Immediate-release Capsules Research Articles

Gastroretentive fibrous dosage forms for prolonged delivery of sparingly-soluble tyrosine kinase inhibitors. Part 4: Experimental validation of the models of drug concentration in blood

In this final part, the models of drug concentration in blood developed in Part 3 are validated on dogs. Both slow-release gastroretentive fibrous and immediate-release particulate dosage forms containing 200 mg nilotinib were tested. After administering, the fibrous dosage form expanded linearly with time in the stomach, to about 1.5 times the initial radius by 4 h. The expanded dosage form fractured after 10 h, and then passed into the intestines. The drug concentration in blood exhibited a broad peak with a maximum of 0.51 μg/ml and a width at half-height of 10.2 h. By contrast, after administering the immediate-release capsule the drug concentration in blood exhibited a sharp peak with a maximum of 0.68 μg/ml and a width at half-height of just 3.6 h. The experimental data validate the theoretical models reasonably. The gastroretentive fibrous dosage forms designed in this study enable a steady drug concentration in blood for increasing the efficacy and mitigating side effects of drug therapies.

Formulation and evaluation of immediate-release capsules of pregabalin

The aim is to develop and evaluate capsules with various excipient compositions that satisfy the reference product's specifications to achieve an in-vitro correlation with the reference product after that. Pregabalin I.R. capsules were formulated using Corn starch, Dibasic calcium phosphate, Lactose anhydrous, and Avicel pH 102(Microcrystalline cellulose). After compatibility studies for the capsule blend were completed, the Drug was determined to be compatible with all excipients used in various formulations. After the blend was put into capsules, several metrics were examined, including average weight, disintegration, and assay. The formulation containing D.C.P. disintegrates at a faster rate than other formulations. It was discovered that the percentage of drug release in the F7 invitro dissolving profile was equal to that of the innovator product. Finally, it was concluded that the F7 formulation is better and similar to the innovator product.

In Vitro In Vivo Extrapolation and Bioequivalence Prediction for Immediate-Release Capsules of Cefadroxil Based on a Physiologically-Based Pharmacokinetic ACAT Model.

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic concept, which helps to judge the effects of biopharmceutical properties of drug product such as in vitro dissolution on its pharmacokinetic and in vivo performance. With the application of virtual bioequivalence (VBE) study, the drug product development using model-based approach can help in evaluating the possibility of extending BCS-based biowaiver. Therefore, the current study was intended to develop PBPK model as well as in vitro in vivo extrapolation (IVIVE) for BCS class III drug i.e. cefadroxil.A PBPK model was created in GastroPlus™ 9.8.3 utilizing clinical data of immediate-release cefadroxil formulations. By the examination of simulated and observed plasma drug concentration profiles, the predictability of the proposed model was assessed for the prediction errors. Furthermore, mechanistic deconvolution was used to create IVIVE, and the plasma drug concentration profiles and pharmacokinetic parameters were predicted for different virtual formulations with variable cefadroxil in vitro release. Virtual bioequivalence study was also executed to assess the bioequivalence of the generic verses the reference drug product (Duricef®).The developed PBPK model satisfactorily predicted Cmax and AUC0-t after cefadroxil single and multiple oral dose administrations, with all individual prediction errors within the limits except in a few cases. Second order polynomial correlation function obtained accurately predict in vivo drug release and plasma concentration profile of cefadroxil test and reference (Duricef®) formulation. The VBE study also proved test formulation bioequivalent to reference formulation and the statistical analysis on pharmacokinetic parameters reported 90% confidence interval for Cmax and AUC0-t in the FDA acceptable limits.The analysis found that a validated and verified PBPK model with a mechanistic background is as a suitable approach to accelerate generic drug development.

Method Development for Simultaneously Determining Indomethacin and Nicotinamide in New Combination in Oral Dosage Formulations and Co-Amorphous Systems Using Three UV Spectrophotometric Techniques.

