Bioequivalence of Related GelShieldⓇ Sustained-release Formulations of Metformin: A Pooled Pharmacokinetic Analysis.

PURPOSE: GlucophageⓇ (Merck Healthcare KGaA, Darmstadt, Germany) is the originator brand of metformin hydrochloride, an oral antidiabetic drug. Metformin is recommended in guidelines as first-line treatment of type 2 diabetes mellitus and increasingly in related insulin-resistant conditions, such as prediabetes and polycystic ovary syndrome. The GelShieldⓇ sustained-release formulation tablet of GlucophageⓇ has been improved from the historic version marketed in 2000. Bioequivalence has been demonstrated stepwise along this evolution; however, a head-to-head evaluation between the initial and the current version is missing. This analysis aims to close this gap and to determine bioequivalence between related originator GelShieldⓇ sustained-release formulations of metformin, GlucophageⓇ (GXR 500 mg), from Europe and the United States. METHODS: Data from seven randomized crossover bioequivalence studies in 361 healthy participants of Asian and non-Asian ethnicity from Europe, the United States, and Asia were considered. All evaluated a single oral dose of 500 mg of the test and reference formulation in healthy male and female participants in fed and fasted state. Bioequivalence was evaluated by means of a combined bridging analysis of available data on the current round tablet from Europe (rGXR EU) and the historic oblong tablet from the United States (oGXR US) in healthy Asian and non-Asian participants under fed and fasting conditions. Bioequivalence between the two formulations was assessed statistically with a mixed effects model for AUC0-t, Cmax, and AUC0-inf. FINDINGS: In all studies, bioequivalence between the respective test and reference formulations of GXR was shown. Statistical analysis of pooled pharmacokinetic data of 2 (primary pooling set) or 3 studies (secondary pooling set) demonstrated bioequivalence between rGXR EU and oGXR US via bridging with oGXR EU. The 90% CI for the geometric mean ratio of all pharmacokinetic parameters was within the bioequivalence range of 0.80 to 1.25. In the primary pooling set, geometric least squares mean ratios in the fed group ranged from 0.9931 (90% CI, 0.9151-1.0778) for AUC0-inf to 1.1344 (90% CI, 1.0711-1.2014) for Cmax; results in the fasted group were similar. The secondary pooling set, which added a study in Asians, confirmed these findings. IMPLICATIONS: Bioequivalence was determined between sustained-release formulations of GlucophageⓇ from Europe and the United States under fasted and fed conditions in healthy men and women, including different ethnicities. The efficacy and safety of GlucophageⓇ XR can be claimed along the evolution from oGXR US, via oGXR EU to rGXR EU, and in several ethnicities and production sites.

Asia-Inclusive Global Development of Enpatoran: Results of an Ethno-Bridging Study, Intrinsic/Extrinsic Factor Assessments and Disease Trajectory Modeling to Inform Design of a Phase II Multiregional Clinical Trial.

Enpatoran is a novel, highly selective, and potent dual toll-like receptor (TLR)7 and TLR8 inhibitor currently under development for the treatment of autoimmune disorders including systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and myositis. The ongoing phase II study (WILLOW; NCT05162586) is evaluating enpatoran for 24 weeks in patients with active SLE or CLE and is currently recruiting. To support development of WILLOW as an Asia-inclusive multiregional clinical trial (MRCT) according to International Conference on Harmonisation E5 and E17 principles, we have evaluated ethnic sensitivity to enpatoran based on clinical pharmacokinetic (PK), pharmacodynamic (PD), and safety data from an ethno-bridging study (NCT04880213), supplemented by relevant quantitative PK, PD, and disease trajectory modeling (DTM) results, and drug metabolism/disease knowledge. A single-center, open-label, sequential dose group study in White and Japanese subjects matched by body weight, height, and sex demonstrated comparable PK and PD properties for enpatoran in Asian vs. non-Asian (White and other) subjects across single 100, 200, and 300 mg orally administered doses. DTM suggested no significant differences in SLE disease trajectory for Asian vs. non-Asian individuals. Aldehyde oxidase (AOX) is considered to be a key contributor to enpatoran metabolism, and a literature review indicated no relevant ethnic differences in AOX function based on in vitro and clinical PK data from marketed drugs metabolized by AOX, supporting the conclusion of low ethnic sensitivity for enpatoran. Taken together, the inclusion of Asian patients in MRCTs including WILLOW was informed based on a Totality of Evidence approach.

