Bioequivalence Interval Research Articles

Evaluation of Drug-Drug Interaction Between Henagliflozin and Hydrochlorothiazide in Healthy Chinese Volunteers.

Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ. This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS/MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated. The 90% CI of the ratio of geometric means (combination: monotherapy) for AUCτ,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80-1.25. For henagliflozin, co-administration increased Css, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased Css, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported. Although Css,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing. ClinicalTrials.gov NCT06083116.

Predictive Potential of Cmax Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ2 Similarity Factor Method.

Pilot bioavailability/bioequivalence (BA/BE) studies are downsized trials that can be conducted prior to the definitive pivotal trial. In these trials, 12 to 18 subjects are usually enrolled, although, in principle, a sample size is not formally calculated. In a previous work, authors recommended the use of an alternative approach to the average bioequivalence methodology to evaluate pilot studies' data, using the geometric mean (Gmean) ƒ2 factor with a cut off of 35, which has shown to be an appropriate method to assess the potential bioequivalence for the maximum observed concentration (Cmax) metric under the assumptions of a true Test-to-Reference Geometric Mean Ratio (GMR) of 100% and an inter-occasion variability (IOV) in the range of 10% to 45%. In this work, the authors evaluated the proposed ƒ2 factor in comparison with the standard average bioequivalence in more extreme scenarios, using a true GMR of 90% or 111% for truly bioequivalent formulations, and 80% or 125% for truly bioinequivalent formulations, in order to better derive conclusions on the potential of this analysis method. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling, accounting for different IOV levels. A redefined decision tree is proposed, suggesting a fixed sample size of 20 subjects for pilot studies in the case of intra-subject coefficient of variation (ISCV%) > 20% or unknown variability, and suggesting the assessment of study results through the average bioequivalence analysis, and additionally through Gmean ƒ2 factor method in the case of the 90% confidence interval (CI) for GMR is outside the regulatory acceptance bioequivalence interval of [80.00-125.00]%. Using this alternative approach, the certainty levels to proceed with pivotal studies, depending on Gmean ƒ2 values and variability scenarios tested (20-60% IOV), were assessed, which is expected to be helpful in terms of the decision to proceed with pivotal bioequivalence studies.

Investigator Impact on Reproducibility of Drug Bioavailability in Stratum Corneum Sampling by Tape Stripping.

Skin sampling by tape stripping measures the local bioavailability of topical drug products in the stratum corneum (SC). The goal of the current study was to evaluate the impact of different investigators in studies that utilize a tape stripping protocol designed to minimize investigator variability. Two open-label clinical studies compared two lidocaine patches and a diclofenac patch and solution in twelve healthy volunteers. The mass of drug was determined in SC samples collected on tape strips at three time points following product removal in duplicate by two investigators. Investigator results were compared with each other and with results for the diclofenac solution measured by another laboratory using a similar protocol. For drug mass, the geometric mean ratio comparing two investigators is within the acceptable bioequivalence interval for most measurement times and drug products. Drug uptake into the SC from the diclofenac solution was not statistically different from that determined in another laboratory. The average flux from the SC over the clearance intervals for the four drug products correspond well with flux measurements from in vitro permeation tests. Results from different investigators are reproducible within the limitations of measurement variability, which can be managed by increasing volunteer numbers.

Consistency evaluation between dispensing granule and traditional decoction from Coptidis Rhizoma by using an integrated quality-based strategy.

Dispensing granule, an innovative product of traditional Chinese medicine decoction, is widely practiced in clinic. As a prerequisite to support the clinical medication, quality consistency between dispensing granule and traditional decoction need to be evaluated. Furthermore, a generally applicable strategy for consistency evaluation of dispensing granule is needed. In this study, we aimed to propose an integrated quality-based strategy to assess consistency between dispensing granule and traditional decoction taking Coptidis Rhizoma (CR) as a case study. For chemical consistency evaluation, efficacy-related Coptis alkaloids were quantified with high-performance liquid chromatography (HPLC). The "Mean ± 3SD" of analyte contents in traditional decoction was considered as the criterion of consistency. And, as auxiliary analysis, principal component analysis (PCA) was employed for data visualisation. For biological consistency evaluation, two one-side t-tests and 90% confidence intervals of the geometric mean ratio of antibacterial zone diameter and 50% inhibitory concentration (IC50 ) of α-glucosidase inhibition were calculated. The scope of 80.00% to 125.00% was taken as in vitro bioequivalence interval. It was considered internally consistent with traditional decoction when the chemical and biological indices of dispensing granule fulfilled the preset criteria simultaneously. Eight out of 20 batches of CR dispensing granule were demonstrated consistent with traditional decoction in chemistry and biological activities. A generally applicable strategy was recommended that integrates chemical and biological characteristics for consistency evaluation of dispensing granule.