This research aims to develop methods for simultaneously determining indomethacin (IND) and nicotinamide (NCT) in binary mixtures, immediate-release capsules, sustained-release capsules, and co-amorphous systems, which were designed in 2021 to improve the solubility, dissolution rate, and stability of the amorphous state of indomethacin. Moreover, this new combination may have also other possible medical benefits. Therefore, there is a need to have simple, sensitive, and precise developed methods for simultaneous quantification analysis of IND/NCT in several different ratios. Three UV-spectrophotometry techniques were deployed: zero-crossing point in the second-order derivative, dual-wavelength in the first-order derivative, and ratio subtraction coupled with spectrum subtraction. The limit of detection and the limit of quantifications (LOD and LOQ) for IND were 0.41 and 1.25, 0.55 and 1.66, and 0.53 and 1.62 μg/mL, respectively, while for NCT were 0.53 and 1.59, 0.38 and 1.14, and 0.36 and 1.08 μg/mL, respectively. All methods were linear at least in the range of 2.5-40.0 μg/mL. All proposed methods were validated according to ICH guidelines and their application on the dosage formulations was carried out. Finally, the proposed methods were compared to a reference method for each IND and NCT, and no significant statistical variance was found.

Population pharmacokinetic modeling of levodropropizine: extended application to comparative analysis between commercial formulations and exploration of pharmacokinetic effects of diet.

Levodropropizine, a nonopioid antitussive agent, is being increasingly used in clinical practice with the development of several formulations for symptomatic relief of acute and chronic bronchitis. However, scientific and quantitative population pharmacokinetic analyses of levodropropizine are lacking. Moreover, no integrated quantitative comparison has been performed between formulations. This study quantitatively evaluated and predicted pharmacokinetic properties of formulations through population pharmacokinetic model-based comparisons of commercially available formulations. Plasma concentration profile results from bioequivalence studies of 60-mg immediate release (IR) levodropropizine tablets in 40 healthy Korean males were used as population pharmacokinetic modeling data. For interindividual variability in levodropropizine pharmacokinetics, body surface area was identified as an effective covariate that was positively correlated with peripheral compartment distribution volume. Population pharmacokinetic model for IR tablets well-described the levodropropizine syrup and capsule datasets, suggesting no significant differences in pharmacokinetics among IR tablets, syrups, and capsules of levodropropizine. In contrast, pharmacokinetic profiles differed between 90-mg controlled release (CR) and IR levodropropizine tablets; however, separate parameter estimation was possible by applying the same model structure. In terms of pharmacokinetics, twice-daily regimen of 90-mg CR tablets was equivalent to thrice-daily regimen of 60-mg IR tablets. However, at steady-state, interindividual plasma concentration variability within population was reduced by approximately 36.71-83.18%. For levodropropizine CR tablets, a high-fat diet significantly delayed gastrointestinal absorption but maintained overall plasma exposure equivalent. This study provides useful quantitative judgment data for precision medicine of levodropropizine and can be helpful in predicting the pharmacokinetics of levodropropizine based on commercialized formulation switching.

WITHDRAWN: Gastroretentive fibrous dosage forms for prolonged delivery of sparingly-soluble tyrosine kinase inhibitors. Part 4: Experimental validation of the models of in vivo expansion, gastric residence time, and drug concentration in blood

In this final part, the models of in vivo expansion, gastric residence time, and drug concentration in blood developed in Part 3 are validated on dogs. Both slow-release gastroretentive fibrous and immediate-release particulate dosage forms containing 200 mg nilotinib were tested. As predicted by the model, in the stomach the fibrous dosage form expanded linearly with time to about 1.5 times the initial radius by 4 h. The expanded dosage form fractured after about 10 h, and then passed into the intestines. The drug concentration in blood exhibited a broad peak with a maximum of 0.5 μg/ml and a width at half-height of 10.2 h. By contrast, after administering the immediate-release capsule the contrast agent particles were expelled from the stomach within 1.5 h. The drug concentration in blood exhibited a sharp peak with a maximum of 0.59 μg/ml and a width at half-height of 3.6 h, a third of that of the fibrous form. The experimental data validate the models reasonably. Thus, upon repeated dosing, the gastroretentive fibrous dosage forms designed in this study enable a steady drug concentration in blood for increasing the efficacy and mitigating side effects of drug therapies.

