Petitioner Amerigen Pharmaceuticals Ltd.
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 1
`
`

`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 2
`Petitioner Amerigen Pharmaceuticals Ltd.
`
`

`
`Petitioner Amerigen Pharmaceuticals Ltd.
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 3
`
`

`
`62 Goldberg et al.
`
`CLINICAL PHARMACOLOGY 8: THERAPEUTICS
`IANUARY 1997
`
`to baseline angiotensin II response). This method
`results in a greater numerical area when there is no
`inhibition (i.e., ratio approaches 1) compared to
`inhibition (ratio less than 1). Time to maximum
`inhibition was also determined, defined as the aver-
`age of the two time points used to calculate the
`moving average defining the maximum effect. Geo-
`metric means were calculated for ratios of maximum
`and 24-hour inhibition.
`Treatment elfects were tested with an ANOVA
`
`model”; data from all three periods were included.
`Ninety-five percent confidence intervals were calcu-
`lated for the mean of each treatment group with the
`mean square error from the ANOVA model on the
`basis of the logs of ratios (when calculated), then
`exponentiated. Pairwise differences between treat-
`ments were assessed with the 95% confidence inter-
`vals on the difference in treatment mean values.
`
`These intervals also used the mean square error
`from the ANOVA model.
`
`A result was determined to be “statistically signif-
`icant” when the statistical test yielded a two-tailed
`probability of 0.05 or less. Statistical analyses were
`restricted to the PRA data from the first study and
`angiotensin II antagonism data from part B of the
`second study.
`
`RESULTS
`
`Subject characteristics and clinical results
`
`A total of 35 subjects (age range, 22 to 45 years)
`were evaluated in both studies. The study treat-
`ments were generally well tolerated. Adverse events
`were mild and self-limited, although one subject was
`discontinued from the first study for a migraine
`headache during placebo, another was discontinued
`for orthostatic hypotension considered to be unre-
`lated to DuP 532 (0.1 mg), and a third was discon-
`tinued for faintness after the 100 mg dose of DuP
`532. No subjects in the second study discontinued
`dosing because of adverse events.
`Fig. 2 summarizes supine blood pressure and
`heart rate changes after the 100 and 200 mg doses of
`DuP 532 in the tolerability study. Clinically apparent
`mean changes in supine and standing blood pressure
`and heart rate were not identified in the healthy
`subjects in this study.
`
`Plasma drug concentrations
`
`Study 1. In the first study, total plasma concen-
`trations of DuP 532 were measured at defined
`
`intervals after closing on most study days. Fig. 3
`shows the concentrations of DuP 532 for two
`
`periods in two representative subjects who had
`received 50 mg DuP 532 1 week before these
`measurements (i.e., period 3): 200 mg at 0 hours
`and placebo 1 week later. Measurable levels of
`DuP 532 were present before dosing on both sam-
`pling days. The drug appeared to be absorbed
`slowly because maximum measured concentra-
`tions were achieved at 6 and 30 hours after the 200
`
`mg dose in the two subjects. Plasma levels of DuP
`532 could be detected throughout the sampling
`period 1 week after administration of the 200 mg
`dose, after administration of placebo on that day.
`These data show an extremely long half-life for
`DuP 532 in humans after a single dose.
`Study 2. In the second study, respective plasma
`concentrations of losartan, its active metabolite
`(EXP3174), and DuP 532 were measured before
`and 2, 4, 8, and 24 hours after the 100 mg dose of
`losartan and the 200 mg dose of DuP 532. Fig. 4
`shows the mean plasma concentrations achieved
`in this study. Plasma concentration profiles of
`DuP 532 were clearly different from losartan, with
`much higher drug concentrations and a very long
`half-life (half-life of losartan averages 1
`to 2
`hours; half-life of EXP3174 averages 6 to 9
`hours).18
`
`In vitro protein binding and blood/plasma
`ratio studies
`
`The binding of DuP 532 in vitro to plasma,
`purified albumin, and GL1-2lCl(l glycoprotein (oro-
`somucoid) was measured by ultrafiltration with
`“C-DuP 532. DuP 532 was extensively bound in
`the plasma of all species examined, with 0.06% i
`0.02%, 0.21% : 0.01%, 0.56% i 0.05%, and
`0.17% : 0.09% free (unbound, mean : SD, n =
`4 samples analyzed in triplicate) at 1.0 ug/ml in
`human, rhesus monkey, beagle dog, and Sprague
`Dawley rat plasma, respectively. Binding was sig-
`nificantly greater in human plasma than in plasma
`from dogs and rhesus monkeys (p < 0.001) and
`nearly significantly greater in human compared
`with rat plasma (p = 0.066). This extreme degree
`of plasma binding (i.e., >99.4%) results primarily
`from binding to albumin because physiologic con-
`centrations (4.5 gm/dl) of rat and human albumin
`bind 99.82% (O.18% : 0.01% free) and 99.62%
`(0.38% : 0.08% free) of added DuP 532, respec-
`tively. Binding to orosomucoid was insignificant,
`with 73.18% : 1.51% and 80.99% : 1.36% free at
`
`physiologic concentrations (1 mg/ml). The blood/
`plasma distribution ratio, assessed with fresh dog
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 4
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1030 — Page 4
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`

