy criteria. For the slowest ER approach, the AAPE ranges were 5-24 and 5-32% for GastroPlus and GI-Sim, respectively, excluding the low permeability drug. In conclusion, the a priori PBBM can be used during candidate selection and early product design to predict the in vivo performance of ER drug products for low to medium colon absorption limitation risk drugs with sufficient accuracy. The results also indicate a limited value in performing human regional absorption studies in which the drug is administered to the colon as a bolus to support PBBM development for ER drug products. Instead, by performing an early streamlined relative bioavailability study with the slowest relevant ER in vitro release profile, a highly accurate PBBM suitable for ER predictions for commercial and regulatory applications can be developed, except for permeability-limited drugs.

TABLET: Relative bioavailability and bioequivalence study of niraparib tablets and capsules in patients with advanced solid tumors.

e17603 Background: Niraparib is a poly (ADP-ribose) polymerase inhibitor, approved as a maintenance treatment (tx) for patients (pts) with advanced ovarian cancer and under investigation in solid tumors, available in 100 mg capsules (starting dose: 200 or 300 mg/day). Compared with capsules, tablets have improved stability in hot and humid conditions. This study assessed the relative bioavailability (BA; Stage 1 [S1]) and bioequivalence (BE; Stage 2 [S2]) between niraparib tablets and capsules. Methods: This was a US, open-label, multicenter, single-cohort, randomized-sequence study with an optional extension phase. Eligible pts were ≥18 years, had histologically/cytologically confirmed advanced solid tumors (metastatic or local), disease progression despite standard therapy (if available), and ECOG performance scores of 0–2. Pts were dosed 1x300 mg tablet or 3x100 mg capsules then crossed over to the other tx after full washout. Pharmacokinetic (PK) parameters were assessed up to 168 hours post-niraparib dose; safety was assessed throughout and for 30 days after last dose (90 days for serious adverse events). A comparison of the log-transformed PK parameters (maximum observed plasma concentration [Cmax], area under the plasma concentration–time curve from time 0 to time of the last quantifiable concentration [AUC0–t] and from time 0 extrapolated to infinity [AUC0–∞]) was carried out to evaluate the formulations using a linear mixed-effects model with fixed effects for sequence, period, and tx and random effect for pt nested within sequence. Results: Pts in both stages completed study drug and washout/PK periods and had sufficient PK samples to estimate PK parameters in both periods. In S1 (n=29), a comparable BA performance of both formulations was demonstrated; the 90% confidence intervals (CI) of the geometric least square means (LSM) for Cmax, AUC0–t, and AUC0–∞ for tablet/capsule were within prespecified 0.80–1.25 limits (intra-pt variability: 12.4–21.9%). An initial 7-day washout period between PK assessments was extended to 14 days in S2 due to significant carryover reported in 6 pts in S1. In S2 (n=108), niraparib PK characteristics were similar following dosing with tablet or capsule (Table); LSM ratios of the key parameters were close to unity and 90% CI for the ratio of Cmax, AUC0–t, and AUC0–∞ were within prespecified 0.80–1.25 limits required to demonstrate BE. No new safety signals were reported. Conclusions: Both niraparib formulations were bioequivalent and can be used interchangeably. Editorial support was provided by Fishawack Health, funded by GSK. Clinical trial information: NCT03329001 . [Table: see text]

Manganese relative oral bioavailability in electric arc furnace steel slag is influenced by high iron content and low bioaccessibility