Bidirectional Pharmacokinetic Interaction Between Amodiaquine and Pioglitazone in Healthy Subjects.

Amodiaquine (AQ) and pioglitazone (PGZ) are both metabolized by CYP2C8, an enzyme also inhibited by PGZ. These drugs are likely to be administered in instances of comorbidity of malaria with type 2 diabetes. This study, hence, evaluated the possibility of a drug interaction resulting from the concurrent use of both drugs. A 3-period crossover design in 10 healthy subjects, that assessed the disposition of AQ and PGZ alone and when coadministered, was implemented with the administration of single oral doses of AQ and PGZ. Whole-blood samples collected between 0 and 24hours on protein saver cards across the study periods were processed and analyzed for AQ and PGZ contents. Pharmacokinetic parameters were derived by a noncompartmental analysis. Geometric mean ratios for the Cmax , area under the concentration-time curve for 24 hours (AUC0-24h ), and AUC0-∞ , alongside their corresponding 90%CIs, were compared across the study periods to infer clinically significant changes in disposition. The coadministration of AQ and PGZ resulted in decreases of about 38% and 54% in the Cmax and AUC0-24h of AQ, respectively. For PGZ, the Cmax increased by about 50%, and AUC0-24 rose by 48%. The 90%CIs of geometric mean ratios for the Cmax , AUC0-24h , and AUC0-∞ were all outside the expected bioequivalence interval of 80% to 125% for both drugs, implying significant interactions. These findings suggest that a bidirectional interaction between AQ and PGZ, with likely implications for the therapy and toxicity of both drugs, may occur in the event of their coadministration.

Application of an Optimized Tape Stripping Method for the Bioequivalence Assessment of Topical Acyclovir Creams.

This study indicates the application of tape stripping (TS) for bioequivalence (BE) assessment of a topical cream product containing 5% acyclovir. A TS method, previously used successfully to assess BE of topical clobetasol propionate and clotrimazole formulations, was used to assess BE of an acyclovir cream (5%) formulation as well as a diluted acyclovir formulation (1.5%) applied to the skin of healthy humans. An appropriate application time was established by conducting a dose duration study using the innovator product, Zovirax® cream. Transepidermal water loss was measured and used to normalize thicknesses between subjects. The area under the curve (AUC) from a plot of amount of acyclovir/strip vs cumulative fraction of stratum corneum (SC) removed was calculated for each application site. BE was assessed using Fieller's theorem in accordance with FDA's guidance for assessment of BE of topical corticosteroids. Adco-acyclovir cream (5%) was found to be BE to Zovirax® cream, where the mean test/reference (T/R) ratio of the AUC's was 0.96 and the bioequivalence interval using a 90% confidence interval was 0.91-1.01 with a statistical power > 95%, whereas the diluted test product fell outside the BE acceptance criteria with T/R ratio of AUC of 0.23 and a 90% CI of 0.20-0.26. This study indicates that the data resulting from the application of this TS procedure has reinforced the potential for its use to assess BE of topical drug products intended for local action, thereby obviating the necessity to undertake clinical trials in patients.