Tramadol Steady-State Pharmacokinetics of Immediate-Release Capsules and Sustained-Release Tablets in Dogs

Tramadol is a veterinary analgesic for dogs. In this study, the steady-state pharmacokinetics of a sustained-release (SR) tablet (Tramagetic OD®) and immediate-release capsules (IR) were compared. In a crossover design, six dogs received five doses of IR 50 mg four times a day (qid), or two doses of SR 200 mg once a day (sid). Eight blood samples were collected per dog, per formulation, up to 6 and 24 h after the last dose, respectively. Serum concentrations of tramadol and its metabolites were measured with LC-MS/MS. Metabolite M1 levels were below the lower limit of quantification (LLOQ) in all samples. The non-compartmental analysis of the time–concentration data showed a later Tmax with the SR formulation (median 6.00 h (3.00–9.00)) and a lower Cmax/D (median 7.74 µg/L/mg/kg (0.09–25.3)) compared to the IR formulation (median Tmax 1.75 h (0.75–2.00) and median Cmax/D 11.1 µg/L/mg/kg (4.8–70.4)). AUCtau/D after SR administration was 55.5 h × kg × µg/L/mg (0–174.1) compared to 29.8 h × kg × µg/L/mg (12.2–140.8) after IR administration. The terminal elimination half-lives were 2.38 h (1.77–6.22) and 1.70 h (0.95–2.11) for the SR and IR formulations, respectively. Strong conclusions cannot be drawn from this study because of the high percentage of samples that were below LLOQ and the great interindividual variability, but these results suggest that Tramagetic OD can be administered less frequently in dogs.

The pharmacological perspective on tablet splitting or crushing

Purpose: It is a common practice to use drugs in tablet form by splitting or crushing. Especially in geriatric and pediatric clinics, it offers important advantages such as providing appropriate dosing, saving costs, and increasing compliance in patients who have difficulty swallowing tablets. The purpose of this review is to evaluate the efficacy and safety of splitting or crushing tablets. Method: Literature was retrieved by a PubMed search, using different combinations of pertinent keywords (e.g., tablet splitting, tablet crushing) without any limitations in terms of publication date and language. Papers, which assessed the efficacy and safety of tablet crushing or splitting, were selected for inclusion according to their relevance for the topic, as judged by the authors. Results: This method, which is based on splitting and breaking the tablets by hand, with the help of scissors, a knife, or a tablet splitter, is often used by both patients and their relatives to facilitate the swallowing of tablets in pediatric patients or patients with swallowing difficulties and/or due to economic reasons. It is reported that almost a quarter of all drugs used in treatments are used by splitting or crushing. It is also known that more than half of the patients (57%) use the drugs in tablet form by splitting them. It states that uncoated, sugar-coated or film-coated tablets can be used by splitting or crushing, considering the patient compliance and pharmacoeconomic benefits of splitting the drugs in tablet form. Active ingredient-containing tablets with a broad therapeutic index and long half-life are suitable candidates for the splitting-crushing process. Clinical studies report that the use of uncoated, sugar-coated, or film-coated tablets with the same dose of crushed forms and their use as a whole tablet has the same efficacy and safety data. Conclusion: In the light of a patient’s needs and in order to increase the patient’s compliance with the treatment, uncoated tablets, film-coated tablets, sugar-coated tablets are suitable for use in terms of drug efficacy and patient safety by breaking, crushing, splitting, or opening immediate-release capsules. Physical manipulations on drugs with these coating properties do not cause any change in bioavailability and pharmacokinetic data. The use of uncoated tablets, film-coated tablets, sugar-coated tablets, or immediate-release capsules by splitting or crushing tablets is an effective and safe application that increases patient compliance. For example, propiverine, ibuprofen, cefuroxime axetil, ciprofloxacin, pseudoephedrine, and praziquantel or quinine are coated with sugar or film to facilitate the swallowing of the drug in terms of taste. Medicines of this nature can be used by splitting or crushing into small pieces to facilitate swallowing in terms of size. In terms of bioavailability and pharmacokinetics, there is no harm in consuming drugs with this structure by breaking and splitting. With tablet breaking, the cost of treatment can be reduced, and it can also increase patients’ compliance with their drug regimens. As a result, unnecessary emergency room visits or hospitalizations can be reduced by preventing non-compliance with the treatment that may develop due to the inability to swallow the drug. Sustained-release drug products, enteric-coated tablets, tablets that are small in size, easily fall apart, or cannot be split in proportion due to having a brittle form, tablets with a narrow therapeutic window and short half-life are not suitable for splitting use. From a pharmacokinetic point of view, the split use of such tablets may increase the risk of side effects or change their effectiveness.