Electric arc furnace (EAF) slag is a rock-like aggregate produced with carbon steel and used for construction, including residential ground cover. It is enriched with manganese (Mn) and other metals, including iron (Fe), but because metals are bound in mineral matrices, in vitro bioaccessibility (BA) is limited. We conducted a relative bioavailability (RBA) study using F344 rats to assess Mn RBA from EAF slag ingestion, compared with Mn in diet. Mn and Fe were measured in liver, and Mn in lung and striatum, the target tissue of the brain. Mn levels in each tissue were fit by dose-to-tissue concentration (D-TC) curves. The D-TC relationship was the most highly significant for the linear model using liver Mn, and the RBA was 48%. The D-TC relationship in lung showed a positive slope for chow, but that for EAF slag was slightly negative, and the RBA was 14%. In comparison, the striatum D-TC remained relatively constant, supporting that homeostasis was maintained. Increased Fe was observed in the liver of EAF slag-dosed groups, suggesting that Mn absorption was inhibited by the high Fe content of slag. Lung and striatum D-TC curves demonstrated that systemic delivery of Mn from EAF slag ingestion is limited and support an RBA of 14% for risk assessment. Although Mn levels in slag are elevated compared with health-based screening guidelines, this study supports that incidental ingestion of Mn in EAF slag is unlikely to pose a neurotoxicity hazard due to homeostatic controls, low BA, and high Fe content.

P748 Pharmacokinetics, relative bioavailability, and dose proportionality of a tablet formulation of the sphingosine 1-phosphate-1 receptor modulator VTX002 (formerly OPL-002)

Abstract Background VTX002 is an oral selective sphingosine 1-phosphate-1 receptor (S1P1R) modulator in clinical development for treatment of ulcerative colitis (UC). Single and multiple doses of a spray-dried dispersion (SDD) oral suspension of VTX002 were well-tolerated up to 45 mg in a phase 1 study in healthy participants and were accompanied by dose proportional reductions in lymphocyte counts, an expected pharmacodynamic outcome of treatment.1 A separate phase 1 study compared the pharmacokinetics (PK) and pharmacodynamics of the SDD oral suspension and a tablet formulation of VTX002. Methods Healthy adult participants (N=12) were randomised (4 per dose group) in an open-label 3-way crossover study to receive single oral doses of 5 mg or 20 mg VTX002 tablets, or 20 mg VTX002 SDD suspension followed by at least a 1-week washout between each dose as shown in Fig. 1. Study assessments included: VTX002 plasma concentrations, PK parameters, change from baseline in absolute lymphocyte count (ALC), and adverse events (AE). Results A total of 10 participants completed the study. Mean plasma VTX002 concentrations were greatest with a single oral dose of 20 mg VTX002 SDD suspension (Fig. 2). The geometric mean peak (Cmax) and total (AUCinf) exposure to VTX002 were lower with the 5 mg (dose normalized to 20 mg tablet) and 20 mg VTX002 tablets compared to the 20 mg VTX002 SDD suspension (Table 1). Geometric mean ratios for the tablet and SDD formulations of VTX002 are shown in Table 2. Maximum percent (SD) reduction in ALC from baseline was greatest for the 20 mg VTX002 SDD suspension and was observed at 6 hours post-dose both for the SDD suspension and the 20 mg VTX002 tablet (59.9% [11.0%] and 51.6% [9.4%], respectively). The maximum percent reduction in ALC from baseline for the 5 mg VTX002 tablet was 22.4% (9.2%) which occurred 2 hours post-dose. A total of 23 AEs were reported; of which 19 were considered mild, and 4 were moderate. Conclusion All doses and formulations of VTX002 were well-tolerated and associated with ALC reductions. Data from this relative bioavailability study was used to convert the results from the prior phase 1 multiple ascending dose study performed with VTX002 SDD suspension to AUC equivalent tablet doses and enable tablet dose selection for phase 2. A phase 2 study of VTX002 tablets for treatment of UC is underway (ClinicalTrials.gov Identifier:NCT05156125). 1Luo A, et al. 2020 Gastroenterology. 2020;158(6):S1188.

The Relative Bioavailability Study of Two Cefdinir Formulations in Healthy Males Under Fasting Conditions

A new oral formulation of cefdinir, Cefdinir 600 mg Tablets has been developed and in this study, its relative bioavailability has been compared with another oral solid dosage form, Cefdinir 300 mg Capsules, which is already on the market. An open-label, randomized, two-period, cross-over relative bioavailability study has been conducted with healthy males under fasting conditions in compliance with Good Clinical Practice (GCP) principles. A single dose of the novel tablet formulation of 600 mg cefdinir has been compared to two doses of Cefdinir 300 mg Capsules (two capsules at once) in terms of their pharmacokinetic properties. The comparison study was performed as a single-center clinical study, and blood samples of the participants were withdrawn at specified time points, before and after dosing. The plasma concentrations and pharmacokinetic properties of two cefdinir formulations were assessed from the collected samples by using a validated LC-MS/MS analytical method. The relative bioavailability of the new formulation has been shown and both products were introduced as safe.