Phase I crossover study of DNA-protein kinase inhibitor peposertib in healthy volunteers: Effect of food and pharmacokinetics of an oral suspension.

Peposertib is an orally administered inhibitor of DNA-dependent protein kinase. We evaluated the effect of food on its pharmacokinetics, and examined the pharmacokinetics of an oral suspension (OS) of disintegrated tablets, in a phase I, open-label, crossover three-period study (NCT04702698). Twelve healthy volunteers were randomized to one of six treatment sequences. They received a single dose of peposertib 100 mg as film-coated tablets under fasted or fed conditions ("tablet fasted" or "tablet fed") or as an OS under fasted conditions ("OS fasted"), with washout between treatments. Using healthy volunteers was possible because, despite its mechanism of action being suppression of DNA repair, peposertib has shown no genotoxic effect in animals. A mild food effect was observed with peposertib tablets. Fed-to-fasted ratios were: area under the curve from time 0 to time t (AUC0-t ), 123.81% (90% confidence interval [CI]: 108.04, 141.87%); AUC from zero to infinity (AUC0-∞ ), 110.28% (90% CI 100.71, 120.77%); and maximum concentration (Cmax ) 104.47% (90% CI: 79.15, 137.90%). Cmax was delayed under fed conditions (median time to maximum concentration [Tmax ] was 3.5 h [tablet fed] vs. 1 h [tablet fasted]). OS-to-tablet (fasted) ratios were: AUC0-t , 124.83% (90% CI: 111.50%, 139.76%); AUC0-∞ , 119.05% (90% CI: 104.47, 135.67%); and Cmax 173.29% (90% CI: 135.78, 221.16%). Median Tmax was 0.5 h (OS fasted) versus 1 h (tablet). All treatments were well-tolerated in healthy volunteers. Peposertib tablets can be taken with or without food; if combined with chemotherapy or radiotherapy, the delay in Cmax must be considered to optimize the chemo- or radiosensitizing effect. The peposertib OS form represents an alternative route of administration in patients with specific cancers causing dysphagia. However, the OS form should be part of future dose optimization strategies in relevant settings.

Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates.

Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring MET exon 14 skipping alterations. The aims of this work were to investigate the potential for drug-drug interactions via cytochrome P450 (CYP) 3A4/5 or P-glycoprotein (P-gp) inhibition. In vitro studies were conducted in human liver microsomes, human hepatocyte cultures and Caco-2 cell monolayers to investigate whether tepotinib or its major metabolite (MSC2571109A) inhibited or induced CYP3A4/5 or inhibited P-gp. Two clinical studies were conducted to investigate the effect of multiple dose tepotinib (500 mg once daily orally) on the single dose pharmacokinetics of a sensitive CYP3A4 substrate (midazolam 7.5 mg orally) and a P-gp substrate (dabigatran etexilate 75 mg orally) in healthy participants. Tepotinib and MSC2571109A showed little evidence of direct or time-dependent CYP3A4/5 inhibition (IC50 > 15 µM) in vitro, although MSC2571109A did show mechanism-based CYP3A4/5 inhibition. Tepotinib did not induce CYP3A4/5 activity in vitro, although both tepotinib and MSC2571109A increased CYP3A4 mRNA. In clinical studies, tepotinib had no effect on the pharmacokinetics of midazolam or its metabolite 1'-hydroxymidazolam. Tepotinib increased dabigatran maximum concentration and area under the curve extrapolated to infinity by 38% and 51%, respectively. These changes were not considered to be clinically relevant. Tepotinib was considered safe and well tolerated in both studies. The potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the clinical dose is considered low. Study 1 (midazolam): NCT03628339 (registered 14 August 2018). Study 2 (dabigatran): NCT03492437 (registered 10 April 2018).

Effect of Moderate Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor.

