Br J Clin Pharniacoll996: 42: 510-512
`
`Food intake and dosage level, but not tablet us solution
`dosage form, affect the absorption of metformin HCl in man
`
`N. C. SAMBOL,'.', L. G. BROOKES,'.* J. CHIANG,' A. M. GOODMAN,? E. T. LIN,' C. Y. LIU' & L. Z. BENET'
`'Departments of Biopharmaceutical Sciences and 'Clinical Pharmacy, University of California, San Francisco and
`tLipha Pharmaceuticals, Inc., New York, USA
`
`The pharmacokinetics of four single-dose treatments of the metformin administered
`orally (as the HCl salt) were compared in 24 healthy subjects: 500 mg and 850 mg
`tablets and 850mg solution fasting and 850mg tablet with food. Solution and
`tablet formulations are bioequivalent. Bioavailability of a 500 mg tablet is 14%
`greater than that of an 850mg tablet. Compared with the fasting state,
`bioavailability is 24% lower, and the peak concentration delayed about 37 min
`when an 850 mg tablet is administered with food.
`
`Keywords metformin pharmacokinetics food interaction dose-proportionality
`dosage form
`
`Introduction
`
`Metformin, a biguanide antihyperglycaemic agent, has
`been widely used for the treatment of diabetes for more
`than three decades [ 1, 21. Pharmacokinetic studies
`show that it is rapidly eliminated by the kidney [3- 51
`and its metabolism and plasma protein-binding are
`negligible [4, 51. Gastrointestinal absorption of metfor-
`min is slow and incomplete when administered as a
`solution or rapidly dissolving tablet [ 3-71.
`We evaluated factors that may influence the absorp-
`tion (or elimination) of metformin: dosage level, dosage
`form. and food. Because in a few patients bioavailability
`decreased with increasing dose [4, 61, we studied the
`pharmacokinetic linearity of two commonly used doses
`of metformin HCl, 500 and 850mg. We compared the
`pharmacokinetics of tablet and solution formulations of
`metformin HCl because of confounding results in an
`earlier study [7]. Metformin is recommended to be
`taken with food to decrease gastrointestinal symptoms,
`but the impact of food on extent and rate of absorption
`is unknown.
`
`Methods
`
`Study design
`
`A four-way randomized, crossover, open-label investi-
`gation was conducted in 24 consenting healthy male
`subjects, ages 21-35 years weighing within 10% of normal
`for height and frame, at the Drug Studies Unit, University
`of California San Francisco, and was approved by the
`Committee on Human Research. Each subject was
`randomized to receive one of four treatment sequences:
`ABCD, BCDA, CDAB or DABC (six subjects per
`sequence), in which A was a 500 mg tablet, B an 850 mg
`tablet, and C an 850 mg/100 ml solution, each adminis-
`tered after an overnight fast. D was an 850mg tablet
`taken 5-10 min after a high-fat high-calorie breakfast.
`Treatments were administered with 240 ml (Treatment C
`140 ml) of water and separated by at least 1 week.
`Venous blood was drawn just before drug adminis-
`tration and at 0.25, 0.50, 0.75, 1.0, 1.5, 2, 2.5, 3, 4, 6, 8,
`12, 16, 24, 36, and 48 h thereafter. Harvested plasma
`was assayed for metformin. Urine (-20ml) was
`obtained just before each treatment and during the
`following intervals relative to the dose: 0-4, 4-8, 8-12,
`12-16, 16-24, 24-36, and 36-48 h. Samples were frozen
`(- 20" C) until analysed.
`
`Drug anulysis
`
`Current address is: *Cortecs Ltd, Clwyd, UK.
`
`Metformin in plasma and urine was quantitated by
`high performance liquid chromatography [ 81, using
`
`Correspondence: Nancy C. Sambol, PharmD, Department of Biopharmaceutical Sciences, University of California, San Francisco,
`CA 94143-0446. USA.
`
`510
`
`0 1996 Blackwell Science Ltd
`
`AUROBINDO EX. 1022, 1
`
`