Time within therapeutic range: A comparison of three tacrolimus formulations in renal transplant recipients

Background: Currently there are three available formulations of tacrolimus in the United States; these include immediate-release capsules (TAC-IR), extended-release capsules (TAC-XL), and extended-release tablets (TAC-XR). Previous studies have demonstrated non-inferiority between the three formulations in terms of efficacy. The purpose of this study was to compare three formulations of tacrolimus (TAC) and assess differences in time within the therapeutic range (TTR) and variability in levels. Results: Renal transplant recipients from January 2013 to October 2017 were retrospectively identified for analysis. Deviation from standard TAC protocol or formulation changes excluded patients. The primary outcome compared percent TTR (TTR %) among 3 TAC formulations over the first 90 days post-transplant. TTR was calculated using the Rosendaal method. Secondary outcomes included differences in TAC levels, TAC dose, eGFR, rejection, patient and graft survival between the TAC formulations. TAC-XR demonstrated a significantly higher TTR % compared to TAC-IR and TAC-XL (62.8% vs. 53.3% vs. 60.9%, p = 0.048). In post-hoc analysis, TAC-XR had a higher TTR % compared to TAC-IR (p = 0.065), which approached statistical significance. Average TAC levels, weight-normalized TAC doses, median dose-normalized TAC levels, rejection rates, eGFR, and graft or patient survival were similar among groups. Conclusion: In the early transplant period, TTR was significantly different among the groups. TAC-XR demonstrated numerically superior time within the therapeutic range. Patient-specific factors such as race, obesity, genetic polymorphisms may impact this variability and clinical outcomes. Further analysis is necessary to understand the effect of each patient-specific factor on TAC exposure.

Tablet and capsule formulations incorporating high doses of a dry optimized herbal extract: The case of Satureja kitaibelii

Aerial parts of Satureja kitaibelii are traditionally used as carminative, for treatment of respiratory and urinary complaints, or as anti-inflammatory agent for skin and mucous membranes. The aim of the present study was to formulate immediate-release capsules and tablets with high content (≥95%) of S. kitaibelii optimized dry extract by direct compression. The influence of ethanol concentration (40–96%, v/v), temperature (25–80 °C) and time (2–8 h) on the extraction yield, total phenolic content (TPC), as well as on the contents of rosmarinic acid (RA) and clinopodic acid O (CAO) in the S. kitaibelii dry extract was investigated using the response surface methodology (RSM). The estimated optimal conditions for the extraction were: ethanol 46.4%, 61.6 °C, 2 h. Dry extract of S. kitaibelii obtained under the optimal conditions (characterized by: yield 24.2%, TPC 170.4 mg gallic acid equivalents/g, RA 10.7 mg/g and CAO 17.1 mg/g) was used to manufacture solid dosage forms. Three formulations (F) were prepared: F1, hard capsules (99% dry extract, 1% magnesium stearate); F2, uncoated tablets (99% dry extract, 1% magnesium stearate) and F3, uncoated tablets (95% dry extract, 4% sodium starch glycolate, 1% magnesium stearate). Hard capsules (F1) with the uniform weight, adequate disintegration time and dissolution rate were obtained. Regarding tablet formulations, F3 exhibited satisfactory tableting properties, disintegration time and dissolution profile. Therefore, immediate-release capsules and tablets with a high content of S.kitaibelii extract were formulated to accomplish the unmet need for convenient solid dosage forms that contains high doses of herbal extracts.

