The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin - PubMed (original) (raw)

Clinical Trial

doi: 10.1007/s40262-015-0346-3.

Arik A Zur 1, Richard A Castro 1, Matthias B Wittwer 1, Ron J Keizer 1, Sook Wah Yee 1, Srijib Goswami 1, Sophie L Stocker 1, Xuexiang Zhang 3, Yong Huang 3, Claire M Brett 4, Radojka M Savic 1, Kathleen M Giacomini 5

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Clinical Trial

The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin

Jennifer E Hibma et al. Clin Pharmacokinet. 2016 Jun.

Abstract

Introduction: Pharmacokinetic outcomes of transporter-mediated drug-drug interactions (TMDDIs) are increasingly being evaluated clinically. The goal of our study was to determine the effects of selective inhibition of multidrug and toxin extrusion protein 1 (MATE1), using famotidine, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers.

Methods: Volunteers received metformin alone or with famotidine in a crossover design. As a positive control, the longitudinal effects of famotidine on the plasma levels of creatinine (an endogenous substrate of MATE1) were quantified in parallel. Famotidine unbound concentrations in plasma reached 1 µM, thus exceeding the in vitro concentrations that inhibit MATE1 [concentration of drug producing 50 % inhibition (IC50) 0.25 µM]. Based on current regulatory guidance, these concentrations are expected to inhibit MATE1 clinically [i.e. maximum unbound plasma drug concentration (C max,u)/IC50 >0.1].

Results: Consistent with MATE1 inhibition, famotidine administration significantly altered creatinine plasma and urine levels in opposing directions (p < 0.005). Interestingly, famotidine increased the estimated bioavailability of metformin [cumulative amount of unchanged drug excreted in urine from time zero to infinity (A e∞)/dose; p < 0.005] without affecting its systemic exposure [area under the plasma concentration-time curve (AUC) or maximum concentration in plasma (C max)] as a result of a counteracting increase in metformin renal clearance. Moreover, metformin-famotidine co-therapy caused a transient effect on oral glucose tolerance tests [area under the glucose plasma concentration-time curve between time zero and 0.5 h (AUCglu,0.5); p < 0.005].

Conclusions: These results suggest that famotidine may improve the bioavailability and enhance the renal clearance of metformin.

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Conflict of interest statement

Conflict of interest

KMG, SWY, XZ, YH have declared the following conflicts of interest that might be relevant to the content of this manuscript: KMG and SWY are co-founders of Apricity Therapeutics, which develops drugs that exploit membrane transporters to enhance their pharmacologic action. KMG receives funds from several pharmaceutical companies (AstraZeneca, Pfizer, Sanofi Aventis and GlaxoSmithKline) for research in her laboratory. XZ and YH are employees of Optivia Biotechnology Inc., a transporter CRO company.

JEH, AAZ, RAC, MBW, RJK, SG, SLS, CMB and RMS, have no conflicts of interest that might be relevant to the content of this manuscript.

Figures

Fig. 1

Fig. 1

a) Volunteers in Arm 1 received metformin alone (1,850 mg in two divided doses), followed by a 7-day washout, then metformin + famotidine (1,850 mg in two-divided doses and 1,000 mg in six divided doses, respectively) during two separate study treatment visits. Volunteers in Arm 2 received the same treatments but in reverse order, i.e., metformin + famotidine, washout, then metformin alone. b) During each 48h treatment visit, Oral Glucose Tolerance Tests (OGTTs) were performed after a 10h overnight fasts on Day 1 and on Day 2. Black bars indicate time of drug administration

Fig. 2

Fig. 2

The effect of famotidine on metformin pharmacokinetics in healthy volunteers (_n_=12). a) The mean metformin plasma concentration-time curves from 0–24h following metformin dosing (1,850 mg in total) alone (closed circles) and during co-administration with famotidine (1,000 mg over 48h) in healthy volunteers (_n_=12). The asterisks indicate significant differences, P < 0.01. b) Cumulative urinary excretion of metformin after two doses of metformin (1,850 mg in total) alone (solid circles) or during co-therapy with famotidine (open circles). Values are expressed as mean ± SEM. c) Estimated metformin bioavailability [Ae∞/Dose]. d) Metformin renal clearance (CLR) for 36h, computed using NONMEM, during metformin treatment alone (square) and during co-administration with famotidine (triangle).

Fig. 3

Fig. 3

The difference in area under the glucose concentration-time curve from 0–0.5h (AUCglu,0.5) a) before (A, triangles) and after metformin (B, solid circles) and b) after metformin (B, solid circles) compared to after metformin plus famotidine (C, open circles)

Fig. 4

Fig. 4

The effect of famotidine on plasma creatinine concentrations in healthy volunteers (_n_=12). Creatinine plasma concentrations at 0, 12 and 36h post the first dose (200 mg) of famotidine (checked bars) and at the same times during metformin alone (solid bars). Dashed lines indicate comparisons within the same study visit, solid lines indicate comparisons between study visits with *P < 0.05 and ** P <0.01. Data represent mean ± SEM

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