BACKGROUND AND OBJECTIVE: Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in phase III development for the treatment of anaemia associated with chronic kidney disease. This study evaluated the effects of moderate hepatic impairment on roxadustat pharmacokinetics, pharmacodynamics and tolerability. METHODS: This was an open-label study in which eight subjects with moderate hepatic impairment (liver cirrhosis Child-Pugh score 7-9) and eight subjects with normal hepatic function (matched for body mass index, age and sex) received a single oral 100 mg roxadustat dose under fasted conditions. Blood samples were collected until 144 h post-dose in subjects with moderate hepatic impairment and until 96 h post-dose in subjects with normal hepatic function. RESULTS: In subjects with moderate hepatic impairment, area under the concentration-time curve (AUC) from the time of drug administration to infinity (AUC∞) and observed maximum concentration (C max) were 23 % higher [geometric least-squares mean ratio (GMR) 123 %; 90 % CI 86.1-175] and 16 % lower (GMR 83.6 %; 90 % CI 67.5-104), respectively, than in subjects with normal hepatic function. Mean terminal half-life (t ½) appeared to be longer (17.7 vs. 12.8 h) in subjects with moderate hepatic impairment, however intersubject variability on apparent total systemic clearance after single oral dosing (CL/F), apparent volume of distribution at equilibrium after oral administration (V z/F) and t ½ was approximately twofold higher. Erythropoietin (EPO) baseline-corrected AUC from administration to the last measurable EPO concentration (AUCE,last) and maximum effect (E max) were 31 % (GMR 68.95 %; 90 % CI 29.29-162.29) and 48 % (GMR 52.29 %; 90 % CI 28.95-94.46) lower, respectively, than in subjects with normal hepatic function. The single oral roxadustat dose was generally well tolerated. CONCLUSIONS: This study demonstrated the effect of moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of roxadustat relative to subjects with normal hepatic function. These differences are not expected to be of clinical significance.

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

PURPOSE: Roxadustat 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. METHODS: This 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/m(2). 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. FINDINGS: The 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. IMPLICATIONS: Based 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.

Pharmacokinetics of licarbazepine in healthy volunteers: single and multiple oral doses and effect of food.

Two studies characterized single- and multiple-dose pharmacokinetics of licarbazepine immediate-release tablets and food effects on single-dose pharmacokinetics. In 1 study, 12 volunteers received 500 mg licarbazepine on day 1, 500 mg bid on days 3 to 6, and 500 mg on day 7. In the second study, 12 subjects received one 500-mg licarbazepine dose under fasted and fed conditions. After multiple dosing, geometric mean (%CV) Cmax ss, Cmin ss, and AUCtau were 77.6 micromol/L (18), 45.3 micromol/L (25), and 747 h.mol/L (19), respectively, with a tmax of 2 hours. Mean half-lives were 9.3 and 11.3 hours for single and multiple dosing, respectively. Food had no clinically significant effect on single-dose pharmacokinetics. Half-life ( approximately 10 hours) and low intersubject variability in main pharmacokinetic parameters were similar under fasted and fed conditions. Median tmax increased from 1.5 to 2.5 hours with food. Licarbazepine is well tolerated and has predictable pharmacokinetics.

Evaluation of the CCK-4 model as a challenge paradigm in a population of healthy volunteers within a proof-of-concept study.

RATIONALE: Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder and might serve as a tool to asses the antipanic potential of novel anxiolytic compounds. However, assessment of CCK-4-induced panic does not follow consistent rules. OBJECTIVES: To provide a basis for the use of the CCK-4 model in proof-of-concept studies, we investigated CCK-4-induced panic according to different criteria in 85 healthy volunteers who underwent a CCK-4 bolus injection. METHODS: We assessed panicker/non-panicker ratios according to different panic criteria and explored whether differences in cardiovascular and neuroendocrine responses to CCK-4 paralleled subjective panic responses. Subjective panic responses were measured with the Acute Panic Inventory (API) and the Panic Symptom Scale (PSS). Heart rate, blood pressure, adrenocorticotropic hormone (ACTH) and cortisol were assessed concomitantly. RESULTS: The API-derived panic rate was 10.6% higher than that derived from the PSS. CCK-4 induced an increase in heart rate, systolic blood pressure and ACTH/cortisol plasma levels, which did not differ between panickers and non-panickers. CONCLUSIONS: The panic criterion applied appears to be of major importance for the panic rate achieved, whereas CCK-4-induced cardiovascular and hormonal alterations are not valuable as an objective "read out". The CCK-4 challenge might serve as a useful model to study putative anxiolytic effects of novel compounds during the early phase of drug development if the challenge procedure is carried out according to strictly comparable conditions.

Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects.