Pharmacokinetics and Pharmacodynamics of Esomeprazole/Sodium Bicarbonate Immediate-Release Capsules in Healthy Chinese Volunteers: A Cross-Over, Randomized Controlled Trial.

Esomeprazole delayed release tablets (ESO) are one of the most effective treatments for acid-related disorders. The purpose of this study is to compare the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of an immediate-release capsule formulation containing esomeprazole 20mg and sodium bicarbonate 1100mg (IR-ESO) compared to those of the esomeprazole delayed release tablet 20mg (ESO). In addition, the impact of CYP2C19 gene polymorphisms on PK and PD was evaluated. A single-center, open-label, randomized, 2-treatment, 2-sequence, and 2-period crossover study was conducted in 40 healthy Chinese subjects. Subjects received either IR-ESO or ESO for 5days. After single- and multiple-dosing administration, blood samples were collected for PK analysis, and intragastric pH was assessed by 24-h pH monitoring. The CYP2C19 gene polymorphisms were analyzed by Sanger sequencing. The geometric mean ratios (90% confidence interval) [GMR (95%CI)] of IR-ESO/ESO for AUCinf [single dose: 103.60% (96.58%, 111.14%), multiple doses: 101.65% (97.88%, 105.57%)] were within the range of 80.00-125.00%. The AUCinf showed an increasing trend between CYP2C19 extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) after single-dose and multiple-dose administration (p<0.05). The GMR (95%CI) of IR-ESO/ESO for 24-h integrated gastric acidity from baseline [single dose: 101.07% (96.56%, 105.78%), multiple doses: 101.24% (97.74%, 104.86%)] were within the range of 80.00-125.00%. The percentage changes in 24-h integrated gastric acidity from baseline was significant difference between EM, IM, and PM after single-dose IR-ESO and ESO (p<0.05). Drugs were all well tolerated, and there were no significant differences in adverse events between IR-ESO and ESO. This study showed that IR-ESO can inhibit the secretion of gastric acid rapidly and continuously, and that the PK and PD of IR-ESO are affected by CYP2C19 genotypes. The GMR (95% CI) of IR-ESO/ESO for AUCinf and the percentage changes in 24-h integrated gastric acidity from baseline were all within the range of 80.00-125.00%. Chinese Clinical Trial Registry: ChiCTR1900024935.

Improved ability to achieve target trough levels with liquid versus capsule tacrolimus in kidney transplant patients with HIV on protease inhibitor- or cobicistat-based regimens.

HIV+patients are commonly accepted for kidney transplantation. However, patients on protease inhibitor (PI)- or cobicistat (cobi)-based regimens have trouble achieving optimal tacrolimus (Tac) levels. Our study compared the ability to achieve target levels using liquid versus immediate-release capsule Tac in kidney transplant patients with HIV on PI- or cobi-based regimens. The study included four kidney transplant patients who were converted to liquid Tac due to inability to achieve acceptable drug levels on the capsule formulation. Tac trough levels were analyzed retrospectively to compare target levels before and after conversion. The individual patient time in the therapeutic range (TTR) was calculated using Rosendaal's linear interpolation method, and the difference between before and after conversion TTR was determined. In combined data, 44.63% of all Tac trough levels were within the target range after conversion to liquid Tac compared to 22.07% prior to conversion (P<.001). Furthermore, 3.31% and 7.44% of Tac trough levels were lower than 3ng/mL or higher than 12ng/mL, respectively, after conversion compared to 11.72% (P=.0564) and 24.14% (P<.0001) prior to conversion. The overall mean TTR was 45.1% after conversion to liquid Tac compared to 16.2% prior to conversion (P=.097). Finally, the coefficient of variation for Tac trough levels was 42.6 after conversion compared to 56.4 prior to conversion. A significantly improved ability to achieve target trough Tac levels was achieved with liquid Tac extemporaneous versus capsule formulation in kidney transplant patients with HIV taking a PI- or cobi-based regimen.