`
`CLINICAL PHARMACOLOGY Sc THERAPEUTICS
`VOLUME 61,NUMBER1
`
`Goldberg Bl‘ fll. 63
`
`Supine Systolic Blood Pressure
`
`10
`
` -0- Placebo
`
`
`
`-I-100 mg DuP 532
`
`-H-200 mg DuP 532
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`Time after Dosing(Hours)
`
`Supine Diastolic Blood Pressure
`
`0
`
`2
`
`4
`
`6
`
`3
`
`1o
`
`12
`
`Time after Dosing(Hours)
`
`Supine Heart Rate
`
`inSuDBP(mmHg)
`Change
`
`_A D
`
`01
`
`
`Change
`
`in SuHFl(bpm)
`
`
`
`
`
`ChangeinSuSBP(mmHg)
`
`o
`
`2
`
`4
`
`6
`
`8
`
`1o
`
`12
`
`Time after Dosing(Hours)
`
`Fig. 2. Mean changes from predose Values in supine systolic blood pressure (top panel),
`diastolic blood pressure (middle panel), and heart rate (bottom panel) in healthy male subjects
`given 100 mg DuP 532 (n = 9), 200 mg DuP 532 (n = 10), and placebo (11 = 19).
`
`and rat blood, was low, ranging from 0.44 i 0.01
`to 0.49 : 0.03 for the rat and 0.56 i 0.02 to 0.61 :
`0.03 for the dog at DuP 532 concentrations of
`0.050 to 2.500 p.g/ml.
`
`Re-°>P0nS°5 to 3“gi°t°“5i11 11 i“f“5i0“S
`Responses to bolus infusions of angiotensin II
`in the crossover phase (part B) of study 2 are
`summarized in Fig. 5, which shows the mean sys-
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 5
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1030 — Page 5
`
`

