Abstract
IntroductionThe aim of the analysis was to characterize the population pharmacokinetics (PKs) and exposure–response (E–R) for efficacy (fasting plasma glucose, glycated hemoglobin) and safety/tolerability [hypoglycemia, genital infections, urinary tract infection (UTI), and volume depletion] of the sodium glucose cotransporter 2 inhibitor, empagliflozin, in patients with type 2 diabetes mellitus. This study extends the findings of previous analyses which described the PK and pharmacodynamics (PD) using early clinical studies of up to 12 weeks in duration.MethodsPopulation pharmacokinetic and E–R models were developed based on two Phase I, four Phase II, and four Phase III studies.ResultsVariability in empagliflozin exposure was primarily affected by estimated glomerular filtration rate (eGFR) (less than twofold increase in exposure in patients with severe renal impairment). Consistent with its mode of action, the efficacy of empagliflozin was increased with elevated baseline plasma glucose levels and attenuated with decreasing renal function, but was still maintained to nearly half the maximal effect with eGFR as low as 30 mL/min/1.73 m2. All other investigated covariates, including sex, body mass index, race, and age did not alter the PK or efficacy of empagliflozin to a clinically relevant extent. Compared with placebo, empagliflozin administration was associated with an exposure-independent increase in the incidence of genital infections and no significant change in the risk of UTI, hypoglycemia, or volume depletion.ConclusionBased on the results from the PK and E–R analysis, no dose adjustment is required for empagliflozin in the patient population for which the drug is approved.FundingBoehringer Ingelheim.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0174-y) contains supplementary material, which is available to authorized users.
Highlights
The aim of the analysis was to characterize the population pharmacokinetics (PKs) and exposure–response (E–R) for efficacy and safety/tolerability [hypoglycemia, genital infections, urinary tract infection (UTI), and volume depletion] of the sodium glucose cotransporter 2 inhibitor, empagliflozin, in patients with type 2 diabetes mellitus
Based on the results from the PK and E–R analysis, no dose adjustment is required for empagliflozin in the patient population for which the drug is approved
The effects of the following covariates on the PK of empagliflozin were investigated: age, body mass index (BMI), sex, race, smoking status, total serum protein, and estimated glomerular filtration rate (eGFR) using the modification of diet in renal disease formula (MDRD), alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (AP), and lactate dehydrogenase (LDH)
Summary
The aim of the analysis was to characterize the population pharmacokinetics (PKs) and exposure–response (E–R) for efficacy (fasting plasma glucose, glycated hemoglobin) and safety/tolerability [hypoglycemia, genital infections, urinary tract infection (UTI), and volume depletion] of the sodium glucose cotransporter 2 inhibitor, empagliflozin, in patients with type 2 diabetes mellitus. Type 2 diabetes mellitus (T2DM) is a progressive disease, and currently available oral antidiabetic agents, initially effective, often fail to maintain long-term glycemic control or are associated with side effects, such as hypoglycemia, weight gain, and edema [1, 2]. Phase III studies of empagliflozin, administered as monotherapy or add-on to other antidiabetic therapies, have shown improvements in glycemic control, in addition to modest reductions in body weight and blood pressure. Placebo-corrected reductions in HbA1c have been demonstrated both with empagliflozin monotherapy (-0.7% for 10 mg and -0.9% for 25 mg) [13], and as add-on therapy (-0.4% to -0.7% for 10 mg and -0.5% to -0.7% for 25 mg) [14,15,16,17], in addition to reductions in FPG (monotherapy, -1.7 mM for 10 mg, and -2.0 mM for 25 mg; add-on therapy, -0.9 to -1.5 mM for 10 mg and -1.2 to -1.8 mM for 25 mg) [13,14,15,16,17]
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