Abstract P1-10-14: Abemaciclib tablet formulation is bioequivalent to capsules

Abstract Introduction: Abemaciclib is being developed for the treatment of cancer, including advanced and metastatic breast cancer. Tablet formulations, which are smaller than the capsules used in the pivotal MONARCH 1, 2 and 3 breast cancer studies, have recently been developed. This study evaluated the bioequivalence of abemaciclib capsule and tablet formulations following single 150-mg doses, and the effect of food on the pharmacokinetics (PK) of abemaciclib following dosing with a 150-mg tablet. Methods: This was an open-label, randomized, 3-part study conducted in 127 healthy male (13%) and female (87%) subjects. Plasma concentrations of abemaciclib and its major metabolites were assessed up to 192 hours postdose using validated LC-MS/MS methods. Part A was a 2-period, crossover pilot study to compare abemaciclib capsules (3 x 50-mg) and tablets (1 x 150-mg) formulations in the fasted state. Results from Part A were used to ensure adequate PK sampling and estimate intra-individual variability to confirm the sample size required for Part B of the study. Part B was a 3-period, crossover, bioequivalence study of a 50-mg capsule (3 x 50-mg) compared to a 150-mg tablet (1 x 150-mg) and a 50mg tablet (3 x 50-mg) in the fasted state. Part C was a 2-period crossover food effect study to determine the effect of a high-fat, high-calorie meal on the PK of abemaciclib when administered as a single 150-mg tablet compared to the fasted state. Abemaciclib Cmax and AUC determined using noncompartmental methods were log-transformed and analyzed using a linear mixed-effects model. Geometric least squares (LS) mean for each treatment, the ratio of the geometric LS means, and their 90% CIs were calculated. Results: In Part A, the abemaciclib intra-subject variability for Cmax was 26.7%, requiring a sample size of 76 subjects for Part B to ensure approximately 90% probability that the 90% CIs of the geometric means would be contained within the 0.80 to 1.25 limits, assuming that the true ratio was 1.09. In Part B, both the 3 x 50-mg and 1 x 150-mg tablets were bioequivalent to the 3 x 50-mg capsules; the 90% CIs of the ratios of geometric LS means for Cmax and AUC were contained within the bioequivalence interval of 0.80 to 1.25. Ratio of geometric LS mean (90% CI) compared to 3x50 mg capsule 1x150 mg tablet3x50 mg tabletAUC(0-tlast)1.02 (0.979,1.06)1.03 (0.987,1.07)AUC(0-∞)1.02 (0.982,1.06)1.02 (0.986,1.06)Cmax1.00 (0.955,1.05)1.03 (0.986,1.08) In Part C, consumption of a high-fat, high-calorie meal before abemaciclib dosing resulted in an increase of 13% (90% CI 1.05,1.22) in AUC(0-∞) and 30% (90% CI 1.20,1.40) in Cmax, which was not considered clinically relevant given the magnitude of the effect relative to the inter-subject variability for Cmax (36.5%). Also, the magnitude of the change was within the therapeutic window for abemaciclib. There was no difference in median tmax in the fed state compared to the fasted state for abemaciclib. Single 150-mg doses of abemaciclib were generally well tolerated when administered with or without food. The majority of the AEs reported during the study were gastrointestinal and mild in severity. Conclusions: Abemaciclib 150-mg and 50-mg tablets are bioequivalent to the 50-mg capsule formulation, based on a single dose in the fasted state, and could be administered with or without food. Citation Format: Turner PK, Chappell JC, Aburub A, Ng WT, Zhang W, Royalty J, Kulanthaivel P. Abemaciclib tablet formulation is bioequivalent to capsules [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-14.

Comparative assessment of pharmacokinetics, and pharmacodynamics between RTXM83\u2122, a rituximab biosimilar, and rituximab in diffuse large B-cell lymphoma patients: a population PK model approach

PurposeThe main objective was to quantify any potential differences in pharmacokinetic (PK) parameters (AUC and Cmax) between RTXM83, a proposed rituximab biosimilar, and its reference product, using a population PK model approach.MethodsRituximab PK and PD data were obtained from a randomized, double-blind, phase III clinical study (RTXM83-AC-01-11) in patients with diffuse large B-cell lymphoma (DLBCL) that received 375 mg/m2 intravenous RTXM83 or its reference product with CHOP regimen, every 3 weeks, for six cycles. Rituximab levels were quantified by Meso Scale Discovery assay. PK analysis was performed using NONMEM 7.3.0. The effect of disease and patient covariates on RXTM83 PK was investigated. Model was evaluated using visual predictive check and non-parametric bootstrap.ResultsIn total, 251 DLBCL patients (127 and 124 in RXTM83-CHOP and rituximab-CHOP arms, respectively) and 5341 serum concentrations (2703 for RXTM83 and 2638 for rituximab, respectively) were available for the population PK analysis. The volume of distribution of the central compartment (V1) and clearance of RXTM83 were estimated at 3.19 L and 12.5 mL/h, respectively. Body surface area allowed to explain the interindividual variability for V1. A statistical analysis showed that systemic exposure (AUC and Cmax) of RTXM83 was similar to rituximab. The 90% confidence intervals for all pairwise comparisons were within the predefined bioequivalence interval of 0.80–1.25. PD similarity of B-cell depletion and recovery was also observed.ConclusionsThe time course of RTXM83 was well characterized by the model developed. The systemic exposure of RTXM83 and its associated variability were similar to those for rituximab reference in DLBCL patients, demonstrating PK similarity. The PD similarity of RTXM83 and rituximab reference product was also demonstrated.