Med Check: Adlarity Transdermal Patch; Qulipta; Nuplazid; and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Adlarity Transdermal Patch; Qulipta; Nuplazid; and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:26 Apr 2022https://doi.org/10.1176/appi.pn.2022.05.5.35Adlarity Transdermal Patch Approved for Treatment of Alzheimer’sIn March the U.S. Food and Drug Administration (FDA) approved Adlarity (donepezil transdermal system) as a treatment for patients with mild, moderate, or severe dementia associated with Alzheimer’s disease, Corium Inc. announced. Adlarity is a once-weekly patch that continuously delivers either 5 mg or 10 mg of donepezil through the skin per day. Either the patient or a caregiver may place the patch on the patient’s back, thigh, or buttocks.The FDA approved Adlarity based on a relative bioavailability study in healthy patients that compared the transdermal system to Aricept (donepezil hydrochloride) tablets. In the study, 60 healthy volunteers received 5 mg of Adlarity per day for five weeks, after which they received either 10 mg of Adlarity or oral donepezil per day for another five weeks. At the end of the study, exposure to donepezil was similar among patients who took Adlarity and those who took oral donepezil. Adlarity is expected to be available in the early fall. Qulipta Promising for Treatment of Chronic MigraineAdults with chronic migraine who took Qulipta (atogepant) in a phase 3 trial experienced fewer monthly migraine days compared with those who took placebo, AbbVie announced in March. Qulipta is currently approved for preventing episodic migraine in adults.In the trial, more than 750 patients with at least a one-year history of chronic migraine were randomized to receive 60 mg of atogepant once a day, 30 mg of atogepant twice a day, or placebo for 12 weeks. All patients had at least 15 headache days with at least eight migraine days in the 28 days before randomization. The trial consisted of two analyses based on regulatory agency feedback in the United States and European Union.The U.S. analysis revealed that patients in the 60 mg and 30 mg atogepant arms experienced a decrease of 6.88 and 7.46 monthly migraine days, respectively, compared with patients in the placebo arm, who experienced a decrease of 5.05 monthly migraine days. The European Union analysis revealed that patients in the 60 mg and 30 mg atogepant arms experienced a decrease of 6.75 and 7.33 monthly migraine days, respectively, compared with patients in the placebo arm, who experienced a decrease of 5.09 monthly migraine days. Acadia Resubmits Nuplazid for Treatment of Alzheimer’s PsychosisAcadia Pharmaceuticals in March announced that the FDA has set an action date for the company’s resubmitted supplemental New Drug Application (sNDA) for Nuplazid (pimavanserin) for the treatment of hallucinations and delusions associated with Alzheimer’s disease psychosis. The FDA’s Division of Psychiatry has also advised the company that it is planning to hold an advisory committee meeting in connection with its review.In April 2021 the FDA rejected pimavanserin for this indication, citing “a lack of statistical significance in some of the subgroups of dementia, and insufficient numbers of patients with certain less common dementia subtypes as lack of substantial evidence of effectiveness to support approval.”The resubmission provides additional analyses from two previously conducted clinical studies, HARMONY and Study-019, to support the proposed indication for the drug and addresses the issues raised in the FDA’s rejection last year.Pimavanserin is currently approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Vraylar sNDA Submitted for Adjunctive Treatment of Major Depressive DisorderIn February AbbVie announced that it has submitted an sNDA for Vraylar (cariprazine) for the adjunctive treatment of major depressive disorder in patients who are receiving ongoing antidepressant therapy. Cariprazine is currently approved for the treatment of schizophrenia in adults, the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, and the treatment of depressive episodes associated with bipolar I disorder in adults.In a phase 3 study of 759 adults with major depressive disorder, patients who took 1.5 mg cariprazine daily experienced a statistically significant change from baseline to week six in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score compared with those who took placebo. In a second study, patients who took 2 mg to 4.5 mg of cariprazine per day also experienced a significant change from baseline to week eight in the MADRS total score compared with those who took placebo. In both of these studies, no new safety events were identified. ■ ISSUES NewArchived

Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside.

