David E. Coutant

Comparison of the Pharmacokinetics and Pharmacodynamics of LY2963016 Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies

OBJECTIVE LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes but with identical amino acid sequences. Three studies evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of LY IGlar and the European Union– and US-approved versions of IGlar. RESEARCH DESIGN AND METHODS These were three single-site, randomized, double-blind, two-treatment, four-period, crossover, euglycemic clamp studies. In each study, fasted healthy subjects received 0.5 units/kg s.c. doses of two different insulin glargine products on two occasions each, following a randomized sequence. A ≥7-day washout period separated the doses. Blood samples were collected predose and up to 24 h postdose to assess PK; PD was assessed by a euglycemic clamp lasting up to 24 h. RESULTS A total of 211 subjects participated in the three studies. The PK (area under the curve [AUC]; maximum observed concentration [Cmax]) and PD (maximum glucose infusion rate [Rmax]; total glucose infusion during the clamp [Gtot]) were similar between LY IGlar and IGlar, with the ratios of geometric means ranging from 0.90 to 0.95 for PK parameters and from 0.91 to 0.99 for PD parameters across studies. In all cases, the 90% CIs for the ratios of geometric means were completely contained in the prespecified acceptance limits of 0.80–1.25. Adverse events were similar between treatments. CONCLUSIONS These studies demonstrated that the PK and PD properties of LY IGlar and IGlar were similar after single 0.5 units/kg s.c. doses in healthy subjects, contributing to the totality of evidence supporting similarity of these products.

Multiple‐Dose Plasma Pharmacokinetic and Safety Study of LY450108 and LY451395 (AMPA Receptor Potentiators) and Their Concentration in Cerebrospinal Fluid in Healthy Human Subjects

The objective of this study was to measure the steady‐state cerebrospinal fluid (CSF) concentration of LY450108 and LY451395 (positive modulators of AMPA receptors) in healthy subjects after the administration of 1 mg and 5 mg. Secondary objectives included the evaluation of safety, pharmacokinetics, and steady‐state ratio of plasma:CSF concentrations of LY450108 and LY451395 after multiple dosing. This study was an open‐label, multiple oral dose study evaluating 1 mg and 5 mg LY450108 and 1 mg and 5 mg LY451395 in 12 (3 subjects per dosing group) healthy subjects, aged 18 to 49 years. Twelve healthy male subjects completed the study. LY450108 and LY451395 were quantifiable in CSF after 1‐mg and 5‐mg multiple‐dose administrations with plasma:CSF ratio of 82:1 and 44:1, respectively. LY450108 and LY451395 1 mg and 5 mg were measured in the CSF. Single and multiple oral doses of LY450108 and LY451395 were determined to be safe and well tolerated in healthy subjects.

Androgen Dependent Mammary Gland Virilism in Rats Given the Selective Estrogen Receptor Modulator LY2066948 Hydrochloride

A selective estrogen receptor modulator (SERM) is a nonsteroidal compound with tissue specific estrogen receptor (ER) agonist or antagonist activities. In animals, SERMs may produce morphologic changes in hormonally-sensitive tissues like the mammary gland. Mammary glands from female rats given the SERM LY2066948 hydrochloride (LY2066948) for 1 month at ≥ 175 mg/kg had intralobular ducts and alveoli lined by multiple layers of vacuolated, hypertrophied epithelial cells, resembling in part the morphology of the normal male rat mammary gland. We hypothesized that these SERM-mediated changes represented an androgen-dependent virilism of the female rat mammary gland. To test this hypothesis, the androgen receptor antagonist flutamide was co-administered with LY2066948 (175 mg/kg) to female rats for 1 month. Female rats given SERM alone had hyperandrogenemia and the duct and alveolar changes described here. Flutamide cotreatment did not affect serum androgen levels but completely blocked the SERM-mediated mammary gland change. In the mouse, a species that does not have the sex-specific differences in the mammary gland observed in the rat, SERM treatment resulted in hyperandrogenemia but did not alter mammary gland morphology. These studies demonstrate that LY2066948 produces species-specific, androgen-dependent mammary gland virilism in the female rat.

Duration of action of two insulin glargine products, LY2963016 insulin glargine and Lantus insulin glargine, in subjects with type 1 diabetes mellitus.

LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes, but with identical amino acid sequences. This study compared the duration of action of LY IGlar and IGlar in subjects with type 1 diabetes mellitus (T1DM).

Substantial Evidence: When is a Single Trial Sufficient for Approval and Promotion?

The Federal Food, Drug, and Cosmetic Act provides FDA and sponsors with a statutory definition of “substantial evidence.” Most often drug effectiveness is established through the conduct of two adequate and well-controlled clinical trials (AWCTs), but there are situations where effectiveness can be sufficiently established through the conduct of a single AWCT. Some of these situations were detailed in FDAs 1998 guidance document, but there remains some uncertainty for sponsors in determining what cases might merit a single AWCT to meet the substantial evidence standard (depending on indication, drug class, etc). This article is meant as an aid for drug development teams, and regulatory professionals in particular, to navigate successfully through such questions of substantial evidence. We review some of the prerequisites and hurdles for drug approval based on FDA interpretation of substantial evidence standards. Finally, we will provide some suggestions to sponsors, in the context of case examples demonstrating FDAs interpretation of substantial evidence to support promotional claims.

Disease–Drug Interactions in Inflammatory States via Effects on CYP‐Mediated Drug Clearance

The human inflammatory response can result in the alteration of drug clearance through effects on drug‐metabolizing enzymes or drug transporters. In this article, clinical examples are reviewed of how diseases with moderate to severe inflammation can decrease cytochrome P450 (CYP)–mediated drug clearance and alter plasma protein binding. Also examined is how albumin, α‐1‐acid glycoprotein, drug fraction unbound in plasma, CYP content, and oral clearance can change dynamically with time in response to inflammation.

LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles

Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator‐blind, parallel‐group, multiple‐ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose‐dependent blockade of the EP4 receptor. Compared with placebo, 24‐h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trials registration number: NCT01968070.

Nonclinical pharmacology and toxicology of the first biosimilar insulin glargine drug product (BASAGLAR®/ABASAGLAR®) approved in the European Union

ABSTRACT Basaglar®/Abasaglar® (Lilly insulin glargine [LY IGlar]) is a long‐acting human insulin analogue drug product granted marketing authorisation as a biosimilar to Lantus® (Sanofi insulin glargine [SA IGlar]) by the European Medicines Agency. We assessed the similarity of LY IGlar to the reference drug product, European Union–sourced SA IGlar (EU‐SA IGlar), using nonclinical in vitro and in vivo studies. No biologically relevant differences were observed for receptor binding affinity at either the insulin or insulin‐like growth factor‐1 (IGF‐1) receptors, or in assays of functional or de novo lipogenic activity. The mitogenic potential of LY IGlar and EU‐SA IGlar was similar when tested in both insulin‐ and IGF‐1 receptor dominant cell systems. Repeated subcutaneous daily dosing of rats for 4 weeks with 0, 0.3, 1.0, or 2.0 mg/kg LY IGlar and EU‐SA IGlar produced mortalities and clinical signs consistent with severe hypoglycaemia. Glucodynamic profiles of LY IGlar and EU‐SA IGlar in satellite animals showed comparable dose‐related hypoglycaemia. Severe hypoglycaemia was associated with axonal degeneration of the sciatic nerve; the incidence and severity were low and did not differ between LY IGlar and EU‐SA IGlar. These results demonstrated no biologically relevant differences in toxicity between LY IGlar and EU‐SA IGlar. HIGHLIGHTSBasaglar®/Abasaglar® (LY IGlar) is the first biosimilar insulin glargine drug product approved in the European Union.We compared nonclinical profiles of LY IGlar and European Union–sourced Lantus (EU‐SA IGlar).We found no biologically relevant differences between LY IGlar and EU‐SA IGlar.

LY2963016 Insulin Glargine and Insulin Glargine (Lantus) Produce Comparable Pharmacokinetics and Pharmacodynamics at Two Dose Levels

LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products with identical amino acid sequences. This was a phase 1 single‐site, randomized, subject‐ and investigator‐blinded, 4‐treatment, 4‐period crossover study to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of LY IGlar and IGlar at 2 different doses. Fasted healthy subjects were randomly assigned to receive 2 single doses of LY IGlar and IGlar (0.3 and 0.6 U/kg for each product). Blood samples were collected up to 24 hours postdose to assess PK, and a euglycemic clamp lasting up to 24 hours postdose was conducted to assess PD. Twenty‐four healthy subjects aged 23 to 52 years participated in the study. The primary PK parameters (area under the concentration versus time curve from 0 to 24 hours [AUC0–24] and maximum observed drug concentration [Cmax]) and PD parameters (total amount of glucose infused during the clamp [Gtot] and maximum glucose infusion rate [Rmax]) were not statistically different between LY IGlar and IGlar at either dose. No safety concerns were noted with either drug. The study demonstrated that the PK and PD parameters for LY IGlar and IGlar were comparable following single doses at both 0.3 and 0.6 U/kg.

Drug Interaction Involving Direct or Indirect Cytokine Modulation Should Be Investigated in Select Circumstances

We concur with the response (commentary) from Pang et al that in most cases therapeutic drug-disease interactions (TP-DDIs) caused by inflammation are not of clinical concern. Indeed, recent data suggest that inflammatory disease states withmild inflammation, such asmultiple sclerosis1 and psoriasis,2 do not causemeaningful TP-DDIs involving cytochrome P450 (CYP) substrates. We also concur that once a lack of drug interaction is robustly demonstrated in a particular disease state (eg, psoriasis), there is no need to conduct additional TP-DDI studies in that disease state. There are only a few inflammatory disease states wherein drug monitoring would be advised, and then primarily when coadministering CYP-sensitive index substrates with a narrow therapeutic index. For instance, there are clinical data that suggest moderate to severe rheumatoid arthritis3,4 and Crohn disease5 can cause a 2-fold change in the clearance and exposure of CYP3A-sensitive substrates. The comment was made in the Letter to the Editor that “ . . . most of the disease-mediated TP-DDIs due to normalization/suppression of proinflammatory cytokines have shown only mild to moderate effects on drug exposures and have rarely led to dose adjustment for the victim drug.” This statement is true if considering patients with only minor systemic inflammation. Psoriasis, hepatitis C, and congestive heart failure are all diseases with negligible to mild effects on CYP-mediated clearance. The magnitude of TP-DI is related to both severity and type of inflammatory disease. Thus, an assessment of TP-DDI potential in patients with rheumatoid arthritis with mild systemic inflammation is expected to give an attenuated response compared to an assessment in patients with moderate to severe rheumatoid arthritis. The authors therefore recommend that 2 or more markers of inflammation (such as interleukin-6, C-reactive protein, albumin, α1-acid glycoprotein) be measured at the beginning and end of any inflammatory TP-DDI trial. In instances where only a mild effect onCYP-mediated clearancewas observed by a cytokine modulator, some of these TP-DDI trials either lacked an assessment of inflammatory markers or the markers Figure 1. Proposed flow scheme for evaluation of drug interactions caused by direct or indirect cytokine modulation.