Development and bioequivalence study of potassium chloride extended release tablets

The purposes of this study are to prepare the generic extended release tablet of potassium chloride (PC) 600 mg and to compare the absorption of potassium ion from the experimental tablets to that of Kaleorid® LP 600 mg (Leo Pharmaceutical Products, Denmark). Carnauba wax was used as retardant in the matrix core tablets. The core tablets were coated with blends of ethyl cellulose (EC) and hydroxypropyl methyl cellulose (HPMC) to modulate the drug release. Results of a selective two-level, three-factor experiment design revealed that a blend of 41.75% of EC and 58.25% of HPMC at 4.5% weight gained could produce the coated tablets having dissolution profiles similar to those of Kaleorid®. A two-treatment, two-period, two-sequence crossover bioequivalence study was carried out on 24 healthy volunteers to compare the absorption of potassium ion from experimental tablets to that from Kaleorid®. The potassium ion in the urine was measured by a selective electrode of the ADVIA 1650 system (Bayer) and used to calculate cumulative urinary excretion and urinary excretion rate. Results of 90 percent confidence interval analysis showed that the limits for natural log-transformed cumulative urinary potassium excretion (Ln Ae0-24) of test product were in the range of 3.73–3.79 mEq, corresponding to 99.08%–100.92% of Kaleorid®, respectively, and the limits for natural log-transformed maximal potassium excretion rate (Rmax) of test product were in the range of 1.72–1.82 mEq/h, corresponding to 97.34%–102.66% of reference product, respectively. Both of them fell within the bioequivalence interval (80%–125%) of reference product, proving that experimental product is bioequivalent to Kaleorid®.

Biocomparison Study of Adult and Paediatric Dose Strengths of the Prostacyclin Receptor Agonist Selexipag

Selexipag is an oral, non-prostanoid, selective prostacyclin receptor agonist recently marketed for the treatment of pulmonary arterial hypertension (PAH) in adults. Selexipag may also be an effective treatment in children with PAH. The aim of this study was to compare the pharmacokinetics of selexipag and its active metabolite ACT-333679 following single oral administration of one tablet of 200µg selexipag (Treatment A) vs. 4 paediatric tablets of 50µg (Treatment B) in healthy adult male subjects. This was an open-label, randomized, two-treatment, two-period, crossover biocomparison study. Bioequivalence criteria were explored and safety variables (vital signs, electrocardiogram, and laboratory parameters) were assessed. The exploratory analysis showed that the 90% confidence intervals of geometric mean ratio (Treatment B/Treatment A) for maximum plasma concentration (C max), area under the plasma concentration-time curve from zero to infinity (AUC0-∞) of ACT-333679, as well as AUC0-∞ of selexipag, were within the bioequivalence interval (0.80, 1.25). In addition, no relevant difference in C max for selexipag between the two treatments can be concluded. Single oral dose administration of 200µg selexipag as one tablet of 200µg or four tablets of 50µg was well tolerated. Pharmacokinetic characteristics of selexipag and its metabolite ACT-333679 following administration of one adult tablet of 200µg selexipag and four paediatric tablets of 50µg selexipag were comparable. ClinicalTrials.gov identifier: NCT02745860.

A pharmacokinetic drug-drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects.

In vitro data showed that selexipag and its active metabolite (ACT-333679) have an inductive effect on CYP3A4, CYP2B6, and CYP2C9 at concentrations approximately 100-fold higher than the maximum plasma concentration (C max) measured under steady-state conditions. In order to confirm in vivo the lack of induction at the enterocyte level, we assessed the effect of selexipag on midazolam, a substrate of hepatic and intestinal CYP3A4. This study was conducted according to an open-label, randomized, two-way crossover design. A total of 20 subjects received a single oral dose of 7.5mg midazolam alone (treatment A) or on top of steady-state selexipag (treatment B). Selexipag was administered twice daily using an up-titration scheme consisting of three steps: 400, 600, 1000, and 1600μg with increments every fourth day. A 24-h pharmacokinetic profile was performed following midazolam administration, and bioequivalence criteria were investigated on an exploratory basis. The C max of midazolam and 1-hydroxymidazolam was decreased by approximately 20 and 14%, respectively, following treatment B compared to A. The time to reach C max for midazolam and 1-hydroxymidazolam was similar between treatments. The terminal half-life was reduced in treatment B compared to A for both midazolam (16%) and 1-hydroxymidazolam (20%). Exposure (area under the curve) to midazolam and 1-hydroxymidazolam was similar between treatments, and the 90% confidence intervals of geometric mean ratios were within the bioequivalence interval. Treatment with midazolam, selexipag, and the combination was safe and well tolerated. Exposure to midazolam and 1-hydroxymidazolam was not affected by treatment with selexipag.