BackgroundTo accelerate the progress towards onchocerciasis elimination, a macrofilaricidal drug that kills the adult parasite is urgently needed. Emodepside has shown macrofilaricidal activity against a variety of nematodes and is currently under clinical development for the treatment of onchocerciasis. The aims of this study were i) to characterize the population pharmacokinetic properties of emodepside, ii) to link its exposure to adverse events in healthy volunteers, and iii) to propose an optimized dosing regimen for a planned phase II study in onchocerciasis patients.Methodology / Principal findingsPlasma concentration-time profiles and adverse event data were obtained from 142 subjects enrolled in three phase I studies, including a single-dose, and a multiple-dose, dose-escalation study as well as a relative bioavailability study. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic properties of emodepside. Logistic regression modeling was used to link exposure to drug-related treatment-emergent adverse events (TEAEs). Emodepside pharmacokinetics were well described by a transit-absorption model, followed by a 3-compartment disposition model. Body weight was included as an allometric function and both food and formulation had a significant impact on absorption rate and relative bioavailability. All drug-related TEAEs were transient, and mild or moderate in severity. An increase in peak plasma concentration was associated with an increase in the odds of experiencing a drug-related TEAE of interest.Conclusions/SignificancePharmacokinetic modeling and simulation was used to derive an optimized, body weight-based dosing regimen, which allows for achievement of extended emodepside exposures above target concentrations while maintaining acceptable tolerability margins.

Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children.

The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability. This article outlines the chronology of dolutegravir pediatric formulation development as granules and conventional and dispersible tablets in a total of 5 pharmacokinetic studies evaluating the relative bioavailability of dolutegravir SE and FDC formulations in healthy adults. The relative bioavailability studies were 2-part, Phase I, open-label, randomized studies in healthy adults. Dolutegravir SE study compared conventional dolutegravir 50 and 25 mg with equivalent conventional 10-mg and dispersible 5-mg tablets, respectively. Subsequently, dolutegravir FDC study compared adult FDC of abacavir/dolutegravir/lamivudine and adult FDC of dolutegravir/lamivudine with their respective pediatric FDC formulations, taken as dispersion immediately or swallowed whole. As observed in previous studies, dolutegravir administered as dispersion (granules/dispersible tablets) showed relatively higher bioavailability compared with conventional tablets. The bioavailability of dolutegravir dispersible tablets (both SE and FDC) was approximately 1.6-fold higher when compared with conventional tablets. In addition, the bioavailability of abacavir/lamivudine was not impacted by dispersible formulation. These studies demonstrate the successful development of pediatric dolutegravir-containing formulations as SE and FDC that permit pediatric dosing in line with WHO recommendations.

Relative bioavailability and pharmacokinetic comparison of a fixed-dose combination tablet of mosapride, pancreatin, and simethicone relative to single-component mosapride tablets in healthy Mexican subjects.

