Fixed-dose Combination Capsule Research Articles

Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women.

Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5mg as the morning dose and an elagolix 300mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300mg/1mg/0.5mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.

Virtual Bioequivalence Assessment of Elagolix Formulations Using Physiologically Based Pharmacokinetic Modeling.

In lieu of large bioequivalence studies and exposing healthy postmenopausal women to additional drug exposure for elagolix coadministered with hormonal add-back therapy, physiologically based pharmacokinetic (PBPK) modeling was used with in vitro dissolution data to test for virtual bioequivalence. For endometriosis, elagolix is approved at doses of 150mg once daily and 200mg twice daily as a tablet. As a combination therapy, two individual tablets, consisting of an elagolix tablet and an estradiol/norethindrone acetate 1/0.5mg (E2/NETA) tablet, were utilized in Phase 3 endometriosis trials. However, the commercial combination drug products consist of a morning capsule (containing an elagolix tablet and E2/NETA tablet as a fixed-dose combination capsule, AM capsule) and an evening capsule (consisting of an elagolix tablet, PM capsule). In vitro dissolution profiles were dissimilar for the tablet and capsule formulations; thus, in vivo bioequivalence studies or a bioequivalence waiver would have been required. To simulate virtual cross-over, bioequivalence trials, in vitro dissolution data was incorporated into a previously verified PBPK model. The updated PBPK model was externally validated using relevant bioequivalence study data. Based on results of the virtual bioequivalence simulations, the commercial drug product capsules met the bioequivalence criteria of 0.80-1.25 when compared to the reference tablets. This was a novel example where PBPK modeling was utilized along with in vitro dissolution data to demonstrate virtual bioequivalence in support of a regulatory bioequivalence waiver.

Pharmacokinetics of a new fixed-dose combination of candesartan cilexetil, hydrochlorothiazide, and rosuvastatin in healthy adult subjects.

A fixed-dose combination (FDC) of candesartan cilexetil, hydrochlorothiazide and rosuvastatin (CC/HCTZ/RSV) has been developed to enhance patient compliance in the primary prevention of cardiovascular diseases. To evaluate if the combination of the product components in the new FDC capsule formulation affects their respective pharmacokinetic and in vitro dissolution patterns. In vitro dissolution profiles were compared in USP-43 and in biorelevant dissolution media. In vivo comparisons were obtained in a randomized, open-label, single-dose, two-treatment, two-way crossover study in 24 healthy subjects. During each treatment period, subjects received the test formulation (FDC hard capsule containing CC/HCTZ/RSV) or the reference formulation (co-administration of a FDC CC/HCTZ tablet and a RSV tablet). Plasma samples were collected periodically over 48 hours post-dose. Safety and tolerability were assessed. Dissolution profiles of all active drugs in the Test (capsule) and Reference Products (as tablets) were within the tolerance dissolution criteria of USP-43 conditions. HCTZ dissolution profiles were closely similar whereas those for RSV and CC did not match at specific pHs. In the pharmacokinetic study, the 90% confidence intervals (CIs) for the geometric least-square mean ratios of Cmax, AUC0-last, and AUC0-inf were 0.95-1.18, 0.95-1.15 and 0.95-1.13 (CC); 0.91-1.10, 0.96-1.08, and 0.96-1.09 (HCTZ) and 0.82-1.23, 0.81-1.13, and 0.82-1.12 (RSV), respectively. All adverse events were mild. The new FDC product (Sinlip Prevent), a stable FDC hard capsule, was bioequivalent (similar pharmacokinetics) when compared to the co-administration of the components and may be considered as a suitable and simplified medication for cardiovascular disease management.