The Hypoxia-inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat (FG-4592) and Warfarin in Healthy Volunteers: A Pharmacokinetic and Pharmacodynamic Drug–Drug Interaction Study

PurposeRoxadustat is a small-molecule hypoxia-inducible factor prolyl-hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in patients with chronic kidney disease (CKD). Warfarin is an oral anticoagulant with a narrow therapeutic window that is often prescribed to treat coexisting cardiovascular diseases in patients with CKD. This clinical trial was designed to evaluate the effect of roxadustat on warfarin pharmacokinetic and pharmacodynamic parameters. MethodsThis open-label, single-sequence crossover study was conducted in healthy volunteers (male or female) aged 18 to 55 years with a body mass index of 18.5 to 30.0 kg/m2. The study consisted of 2 periods separated by a minimum washout period of 14 days. After an overnight fast, volunteers received a single oral dose of 25 mg (5 × 5 mg tablets) warfarin on Day 1 of Period 1 and Day 7 of Period 2. Volunteers received oral doses of 200 mg (2 × 100 mg tablets) roxadustat on Days 1, 3, 5, 7 (concomitant with warfarin), 9, 11, 13, and 15 of Period 2. Plasma S- and R-warfarin (unbound and total concentrations) and prothrombin time were determined at multiple time points up to 216 hours postdose. Pharmacokinetic and pharmacodynamic parameters were estimated via noncompartmental methods. Tolerability was evaluated by monitoring adverse events, laboratory assays, vital signs, and 12-lead ECGs. FindingsThe geometric mean ratios and 90% CIs for Cmax and AUC∞ of total and unbound S- and R-warfarin (with and without roxadustat) were within the standard bioequivalence interval of 80.00% to 125.00%. Roxadustat increased the geometric mean (GM) prothrombin (PT) and international normalized ratio (INR) AUC from time zero to last measurable sample (AUCPT,last and AUCINR,last) by 24.4%. Coadministration of roxadustat and warfarin in healthy volunteers was associated with a favorable tolerability profile, with most treatment-associated adverse events mild in severity. ImplicationsBased on the lack of clinically significant pharmacokinetic interactions and the limited influence on warfarin pharmacodynamic parameters, no dose adjustment of warfarin should be required when coadministered with roxadustat. ClinicalTrials.gov identifier: NCT02252731.

Are We Getting the Best Return on Investment From Clinical Drug-Drug Interaction Studies?

Are We Getting the Best Return on Investment From Clinical Drug-Drug Interaction Studies?

Fed and Fasted Single-dose Assessment of Bioequivalence of Dapagliflozin and Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects

PurposeIn patients with type 2 diabetes mellitus, fixed-dose combinations (FDCs) of antihyperglycemic medications may provide complementary efficacy while reducing tablet burden and improving compliance. The aim of this study was to assess the bioequivalence and tolerability of 2 FDCs of dapagliflozin and metformin extended-release (XR) versus their individual component (IC) tablets. MethodsAn open-label, balanced, randomized, 2-way crossover, 4-arm study was conducted in 129 healthy Brazilian subjects (aged 18–55 years). Two oral doses of the FDCs (5 mg dapagliflozin and 500 mg metformin XR, and 10 mg dapagliflozin and 1000 mg metformin XR) were evaluated in fed and fasted states. FindingsUnder fed and fasted conditions the 5 mg dapagliflozin and 500 mg metformin XR FDC showed bioequivalence to its ICs. The 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent to its ICs in fed subjects. Although AUC for the 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent in fasted subjects, the Cmax for metformin was not bioequivalent to its ICs in fasted subjects (upper 90% CI was 127.5%, and thus outside the 80%–125% bioequivalence interval). The small increase in the fasted state is not considered clinically meaningful due to the small magnitude of the difference (9.2%), the lack of metformin Cmax being associated with efficacy or tolerability concerns, and the fasted state not being the recommended state for dosing of metformin XR. The safety profile and tolerability of the FDCs were similar to those of their ICs and no deaths or serious adverse events were reported. ImplicationsBoth FDCs of dapagliflozin and metformin XR were bioequivalent to their ICs in fed and fasted subjects, except for the metformin Cmax from the 10 mg dapagliflozin and 1000 mg metformin XR FDC in fasted subjects. These data support the use of a dapagliflozin and metformin XR FDC in patients with type 2 diabetes mellitus.