Anti-obesity effect with reduced adverse effect of the co-administration of mini-tablets containing orlistat and mini-tablets containing xanthan gum: In vitro and in vivo evaluation.

The purpose of this study was to develop an oral dosage form of orlistat for the treatment of obesity with reduced adverse effects, for example, fatty and oily stool that have been reported to be associated with the mechanism of action of orlistat. Based on the in vitro results obtained in this study, xanthan gum was selected as an oil-entrapping agent. Thus, the co-administration of mini-tablets containing orlistat and mini-tablets containing xanthan gum was proposed as the optimized dosage form for orlistat. The prepared mini-tablets showed an equivalent drug release profile with a similarity factor value, f2, more than 50 to that of commercially marketed orlistat immediate-release capsules, Xenical® capsules. In addition, the optimized formulation also showed the in vivo anti-obesity effects similar to those of Xenical® capsules. In particular, the analysis of feces excreted by Sprague-Dawley rats revealed that the optimized formulation resulted in significantly less oily stool, steatorrhea, than Xenical® capsules (P<0.05). Consequently, the proposed formulation, the co-administration of mini-tablets containing orlistat and mini-tablets containing xanthan gum, may be considered as a promising anti-obesity treatment with reduced adverse effects related to orlistat.

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.

Development of a Novel Controlled-Release Tablet of Pregabalin: Formulation Variation and Pharmacokinetics in Dogs and Humans.

BackgroundNovel three-layered (TL) tablet systems were compared with both monolithic matrix (MM) formulations and a commercial immediate-release (IR) capsule to develop once-a-day (OAD) pregabalin tablets.MethodsThe physical properties of the TL tablets, including dissolution and swelling rates, were compared with those of the MM tablets and the pharmacokinetic parameters of the TL tablet were compared with those of an IR capsule in beagles and humans.ResultsOur results indicated that the same amount of a hydrophilic polymer in the formulations had similar dissolution profiles at 12 h, regardless of the tablet geometry. However, the degree of tablet swelling differed, with larger amounts of polymer in the tablets showing a greater degree of swelling. In addition, TL tablets swelled more rapidly compared with MM tablets. For the pharmacokinetic study of the TL tablet, the beagles demonstrated absorption results similar to those of an IR capsule, whereas the humans demonstrated low total absorption compared with an IR capsule. The time of the peak plasma concentration at 6 h in the fed state of humans coincided with the results of the study on beagles.ConclusionThe novel TL tablet system of pregabalin may prove to be helpful in developing improved formulations with better continuous drug absorption for OAD administration.

Development of In Vitro\u2013In Vivo Correlation for Upadacitinib Extended-Release Tablet Formulation

Upadacitinib is a selective Janus Kinase 1 inhibitor which is being developed for the treatment of several inflammatory diseases including rheumatoid arthritis. Upadacitinib was evaluated in Phase 3 studies as an oral extended-release (ER) formulation administered once daily. The purpose of this study was to develop a level A in vitro–in vivo correlation (IVIVC) for upadacitinib ER formulation. The pharmacokinetics of four upadacitinib extended-release formulations with different in vitro release characteristics and an immediate-release capsule formulation of upadacitinib were evaluated in 20 healthy subjects in a single-dose, randomized, crossover study. In vivo pharmacokinetic data and in vitro dissolution data (USP Dissolution Apparatus 1; pH 6.8; 100 rpm) were used to establish a level A IVIVC. Three formulations were used to establish the IVIVC, and the fourth formulation was used for external validation. A non-linear IVIVC best described the relationship between upadacitinib in vitro dissolution and in vivo absorption profiles. The absolute percent prediction errors (%PE) for upadacitinib Cmax and AUC were less than 10% for all three formulations used to establish the IVIVC, as well as for the %PE for the external validation formulation and the overall mean internal validation. Model was cross-validated using the leave-one-out approach; all evaluated cross-validation runs met the regulatory acceptance criteria. A level A IVIVC was successfully developed and validated for upadacitinib ER formulation, which meets the FDA and EMA regulatory validation criteria and can be used as surrogate for in vivo bioequivalence.