Abbott Laboratories de México S.A. de C.V. developed a new fixed-dose combination of mosapride 5mg, pancreatin 170 mg, and simethicone 125 mg as an alternative to the mosapride monotherapy to improve overall satisfaction and adequate relief of gastrointestinal disorders symptoms and to reduce multiple pill burden. As a part of the fixed-dose combination registration process in Mexico, a pharmacokinetic and relative bioavailability study was carried out to demonstrate nonexistence of pharmacokinetic interaction when mosapride is administered alone or in combination with pancreatin and simethicone using DOSIER® (mosapride) 5-mg tablets as a reference product. Tolerability of the fixed-dose combination tablet was assessed. In this open-label, randomized, oral single-dose, two-way crossover study, 65 healthy male and female subjects received either the fixed-dose combination tablet or the reference product during each study period. The two study periods were separated by a 7-day washout period. Mosapride concentrations in plasma samples were determined using a validated ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method. Blood samples were collected for up to 16 h post dose. The primary evaluation criteria were Cmax and AUC0-t for mosapride. The 90% confidence intervals for the ratio of geometric means for Cmax (96.12% to 110.90%) and AUC0-t (99.07% to 108.06%) were within the defined acceptance limits of 75% to 133% and 80% to 125% for Cmax and AUC0-t , respectively, indicating bioequivalence between the two products. Both products were safe and well tolerated. Therefore, mosapride in combination with pancreatin and simethicone tablet is bioequivalent to mosapride alone, and no new safety signals emerged.

Pharmacokinetics of Oral Formulations of Gepotidacin (GSK2140944), a Triazaacenaphthylene Bacterial Type II Topoisomerase Inhibitor, in Healthy Adult and Adolescent Participants.

ABSTRACTGepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that may provide a new treatment option for antibiotic-resistant pathogens. Two pharmacokinetic evaluations of oral gepotidacin are presented: a relative bioavailability study that guided formulation development, followed by an adult and adolescent study of the final formulation. In the relative bioavailability study, after gepotidacin administration to 26 healthy adults as free-base roller-compacted (RC) tablets, free-base high-shear wet granulation (HSWG) tablets, and mesylate salt reference capsules, the RC tablet exposure ratios and 90% confidence intervals (CIs) were within the 0.80-to-1.25 confidence bounds; however, the HSWG tablet maximum observed concentration (Cmax) was higher than the reference (ratio, 1.15; 90% CI, 1.0113, 1.3047). In the healthy adult (n = 16) and adolescent (n = 17) study, a gepotidacin mesylate salt tablet was evaluated as a 1,500-mg single dose or 2 doses administered 6 or 12 h apart (6,000 mg total), or placebo was administered. The single-dose mean Cmax was ∼27% higher in adolescents than in adults, and area under the concentration-time curve (AUC) values were comparable in both populations. After 2 doses were administered, the mean Cmax values were similar for both age groups, and the mean AUC was ∼35% higher in adolescents than in adults. Concentrations increased proportionally with dose. Safety-risk profiles were similar for both age groups. Across studies, the most common adverse events were gastrointestinal. Overall, the pharmacokinetics of the final gepotidacin mesylate salt tablet have been well characterized, enrollment of adolescents into the pivotal trials is supported, and dosing intervals were determined that should provide adequate exposures for microbiological efficacy. (This study has been registered at ClinicalTrials.gov under identifiers NCT02853435 and NCT04079790.)

Pharmacokinetics, Safety, and Tolerability of the α2C‐Adrenoreceptor Antagonist BAY 1193397 in Healthy Male Subjects

The α2C -adrenoreceptor antagonist BAY 1193397 is in development for the oral treatment of diabetic foot ulcers. Safety, tolerability, and pharmacokinetics of BAY 1193397 were investigated in 3 randomized, single-center phase 1 studies in healthy male subjects: a first-in-human study (single oral doses of 0.5-50mg), a relative bioavailability and food effect study (single doses of 1 and 10mg), and a multiple-dose escalation study (using 2 and 5mg twice daily and 10 and 20mg once daily for 9 consecutive days). BAY 1193397 was rapidly absorbed in the fasted state, peak concentrations were reached between 0.6 and 2 hours. The mean terminal half-life was in the range of 17 to 20 hours. Area under the plasma concentration-time curve and maximum concentration appeared to be dose proportional, with a negligible food effect. There were no high-accumulation effects of BAY 1193397 after repeated dosing. BAY 1193397 was safe and well tolerated. At supratherapeutic plasma concentrations, there were slight transient increases in norepinephrine levels, heart rate, and blood pressure that were more pronounced after a single dose compared to steady state and appeared to be maximum concentration dependent. The results of the presented studies support the conduct of subsequent clinical trials with BAY 1193397 in patients with diabetes and compromised microcirculation.