Biocomparison of Three Formulations of the S1P1 Receptor Modulator Ponesimod in Healthy Subjects.

BackgroundPonesimod is a potent selective sphingosine-1-phosphate receptor 1 (S1P1) modulator, which leads to a reduction in circulating lymphocytes, reflecting their sequestration within lymphoid organs. Modulation of the S1P1 receptor has been previously described to be an effective treatment of autoimmune diseases (e.g., multiple sclerosis).ObjectivesThe aim of this study was to compare the relative bioavailability of two polymorphic forms of ponesimod in capsules (Form A versus Form C; Study 1) and the relative bioavailability of a capsule formulation and a tablet formulation (both polymorphic Form C; Study 2).MethodsTwo open-label, randomized, two-way crossover studies in healthy subjects were performed. In Study 1, 12 male subjects received a single dose of 20 mg of polymorphic Form A or Form C of ponesimod in a capsule. In Study 2, 14 male and female subjects (ratio 1:1) received a single dose of 40 mg of polymorphic Form C of ponesimod in either a capsule or a tablet formulation. Pharmacokinetic and safety variables (clinical laboratory test results, vital signs, and an electrocardiogram) were assessed.ResultsComparison of the exposure to ponesimod following administration of the formulations in Study 1 showed that the 90 % confidence intervals of the geometric mean ratios for the area under the curve from time zero to infinity (AUC0–inf), the area under the curve from time zero to the time of the last measurable concentration (AUC0–t), the terminal half-life (t½), and the maximum plasma concentration (Cmax) were all within the 0.80–1.25 bioequivalence interval. In Study 2, more rapid absorption of ponesimod was observed from the tablet formulation than from the capsule formulation. There were no relevant differences in the safety and tolerability profiles between the different formulations.ConclusionThe two polymorphic forms of ponesimod and tablet versus capsule formulations were similar in terms of pharmacokinetics, safety, and tolerability.

Study of pharmacokinetic interaction of paroxetine and roxithromycin on bencycloquidium bromide in healthy subjects

PurposeThe aim of this study was to investigate the potential drug–drug interaction between Bencycloquidium bromide (BCQB) and paroxetine, and between BCQB and roxithromycin. MethodsTwo studies were conducted on healthy male Chinese volunteers. Study A was an open-label, two-period, one-sequence crossover study (n=21). Each participant received a single nasal spray dose of BCQB 180μg on day 1. After a 7-day wash-out period, subjects received 20mg of paroxetine from day 8 to 17, and were co-administered 20mg of paroxetine and BCQB 180μg on day 18. In study B, participants (n=12) were randomly assigned to two groups. In period I, group A received BCQB 180μg on day 1, followed by the same dose four times daily from day 4 to 10, then, on day 11 a single dose of 150mg roxithromycin with BCQB 180μg were co-administered. In parallel, group B received a single dose of roxithromycin 150mg on day 1, followed by 300mg of roxithromycin from day 4 to 10, then, on day 11 a single dose of BCQB 180μg with roxithromycin 300mg were co-administered. After a wash-out time of 7days the respective treatments of each group (A and B) were swapped in period II. Blood samples were collected for pharmacokinetic analysis. Statistical comparison of pharmacokinetic parameters was performed to identify a possible drug interaction between treatments. Tolerability was evaluated by recording adverse events. ResultsStudy A: Geometric mean AUC0–36 for BCQB alone and co-administered with paroxetine were 474.3 and 631.3pgh/ml, respectively. The geometric mean ratio (GMR) of AUC0–36 was 1.33 (1.13–1.46), 90% C.Is, and was out the predefined bioequivalence interval (90% C.Is, 0.80–1.25). Geometric mean Cmax were 187.0 and 181.2pg/ml. Study B: The GMR of AUC0–36 was 0.98 (0.90–1.07), 90% C.Is for BCQB, and the GMR of AUC0–72 was 0.98 (0.87–1.11), 90% C.Is for roxithromycin. Both GMRs were within the predefined bioequivalence interval (90% C.Is, 0.80–1.25). Other pharmacokinetic parameters were within the predefined interval. No serious adverse events were reported and no significant clinical changes were observed in laboratory test results, vital signs and ECGs in any of the studies. All treatments were well tolerated. ConclusionThe co-administration of BCQB with paroxetine showed a moderate increase in BCQB exposure, but was not clinically relevant. Also, no drug interaction was found between BCQB and roxithromycin.