`

`Table 1
`Pharmacokinetic parameter estimates of metformin in 24 healthy subjects following oral administration of metformin
`HCl as a 500 mg tablet, a 850 mg tablet, and 850 mg HCI solution in the fasting state, and as a 850 mg tablet in the fed state
`
`Estimate (mean f s.e. mean)
`
`Short report 51 1
`
`Parameter
`
`500 mg tablet
`fasting
`(Treatment A )
`
`850 mg tablet
`fasting
`(Treatment B)
`
`850 mg solution
`fasting
`(Treatment C )
`
`850 mg tablet
`fed
`(Treatment 0)
`
`1.75 fO.l I t
`2.75 f 0.17
`11.47 f0.61t
`0.153 fO.011
`5.10f0.36
`1025+_48
`451 f 4 3
`385 f 12.8t
`598 f 27
`
`1.58f0.08
`2.77f0.14
`10.07 f0.56
`0.133 + 0.009
`5.76 f 0.40
`1183k63
`575 f 41
`329 f 17.6
`573 f 32
`
`1.50+_0.08
`2.49f0.14
`9.59 f 0.57
`0.147 f 0.01 1
`5.26 f0.36
`1243f64
`559 f 43
`323 14.9
`605 f 26
`
`~~
`
`0.97 k0.04
`3.38 0.27
`7.65 f0.32
`0.142 fO.009
`5.54 f 0.53
`1508f57
`712 f 63
`276 f 11.1
`633 f 33
`
`Statistically
`signijcant
`difSerence*
`
`A B B C D
`_ _ _ _ _
`D B A C
`- _ _
`A B C D
`A C D B
`B D C A
`D C B A
`- _ _ _
`D B B C A
`_ _ _ _ _
`A B C D
`D C A B
`
`*Treatments over same line do not differ significantly
`t Normalized to 850 mg.
`
`propylbiguanide as the internal standard. The limit of
`quantitation was 10 ng ml-' for plasma and 4 pg ml-'
`for urine. Coefficients of variation for interday and
`intraday were < 10% for all assays.
`
`Pharmacokinetic analysis
`
`Using standard non-compartmental methods, estimates
`of peak plasma concentration (C,,,),
`time of C,,,
`extrapolated area-under-the-curve (AUC), ter-
`(lmaX),
`minal rate constant of elimination (k), terminal half-life
`(tl,J, clearance/bioavailability
`(CLIF), volume of
`distribution/bioavailability (F&/F),
`total amount of
`drug excreted in the urine (Ae), and renal clearance
`(CLR) were obtained [9]. AUC was estimated using
`the linear trapezoidal rule when concentrations were
`ascending and the log-linear trapezoidal rule when
`descending. Subjects whose Ae was unevaluable (due to
`missing samples) were excluded from that analysis
`(three subjects/treatments), and CLR was estimated by
`dividing the sum of the Ae values for the evaluable
`intervals of collection by the sum of the AUC for the
`the 500 mg
`respective
`intervals. Calculations
`for
`that depend on dose were normalized
`treatment
`to 850mg.
`
`Results
`
`There was no significant difference (P<0.05) in any
`pharmacokinetic parameter estimate of metformin
`between Treatments B and C, and no significant
`difference among all treatments with respect to CL,, k,
`or tll, (Table 1; Figure 1). The 90% confidence intervals
`and of AUC for Treatment B:C
`of the ratio of C,,,
`were (0.99, 1.14) and (0.99, 1.12), respectively, indicating
`bioequivalence. On average, treatment A had a 14%
`larger AUC, 17% larger Ae (normalized for dose), and
`13% smaller CLiF than Treatment B. Treatment D
`
`iooa
`
`10 ooc
`-
`7 L
`-
`E
`Z'
`0 .-
`C
`c
`2
`c
`C
`Q) 0 c 8
`F?
`m ii:
`
`ioa
`
`Statistical analysis
`
`Differences in parameter estimates between treatments
`were tested using ANOVA and Ryan-Einot-Gabriel-
`Welsch Multiple F Test (a value = 0.05). Bioequivalence
`of the (850 mg) tablet formulation to solution (reference)
`was defined as estimated 90% confidence intervals of
`and of AUC that are
`the ratio (test/reference) of C,,,
`within 80 to 125%.
`
`1C
`1
`
`I
`6
`
`I
`12
`Time (h)
`
`I
`18
`
`1
`24
`
`Figure 1
`Mean metformin plasma concentration vs. time
`curves in 24 healthy subjects after oral administration of
`metformin HC1 as a 500 mg tablet (-),
`an 850 mg tablet (. . .)
`and 850 mg solution (---)
`in the fasting state, and as an
`850 mg tablet (-)
`in the fed state. Error bars have been
`omitted for clarity.
`
`0 1996 Blackwell Science Ltd Britisla Journal of Clinicat Pharmacology 42, 510-512
`
`AUROBINDO EX. 1022, 2
`
`

`

`512 Short report
`
`had, on average, a 37min later tmax, 39% lower C,,,,
`24% lower AUC, 27% larger CLIF, and 16% lower Ae
`than Treatment B. Over 95% of elimination of absorbed
`drug occurred within the first 24h. Mean urinary
`excretion of unchanged drug during the first 24 h ranged
`from 41.5% (Treatment D) to 57.3% (Treatment A) of
`the dose. Only minor adverse reactions (i.e. headaches.
`diarrhoea. nausea, and anorexia) occurred.
`
`Discussion
`
`Because metformin is eliminated almost exclusively by
`the kidney (i.2. CL, is 390% of C L ) [3-51, the ratio
`of Ae/Dose (range 42-58%) is an estimate of absolute
`bioavailability and its values are consistent with previous
`reports [ 3-61.
`The smaller C L ‘F with 500 mg compared with 850 mg
`was probably due to a higher F because CL, did not
`differ significantly and Ae (normalized for dose) was
`significantly greater. Incomplete absorption of metfor-
`min and its dose-disproportionality [4. 61 may be
`related to physicochemical properties that limit its
`permeability [ 7 ] , increasingly so as it moves down the
`small intestine [ 101 (it is largely ionized in the gut and
`is nonlipophilic). Less likely, a saturable
`transport
`process may exist 161.
`Contrary to the findings of Pentikainen [ 71, in which
`AUC (but not other measurements) was greater with
`the solution than with the tablet, we found that these
`formulations of metformin HCl are bioequivalent. This
`finding is expected because the tablet is completely
`dissolved within 1 h [ 7 ] .
`Metformin HCl is recommended to be taken with
`meals because gastrointestinal side-effects occur in about
`30% of patients [2, 111. We showed that concurrent
`food intake decreases the rate and extent of metformin
`HCI tablet absorption. We cannot determine whether
`food decreases the dissolution of the tablet or some
`other aspect of the absorption process because food
`was not given with the solution. The clinical benefit
`of administering metformin with food
`to decrease
`
`gastrointestinal symptoms must be weighed against the
`potential disadvantage that it may decrease the systemic
`exposure to the drug (by about 24% in the average
`person). Because dosages are titrated to effect, the
`benefit seems to outweigh the potential disadvantage in
`the average person.
`
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`(Received 21 August 1995,
`accepted 28 March 1996)
`
`C 1906 Blackwell Scicnce Ltd British Journal of Clinical P h ~ r ~ i a c ~ l o g y
`42, 510-512
`
`AUROBINDO EX. 1022, 3
`
`