The influence of genetic polymorphisms in drug metabolism enzymes and transporters on the pharmacokinetics of different fluvastatin formulations

The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics. In addition, we compared the fluvastatin pharmacokinetics differences between extended-release (ER) 80 mg tablet and immediate-release (IR) 40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms. In this open-label, randomized, two-period, two-treatment, crossover study (n = 24), effects of ABCG2, SLCO1B1, ABCB1, CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed. The administration dosage for IR 40 mg and ER 80 mg were twice and once daily, respectively, for total 7 d. Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d. The lower exposure following ER was observed. For ER tablets, SLCO1B1 T521C genotype correlated with AUC0-24 of repeat doses (P = 0.010). SLCO1B1 T521C genotype had no statistically significant effect on AUC0-24 of IR capsule of fluvastatin after single or repeated doses. In vitro study demonstrated that when the concentration of fluvastatin was low (< 1 µmol/l), the uptake of fluvastatin in the HEK293-OATP1B1 with SLCO1B1 521TT (Km=0.18 µmol/l) was faster than that with SLCO1B1 521CC (Km=0.49 µmol/l), On the other hand, when concentration reached to higher level (> 1 µmol/l), transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1 521TT (Km = 11.4 µmol/l) and with SLCO1B1 521TCC (Km=15.1 µmol/l) tend to be the same. It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations. We recommend that formulation should be incorporated into future pharmacogenomics studies.

Clinical Pharmacokinetic Performance of a Ralinepag Extended-Release Tablet

Purpose Ralinepag is an oral, potent, and selective prostacyclin receptor agonist in development for treating pulmonary arterial hypertension. The study goal was single-dose pharmacokinetic (PK) comparison of ralinepag extended-release (XR) and ralinepag/selexipag immediate-release (IR) formulations and multiple-dose PK performance of ralinepag XR under fasted/fed conditions. Methods Study 1: cohort 1 (n=12) - fasted healthy subjects took single ralinepag doses sequentially over 4 treatment periods: 30 mcg IR capsule, then 60, 120, and 180 mcg doses of an XR tablet. Cohort 2 (n=12) - fasted subjects took single selexipag doses sequentially over 3 treatment periods: 200, 400, and 600 mcg IR tablets. Study 2: fasted (n=19) or fed (n=18) healthy subjects received ralinepag XR tablets in a repeat dose-escalation paradigm over 25 days (starting dose 60 mcg once daily [qd], titrated by additional 60 mcg increments every 5 days up to 300 mcg qd as tolerated). Results Study 1: dose-adjusted peak plasma exposure (Cmax/D) measures were lower for ralinepag XR versus IR (geometric mean ratio [GMR] range up to 41.2%). Dose-adjusted total plasma exposure (AUC/D) measures were similar for XR and IR (GMR range up to 97.9%). Selexipag and MRE-269 plasma PK profiles were consistent with the need for administration at least twice daily. Study 2: dose-dependent plasma exposure measures were observed for ralinepag XR tablet with low steady-state peak-to-trough ratio (≤2) upon qd dosing, approximating the ‘ideal’ continuous IV infusion-like PK profile for agents in this drug class, and minimal food effect. Females had higher mean exposure measures than males, for which such differences were not statistically significant or considered clinically meaningful. Conclusion The ralinepag XR tablet offers improved PK performance over both ralinepag and selexipag IR formulations, with extended exposure and low peak-to-trough ratio with qd dosing, supporting its use in the ADVANCE Phase 3 program.