Design and Evaluation of a New Fixed-Dose Immediate Release Capsule of Atenolol, Enalapril Maleate and Hydrochlorothiazide

Aim and Objectives: To design, formulate and perform in vitro studies of a fixed dose combination (FDC) immediate release solid dosage form of the antihypertensive drugs atenolol, enalapril and hydrochlorothiazide. The objectives of the study were to perform pre-formulation studies, design an immediate-release FDC capsule dosage form, and evaluate the prepared dosage form. Methods: Differential Scanning Calorimetric (DSC) analysis of physical mixtures of drugs and drug-excipient combinations was used to assess compatibility. Binary mixtures of atenolol and enalapril form a eutectic mixture indicating that a tablet dosage form, in which the drugs would be highly compressed together, may not be stable. Hard gelatin shell encapsulation was therefore employed. Atenolol and enalapril were separately dry-granulated with hydrochlorothiazide and excipients and mixed together at appropriate therapeutic proportions and encapsulated in size 1 hard gelatin capsules (HGC). Preliminary screening produced five formulations each with similar proportions of the 3-drug FDC but with 5 different levels of disintegrant. Capsule weight variation, disintegration time and dissolution rate were determined as output variables, following USP procedures. For the dissolution studies, a reverse phase high-pressure liquid chromatographic (RP-HPLC) method was developed for simultaneous analysis of the three drugs. Results: Granules possessed good fluidity (compressibility index 8.53 to 11.63 and tapped bulk density 1.09 to 1.132). Capsule disintegration time was generally £ 2 minutes while 80% of each drug dissolved within 20 minutes. Capsules showed no sign of physical instability or adverse effect during a period of 1 year shelf storage at room temperature (average temperature 25°C). Conclusions: Granules possess adequate fluidity and compressibility for filling into HGC. Results generally indicated that an immediate release FDC capsule of atenolol, enalapril and hydrochlorothiazide was stable for more than 1 year of observation. Capsule disintegration time and dissolution rate were generally within the USP specification.

Pharmacokinetics and relative bioavailability of fixed-dose combination of clopidogrel and aspirin versus coadministration of individual formulations in healthy Korean men.

BackgroundSimultaneous prescription of clopidogrel and low-dose aspirin is recommended for the treatment of acute coronary syndrome because of improvements in efficacy and patient compliance. In this study, the pharmacokinetics of a fixed-dose combination (FDC) of clopidogrel and aspirin was compared with coadministration of individual formulations to clarify the equivalence of the FDC.MethodsThis was a randomized, open-label, two-period, two-treatment, crossover study in healthy Korean men aged 20–55 years. Subjects received two FDC capsules of clopidogrel/aspirin 75/100 mg (test) or two tablets of clopidogrel 75 mg and two capsules of aspirin 100 mg (reference) with a 14-day washout period. Plasma concentrations of clopidogrel, aspirin, and salicylic acid were measured using validated ultraperformance liquid chromatography–tandem mass spectrometry. Bioequivalence was assessed by analysis of variance and calculation of the 90% confidence intervals (CIs) of the ratios of the geometric means (GMRs) for AUClast and Cmax for clopidogrel and aspirin.ResultsSixty healthy subjects were enrolled, and 53 completed the study. Clopidogrel, aspirin, and salicylic acid showed similar absorption profiles and no significant differences in Cmax, AUClast, and Tmax between FDC administration and coadministration of individual formulations. The GMRs (90% CI) for the Cmax and AUClast of clopidogrel were 1.08 (0.95, 1.23) and 0.93 (0.84, 1.03), respectively. The GMRs (90% CI) for the Cmax and AUClast of aspirin were 0.98 (0.84, 1.13) and 0.98 (0.93, 1.04), respectively. Both treatments were well tolerated in the study subjects.ConclusionThe FDC of clopidogrel and aspirin was bioequivalent to coadministration of each individual formulation. The FDC capsule exhibited similar safety and tolerability profiles to the individual formulations. Therefore, clopidogrel/aspirin 75 mg/100 mg FDC capsules can be prescribed to improve patient compliance.

A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer’s disease

Currently available therapies for the treatment of Alzheimer’s disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified.

PHARMACOKINETICS OF MEMANTINE AND DONEPEZIL AFTER A SINGLE DOSE OF A ONCE-DAILY FIXED-DOSE COMBINATION CAPSULE OF MEMANTINE EXTENDED RELEASE AND DONEPEZIL IN TWO PHASE I TRIALS