OBJECTIVE: This study was carried out to investigate the influence of CYP3A induction with rifampicin on imatinib (Gleevec) exposure. METHODS: The study employed a single center, single-sequence design. A group of 14 healthy male and female subjects received imatinib as a single 400 mg oral dose on two occasions: on study day 1 and on study day 15. Rifampicin treatment (600 mg once daily) for CYP4503A induction was initiated on study day 8 and maintained until day 18. Imatinib pharmacokinetics were determined up to 96 h after dosing on day 1 (no induction) and on days 15-18 (during concomitant rifampicin). Plasma concentrations of imatinib and its main metabolite CGP74588 were determined using a LC/MS/MS method. The ratio of 6beta-hydroxycortisol to cortisol excreted in the urine was measured to monitor the induction of CYP3A. RESULTS: During concomitant rifampicin administration, the mean imatinib C(max), AUC(0-24) and AUC(0- infinity ) decreased by 54% (90% CI: 48-60%), 68% (64-70%) and 74% (71-76%), respectively. The increase in clearance (Cl/f) was 385% (348-426%) during rifampicin treatment. The mean C(max) and AUC(0-24) of the metabolite CGP74588 increased by 88.6% (68.3%-111.4%) and 23.9% (13.5%-35.2%) after rifampicin pretreatment. However, the AUC(0- infinity ) decreased by 11.7% (3.3-19.4%). All subjects demonstrated a marked induction of hepatic microsomal CYP3A analyzed by the excretion ratio of 6beta-hydroxycortisol to cortisol from a mean baseline concentration of 5.6 U to 50.5 U. CONCLUSION: Concomitant use of imatinib and rifampicin or other potent inducers of CYP4503A may result in subtherapeutic plasma concentrations of imatinib. In patients in whom rifampicin or other CYP3A inducers are prescribed, alternative therapeutic agents with less potential for enzyme induction should be selected.

Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Transfusional iron overload is a potentially fatal complication of the treatment of thalassaemia. We aimed to investigate short-term efficacy, pharmacokinetic/pharma- codynamic (PK/PD) relations, and safety of ICL670, a novel, tridentate, orally active iron chelator. METHODS: We enrolled 24 patients and divided them into three cohorts consisting of a minimum of seven individuals. Patients were admitted to a metabolic unit and consumed a diet with a defined content of iron. Two patients in each cohort were randomly allocated placebo. Five or more patients received one daily dose of ICL670 at 10, 20, or 40 mg x kg(-1) x day(-1), from day 1 to 12. Net iron excretion (NIE) was measured between days 1 and 12. Primary objectives included assessment of safety and tolerability (measured by adverse events and clinical laboratory monitoring), pharmacokinetics (measured as drug and drug-iron complex), and cumulative net iron excretion (measured by faecal and urine output minus food input). Analysis was for efficacy. FINDINGS: ICL670 was absorbed promptly and was detectable in the blood for 24 h. Exposure (area under the curve of plasma concentration) to ICL670 at pharmacokinetic steady state was proportional to dose. All three doses resulted in positive NIE. The NIE achieved at 20mg x kg(-1) day(-1) would prevent net iron accumulation in most patients transfused with 12-15 mL packed red-blood-cells kg(-1) month(-1), equivalent to 0.3-0.5 mg iron kg(-1) x day(-1). A linear relation (PK/PD) was recorded between exposure to ICL670 and total iron excretion, by contrast with placebo (r2=0.54, p<0.0001). Skin rashes were noted in four patients treated at 20 and 40 mg x kg(-1) x day(-1), and one patient also developed grade 2 transaminitis. INTERPRETATION: ICL670 given once daily at 20 mg/kg seems to be an effective orally active iron chelator and is reasonably well tolerated. Long-term studies are now necessary to establish the practical contribution of this drug.

Validation of MRI measurement of cardiac output in the dog: the effects of dobutamine and minoxidil.

The use of magnetic resonance imaging (MRI) for the measurement of cardiac output parameters in anesthetized adult male beagle dogs has been validated against a widely accepted thermodilution method. Using a multislice cine gradient echo MRI method to acquire images of the entire heart, left ventricular lumen volumes were measured at systole and diastole in seven animals. Cardiac output correlated well (R 2 = 0.88) with thermodilution measurements made in a parallel manner, both before and during acute stimulation with the inotrope dobutamine. In a chronic study of changes in cardiac morphology and function brought about by the antihypertensive minoxidil, MRI reliably detected the expected increases in stroke volume (28%) and cardiac output (58%) resulting from neural reaction to decreased blood pressure. Left ventricular lumen enlarged as well in response to fluid retention and plasma volume increase. Two in four minoxidil-treated animals also developed clear MRI-visible pericardial effusion.