Question

Lowagliflozin is a medicine that will be used as a treatment for type 2 diabetes mellitus, what acute adverse effects would you be most worried about? What can be done in phase 1 to prevent the risk of this/these adverse effect(s)? How can this be controlled for in the initial phase 1 trial in regards to the mechanism(s) of action for lowagliflozin? What measurements would you advise the clinical personnel to be particularly concerned about? What would your study design look like for the very first trial in regards to dosing and monitoring of patients (hint: what is a very good and reliable marker for anti-diabetic effect)?

Answer 1

Lowagliflozin is in a class of medications called sodium-glucose co-transporter 2 (SGLT2) inhibitors. It lowers blood sugar by causing the kidneys to get rid of more glucose in the urine.

Adverse effects

This leads to heavy glycosuria (sometimes up to about 70 grams per day) it can lead to rapid weight loss and tiredness.The glucose acts as an osmotic diuretic (this effect is the cause of polyuria in diabetes) which can lead to dehydration. The increased amount of glucose in the urine can also worsen the infections already associated with diabetes, particularly urinary tract infections and thrush (candidiasis). Rarely, use of a SGLT2 drug, including Lowagliflozin , is associated with necrotizing fasciitis of the perineum, also called Fournier gangrene.

It is also associated with hypotensive reactions. There are concerns it may increase the risk of diabetic ketoacidosis.

Lowagliflozin can cause dehydration, serious urinary tract infections and genital yeast infections.Elderly people, people with kidney problems, those with low blood pressure, and people on diuretics should be assessed for their volume status and kidney function. People with signs and symptoms of metabolic acidosis or ketoacidosis (acid buildup in the blood) should also be assessed.It can cause serious cases of necrotizing fasciitis of the perineum (Fournier’s Gangrene) in people with diabetes and low blood sugar when combined with insulin.

Mechanism of action

iIt inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine. In clinical trials, it lowered HbA1c by 0.6 versus placebo percentage points when added to metformin.

Regarding its protective effects in heart failure, this is attributed primarily to haemodynamic effects, where SGLT2 inhibitors potently reduce intravascular volume through osmotic diuresis and natriuresis. This consequently may lead to a reduction in preload and afterload, thereby alleviating cardiac workload and improving left ventricular function.

Dosage Modifications

Renal impairment

• Use for glycemic control in T2DM

  • eGFR ≥45mL/min/1.73 m2: No dosage adjustment required
  • eGFR 30 to <45 mL/min/1.73 m2: Not recommended
  • eGFR <30 mL/min/1.73 m2: Contraindicated

• Reduce risk of hHF in T2DM with CVD

  • eGFR ≥45mL/min/1.73 m2: No dosage adjustment required
  • eGFR <45 mL/min/1.73 m2: Insufficient data to support a dosing recommendation
  • ESRD/dialysis: Contraindicated

• Reduce risk of CV death and hHF with or without T2DM

  • eGFR ≥30mL/min/1.73 m2: No dosage adjustment required
  • eGFR <30 mL/min/1.73 m2: Insufficient data to support a dosing recommendation
  • ESRD/dialysis: Contraindicated

Hepatic impairment

• Mild or moderate: No dosage adjustment required
• Severe: Not studied

Dosing Considerations

Limitation of use: Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis

Before initiation

• Assess renal function and periodically thereafter
• Correct volume depletion.
• study design
• Food effect

  Food effect studies are conducted to allow a preliminary assessment of how absorption of the compound is affected when administered after a specifically designed and standardized test meal, usually a high fat breakfast in the first instance. Such studies are usually conducted following a crossover design such that the same subjects receive doses of the study drug on different occasions under fasted and fed conditions. In such studies, each subject acts as his or her own control such that the impact of intersubject variability is reduced. These studies are important as the results are likely to contribute to the wording on the label as to when drugs should be administered relative to food in order to increase, or indeed decrease, exposure.

  Drug-drug interaction

  These studies form an extension of the in vitro and in vivo preclinical studies in which the routes of metabolism are identified. Correlation of the results allows the identification of enzymes which may be subject to inhibition or induction by the test drug or which are responsible for its metabolism. Clearly, the selection of drugs for drug-drug interaction studies is based upon those for which co administration is likely for the particular indication and target population of the compound. A common study design involves co administration of a compound with a strong inhibitor (e.g., ketoconazole) or a strong inducer (e.g., rifampicin) of the metabolizing enzyme cytochrome P450 3A4. The route of administration should be based upon that planned for the marketed compound, assuming this is known, and studies should use the highest proposed or approved doses of the test drugs and the shortest dosing intervals to maximize the likelihood of an interaction, unless this is precluded for safety reasons. There should be a particular emphasis on monitoring for adverse events (AEs) that occur at a greater frequency or severity during combination treatment than during treatment with either drug alone. In addition, there should be extensive PK sampling to allow for full characterization of the parent drug and important metabolites, if applicable, and any potential temporal relationship to AEs.

  Bioavailability and bioequivalence

  Studies to measure bioavailability and/or establish bioequivalence of a compound are important elements in support of regulatory submissions. For orally administered compounds, bioavailability studies elucidate the process by which a drug is released from the oral dosage form and moves to the site of action within the body. Bioavailability data provide an estimate of the fraction of drug absorbed, as well as its subsequent distribution and elimination. This can either be absolute bioavailability (the compound is compared to intravenous administration, which is assumed to be 100% bioavailable) or relative bioavailability (the compound is compared to another formulation or non-intravenous route of administration).

  In bioequivalence studies, the systemic exposure profile of a test compound is compared to that of a reference drug product. To be considered bioequivalent (or statistically ‘non-different’), the active drug ingredient or active moiety in the test compound must exhibit a rate and extent of absorption that is comparable to the reference drug product, according to strict statistical rules. Two treatments are considered to be not different to one another if the 90% confidence interval (CI) for the ratio of the log transformed exposure measure falls completely within the range 80% 125%. If the 90% CI falls outside the 80% 125% range, the 2 treatments are concluded to be different from one another.

• Bioequivalence studies are performed if there is a change in dose form, structure, manufacturing process, or excipients to ensure the ‘new’ form is equivalent to the previous version. Bioequivalence studies are also performed when generic drugs are developed which contain the same active ingredients as the original formulation, which is no longer under patent protection. Bioavailability and bioequivalence studies are routinely conducted in a small number of subjects in Phase 1 CRUs and reported according to strict regulations.