Combining two standard-of-care therapeutics into a single dosage unit may increase compliance and adherence to treatment, leading to an improved therapeutic outcome. A fixed-dose combination (FDC) capsule containing 28-mg memantine extended release (ER) and 10-mg donepezil was developed and tested for (1) bioequivalence with co-administered commercially available memantine ER (Namenda XR, 28 mg) and donepezil (Aricept, 10 mg), (2) bioavailability following food intake, and (3) bioavailability following sprinkling of the capsule contents on applesauce. Both studies were single-dose, randomized, open-label, and crossover (with 21-day washout periods between treatments), conducted in 18-45-year-old healthy individuals. In Study 1, fasting participants (N=38) received Treatment A (co-administration of Namenda XR and Aricept) or Treatment B (FDC). In Study 2, participants (N=36) received three treatments: Treatment A (intact FDC capsule, while fasting), Treatment B (intact FDC capsule, following a high-fat meal), and Treatment C (FDC contents sprinkled on applesauce, while fasting). In both studies, C max and AUC 0- ˇž for memantine and donepezil were compared using a linear mixed-effects model. Bioequivalence or no effect in the comparison of treatments was declared if the 90% confidence intervals (CI) of the least-squares geometric mean ratios of C max and AUC 0- ˇž were within the range of 80.00%-125.00%. T max values were compared using a Wilcoxon signed-rank test. Safety parameters were also evaluated. CIs of all the comparisons were within 80.00%-125.00% window. The FDC capsule containing memantine ER and donepezil was bioequivalent to co-administered Namenda XR and Aricept. There was no significant food effect on the bioavailability of the FDC capsule. The intact FDC capsule and capsule contents sprinkled on applesauce were bioequivalent. There were no clinically relevant differences in T max across treatments. Safety profiles were also similar across treatments. A FDC capsule containing 28-mg memantine ER and 10-mg donepezil is bioequivalent to co-administered commercially available memantine ER and donepezil. In addition to ingestion by swallowing with or without food, the formulation allows for sprinkling of the capsule contents on applesauce, making ingestion and administration easier for patients and caregivers, respectively. Sponsorship: Forest Research Institute.

Pharmacokinetic Properties of Single-Dose Lamivudine/Adefovir Dipivoxil Fixed-Dose Combination in Healthy Chinese Male Volunteers

BackgroundBoth lamivudine and adefovir dipivoxil are approved for the treatment of chronic hepatitis B (CHB) and have established safety profiles. A fixed-dose combination (FDC) formulation of lamivudine/adefovir dipivoxil for the treatment of CHB may provide dosing convenience and improve adherence. ObjectiveThis study compared the pharmacokinetic profiles of an FDC capsule containing lamivudine/adefovir dipivoxil 100/10 mg and conventional lamivudine 100-mg + adefovir dipivoxil 10-mg tablets to determine bioequivalence. MethodsThis randomized, open-label, single-dose, 2-period crossover study was conducted in healthy male Chinese subjects. The study included a screening visit, 2 treatment sessions, and a follow-up visit. Subjects who met the inclusion/exclusion criteria were assigned to receive, in randomized order, 1 FDC capsule or 1 tablet each of lamivudine and adefovir dipivoxil. After a 7- to 10-day washout period, alternate treatment was given to the subjects during the second treatment session. Blood samples were collected immediately before and after dosing for 48 hours for plasma drug concentration measurement. Data on adverse events (AEs) were collected from the start of dosing until the follow-up visit. Tolerability assessments included physical examinations with vital sign measurements and clinical laboratory evaluations throughout the study. ResultsForty subjects were enrolled into the study (mean age, 22.4 years [range, 19–28 years]; weight, 63.8 kg [range, 54–78 kg]). The pharmacokinetic profiles of lamivudine and adefovir were similar between the FDC and reference formulations. The geometric mean ratios (GMRs) for lamivudine Cmax and AUC0–last were 1.02 (90% CI, 0.92–1.12) and 0.99 (90% CI, 0.95–1.04), respectively; adefovir, 0.94 (90% CI, 0.89–0.99) and 0.95 (90% CI, 0.91–1.00). A limited number of mild AEs were reported, with no clinically significant changes in vital signs or laboratory results. ConclusionsThe FDC capsule was bioequivalent to the concurrent administration of lamivudine + adefovir dipivoxil tablets based on the 90% CIs of the GMRs for Cmax, AUC0–∞, AUC0–last, and t12 (all were between 0.80 and 1.25). Both treatments were well-tolerated. Clinicaltrial.gov identifier: NCT01353742.