Effects of ketoconazole on the pharmacokinetics of lenvatinib (E7080) in healthy participants

BackgroundLenvatinib is an oral, multitargeted, tyrosine kinase inhibitor under clinical investigation in solid tumors. In vitro evidence indicates that lenvatinib metabolism may be modulated by ketoconazole, an inhibitor of CYP3A4 and p-glycoprotein.MethodsIn this Phase I, single-center, randomized, open-label, two-period, crossover study, healthy adults (18–55 years; N = 18) were randomized to one of two sequences (ketoconazole → placebo or vice versa). Ketoconazole (400 mg) or placebo was administered orally once daily for 18 days; a 5 mg dose of lenvatinib was orally administered on Day 5 of each treatment period. Blood samples were collected over 14 days and lenvatinib plasma concentrations measured by high-performance liquid chromatography/tandem mass spectrometry.ResultsSystemic exposure to lenvatinib increased slightly (15–19%) with coadministration of ketoconazole. Although the 90% confidence interval (CI) for area under the plasma concentration–time curve (AUC) was within the prespecified bioequivalence interval of 80–125%, Cmax slightly exceeded the 125% CI bound (134%). No changes in tmax, tlag, or t½ were observed. Thirteen subjects (72%) experienced treatment-emergent adverse events (11 mild, 2 moderate), most commonly headache (22%) and diarrhea (17%).ConclusionsLenvatinib exposure was slightly increased by ketoconazole; however, the magnitude of the change was relatively small, and likely not clinically meaningful.

Open-label, randomized, crossover comparative bioavailability study of cefixime from two tablet formulations after single oral administration

Background: Cefixime is an oral extended spectrum third generation cephalosporin, which has marked in vitro bactericidal activity against a wide variety of Gram-positive and Gram-negative organisms, effective in the treatment of community-acquired infections such as respiratory tract infection and urinary tract infection. The objective of this randomized, crossover study was to compare the bioequivalence (BE) of two tablets of test (Milixim ® 200 mg, containing 200 mg of cefixime) with Reference formulation (Cefixime, 400 mg). Methods: A total of 12 healthy volunteers were randomly assigned to crossover, single-dose treatment regimens. Serial blood samples were collected, and plasma concentrations of cefixime were analyzed using the high-performance liquid chromatographic technique. Pharmacokinetic parameters and BE limits were calculated using non-compartmental methods. Results: The mean C max for the test and reference formulations were 4435.0298±149 and 4408.2150±1021 ng/mL, respectively. The mean area under the serum concentration curve (AUC) 0-t were 38108.2614±8583.6535 and 38457.5791±8105.2529 ng/hr/mL The mean ratios (test: reference) for C max , AUC 0-t , were 99.7% and 98.5%, respectively. There were no significant differences in pharmacokinetic parameters between groups. Overall, the 90% confidence interval for the intra-individual ratios of the log-transformed C max and AUC values of the two formulations were within the BE interval of 80-125%. Conclusion: The study has demonstrated the BE of milixim and reference formulation of cefixime.

Abstract A5: Effects of rifampin on the pharmacokinetics (PK) of lenvatinib (L) in healthy participants.