Comparative Pharmacokinetics of a Controlled-release Pregabalin Tablet (GLA5PR GLARS-NF1) and an Immediate-release Pregabalin Capsule in Healthy Male Volunteers

PurposePregabalin is a widely used drug for the management of neuropathic pain. This study compared the pharmacokinetics of the GLA5PR GLARS-NF1 tablet, a 150-mg controlled-release formulation of pregabalin taken once daily, with those of a 75-mg immediate-release (IR) capsule formulation of pregabalin taken twice daily with a 12-h interval between doses. MethodsTwo separate studies, single dose and multiple dose, were conducted with a sequence-randomized, open-label crossover design. In the single-dose study, 30 participants each received 3 treatments: two 75-mg IR capsules taken 12 h apart, each after a high-fat meal (SRF treatment); a single 150-mg GLA5PR GLARS-NF1 tablet taken after a high-fat meal (STF treatment); and a single 150-mg GLAR5PR GLARS-NF1 tablet taken in an overnight-fasted state (ST treatment). In the multiple-dose study, 24 participants each received 2 treatments, both of which occurred over 3 days: one 75-mg IR capsule in the evening after a standardized meal and a second 75-mg IR capsule the following morning after a standardized meal, for 3 days (MRF treatment); and a single 150-mg GLA5PR GLARS-NF1 tablet in the evening after a standardized meal, for 3 days (MTF treatment). Blood samples for pharmacokinetic assessments were collected over the 36 h following drug administration in each treatment period. FindingsIn the single-dose study, the geometric mean ratios (GMRs) of the Cmax and the AUClast values of the GLA5PR GLARS-NF1 tablet to those of the IR capsules (STF/SRF) were 1.047 (90% CI, 0.971–1.129) and 0.757 (90% CI, 0.694–0.826), respectively. In the multiple-dose study, the GMRs (MTF/MRF) of the Cmax and the AUC values over the dosing interval were 1.277 (90% CI, 1.210–1.348) and 0.974 (90% CI, 0.933–1.017), respectively. The systemic pregabalin exposure from the GLA5PR GLARS-NF1 tablet was higher in the fed state than in the fasted state; GMRs (STF/ST): Cmax, 1.458 (90% CI, 1.353–1.573) and AUClast, 1.655 (90% CI, 1.518–1.804). ImplicationsThe overall pregabalin exposure after multiple administrations of GLA5PR GLARS-NF1 tablets was comparable to that after multiple administrations of the IR capsules. A single administration of the GLA5PR GLARS-NF1 tablet produced lower overall pregabalin exposure than that of the same dose administered in 2 IR capsules taken every 12 h. A high-fat diet significantly increased the bioavailability of the GLA5PR GLARS-NF1 tablet. ClinicalTrials.gov identifiers: NCT01638273 and NCT02326987.

Effect of Gastric Fluid Volume on the In Vitro Dissolution and In Vivo Absorption of BCS Class II Drugs: a Case Study with Nifedipine.

Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large inter-patient variability in nifedipine absorption results in variable exposure among different patients. We conducted in vitro dissolution studies to compare nifedipine dissolution from immediate release (IR) capsules with different volumes of dissolution media. Results from dissolution studies were used to design a crossover study in healthy volunteers to evaluate the effect of coadministered water volume with nifedipine 10mg IR capsules on nifedipine pharmacokinetics, especially absorption (C max, t max, and AUC0-6). Dissolution studies demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution from 10mg IR cosolvent capsules (73 vs. 17% in 200 and 100mL simulated gastric fluid, respectively, at 30min). The pharmacokinetic crossover study in healthy volunteers (N = 6) did not show a significant effect of the water volume administered with the capsule (50 vs. 250mL) on C max, t max, or AUC0-6 of orally administered nifedipine IR capsules (10mg). However, administration of large water volumes resulted in lower variability in nifedipine C max (47 vs. 70% for 250 and 50mL, respectively). Administration of large water volumes with nifedipine 10mg IR cosolvent capsules may reduce inter-individual variability in plasma exposure. Evaluation of similar effects in other BCS Class II drugs is recommended.