Abstract Background: L is an orally administered multitargeted tyrosine kinase inhibitor of VEGF receptors 1, 2, 3; FGF receptors 1, 2, 3, 4; PDGFR-β; RET; and KIT under clinical investigation in solid tumors at doses of 24 mg/d. This study in volunteers assessed the influence of P-glycoprotein (Pgp) inhibition (single-dose R) and simultaneous CYP3A4 and Pgp induction (multiple-dose R) on L PK parameters. Methods: This was a single-center, single-dose, open-label, sequential, 3-period study. Subjects were administered 3 regimens with a 14-day washout between each treatment. Subjects received a single oral dose of L 24 mg on Day 1 (Period 1), Day 15 (Period 2), and Day 43 (Period 3). In Period 2 on Day 15, subjects received a single oral dose of rifampin 600 mg coadministered with L. In Period 3, subjects received oral rifampin 600 mg/d for 21 days (Days 29 to 49). Results: 15 subjects were enrolled and completed the study. Single-dose rifampin increased free (unbound) L AUC0-∞ (32%) and Cmax (30%). Multidose rifampin decreased free L AUC0-∞ (9%) without a corresponding decrease in Cmax; mean t1/2(free L) decreased by ∼2.5 h (to ∼17 h) following single-dose rifampin and by ∼5 h following multidose R. The 90% confidence intervals (CIs) of the geometric least squares (GLS) mean ratios for Cmax and AUCs were above the upper CI boundary of the prespecified bioequivalence interval of 80%-125% following a single rifampin dose but within the prespecified bioequivalence interval following multidose R. Headache (n=3, 20%) was the most frequently reported treatment-emergent adverse event (TEAE); 5 subjects reported mild or moderate treatment-related TEAEs (n=5, 33%) most frequently nausea (n=3, 20%) and diarrhea (n=2, 13%). Conclusions: L exposure was increased by single-dose rifampin but decreased by multiple rifampin doses. The magnitude of these changes was relatively small and likely not clinically meaningful. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A5. Citation Format: Robert Shumaker, Jagadeesh Aluri, Jean Fan, Gresel Martinez, Gary A. Thompson, Min Ren. Effects of rifampin on the pharmacokinetics (PK) of lenvatinib (L) in healthy participants. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A5.

Abstract 755: A randomized, open-label, phase 1 study to evaluate the effect of food on tivantinib (ARQ 197) pharmacokinetics

Abstract Background: Tivantinib (ARQ 197) is a selective inhibitor of c-MET that is administered orally. Therefore, the bioavailability of tivantinib may be affected by changes in gastric pH or emptying and gastrointestinal motility that occur in the presence of food. This study evaluated the effect of food on tivantinib pharmacokinetics (PK) to provide guidance regarding intake of meals in conjunction with tivantinib dosing in future clinical studies, and estimated the intra-subject variability of tivantinib when administered in fasting and fed conditions. Methods: Young healthy adults 18-45 years of age were eligible for the study. Subjects were randomized to 1 of 2 sequences. In sequence 1, subjects received a single dose of tivantinib (360 mg) in fasting conditions in Period 1 and in fed conditions in Periods 2 and 3. In sequence 2, subjects received a single dose of tivantinib (360 mg) in fed conditions in Period 1 and in fasting conditions in Periods 2 and 3. Each period was separated by ≤ 4 days, during which serial blood samples were collected for tivantinib analysis. PK parameters, including area under the curve (AUC), maximum concentration (Cmax), time to peak concentration (tmax), and terminal half-life (t1/2), were calculated and compared. Results: A total of 20 subjects (19 male and 1 female) were randomized. Under fed conditions, total exposure of tivantinib was significantly higher (approximately 2.7-times for AUC and 3.6-times for Cmax) compared with fasting conditions (ratios of geometric least-square means and 90% confidence intervals were outside the 80%-125% bioequivalence interval). Time to maximum concentration (tmax) was prolonged when tivantinib was administered in fed conditions versus fasting conditions (4.0 vs 2.5 hours). Although t1/2 was longer in fasting versus fed conditions (19.0 vs 4.0 hours), nonparametric statistical analysis demonstrated that this difference was not statistically significant. Intra-subject variability was roughly 2-fold lower in fed conditions compared with fasting conditions. Five adverse events were reported in 2 subjects (10%), all of which were considered unrelated to study treatment. One subject withdrew consent and discontinued from the study for reasons unrelated to treatment. Conclusions: Administration of tivantinib in fed conditions results in relatively higher exposure with lower variability compared with fasting conditions. This may be explained by increased tivantinib solubility and more consistent absorption in the fed state. Based on this observation, tivantinib is currently recommended to be administered with meals in ongoing clinical studies, including the ongoing phase 3 study (MARQUEE™) in patients with nonsquamous non-small cell lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 755. doi:1538-7445.AM2012-755