`
`64 Golalberg at al.
`
`CLINICAL PHARMACOLOGY 8: THERAPEUTICS
`IANUARY 1997
`
`10000
`
`1000
`
`100
`
`0
`
`50
`
`1 00
`
`1 50
`
`200
`
`Time after Dosing (Hours)
`
`EU?
`
`5C
`
`.2
`
`E '
`
`5',
`
`UCOoNC
`
`9I-D
`D.
`
`3D
`
`Fig. 3. Plasma concentrations of DuP 532 during periods 4 (200 mg at hour 0) and 5
`(placebo at hour 168) in two subjects from the tolerability study who received 50 mg DuP
`532 in period 3.
`
`tolic and diastolic blood pressure and heart rate
`responses to angiotensin II at each time point.
`Table I summarizes the statistical analysis of these
`data,
`including 95% confidence intervals about
`treatment effect parameters. Angiotensin 11 doses
`that produced approximately 25 mm Hg increases
`in systolic blood pressure averaged 30 ng/kg; four
`subjects received this dose and one each received
`20 and 40 ng/kg. The average blood pressure in-
`crease in response to angiotensin II after placebo
`was about 28/25 mm Hg, with a 14 beats/min
`decrease in heart rate. The smallest mean pressor
`response to angiotensin II—15/13 mm Hg, -8.3
`beats/min——occurred 8 to 9 hours after 200 mg
`DuP 532, Whereas the smallest mean response to
`angiotensin II—5.5/4.3 mm Hg, -6.7 beats/min-—
`occurred 4 to 6 hours 100 mg after losartan. As
`seen in Fig. 5, apparent inhibition produced by
`losartan and DuP 532 was similar 24 hours after
`
`dosing.
`Responses to the angiotensin II challenges were
`analyzed statistically by comparison of four param-
`eters derived from the individual time courses of
`
`responses to angiotensin II: maximum and 24-hour
`elfects (as ratios), area about the response curve
`(with a greater area indicating less inhibition), and
`
`time to maximum eifect. Results of the statistical
`
`analysis of these parameters are summarized in Ta-
`ble I. Both losartan and DuP 532 significantly inhib-
`ited responses to angiotensin II (Fig. 5); however,
`the time course and extent of inhibition differed
`
`significantly between the two antagonists. The level
`of inhibition was greater for losartan than for DuP
`532, as shown by the analysis of both maximum
`(86% versus 48%) level of inhibition and integrated
`eifects (9.2 versus 15.1 mm Hg-hr). Further, the
`mean time of maximal inhibition was delayed about
`4 hours for DuP 532 relative to losartan (4.6 versus
`8.7 hours for inhibition of diastolic responses, p <
`0.05). Interestingly, the 24-hour effect was similar
`for the two treatments.
`
`PRA and angiotensin II concentrations
`
`Study 1. In the tolerability study, PRA was mea-
`sured frequently after dosing with placebo and DuP
`532 doses of 25 to 200 mg. However, in View of the
`plasma concentration data cited earlier, potential
`effects of the previous dose of DuP 532 on PRA
`must be considered. Nonetheless, PRA appeared to
`increase relative to placebo after the 200 mg dose of
`DuP 532. The diiference between 200 mg DuP 532
`and placebo was most apparent from 6 to 24 hours
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 6
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1030 — Page 6
`
`

`
`CLINICAL PHARMACOLOGY Sc THERAPEUTICS
`VOLUME 61, NUMBERI
`
`Goldberg et al.
`
`65
`
`1 0000
`
`1 000
`
`/
`
`
`
`Concentration(nglml)
`
`100
`
`8
`
`—I— Losartan
`
`—EI— E-31 74
`
`-0- Dup 532
`
`
`
`0
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time after Dosing(Hours)
`
`Fig. 4. Mean plasma concentrations of DuP 532, losartan, and EXP3l74 after administration
`of 200 mg DuP 532 in period 3 and 100 mg losartan in period 1 or 2 of the antagonism study
`(11 = 6).
`
`after the dose. These data were analyzed statistically
`by calculating an area under the PRA versus time
`curve (ng angiotensin I
`[AI]/ml/hr ~ hr). Respec-
`tively, geometric mean areas were 61.7 (95% CI,
`50.0, 76.1) and 42.2 (95% CI, 34.2, 52.2) for 200 mg
`DuP 532 and placebo (p < 0.01).
`Study 2. Analysis of PRA and angiotensin II
`changes in the antagonism study was confounded by
`the presence of carryover effects (not shown) so
`that, with the small sample size, a formal statistical
`analysis of these data could not be done. However,
`8 hours after dosing, losartan (100 mg) administra-
`tion resulted in mean : SD increases in angiotensin
`II from 2.5 : 1.9 to 10.8 i 4.3 fmol/ml. After 200 mg
`DuP 532, there was a mean increase from 2.8 : 1.7
`to 7.4 i 6.8 fmol/ml. Corresponding changes in
`PRA were from 0.5 : 0.2 to 5.5 : 3.7 ng AI/ml/hr
`for 100 mg losartan and 0.5 i 0.2 to 2.0 : 2.2 ng
`AI/ml/hr for 200 mg DuP 532.
`
`DISCUSSION
`
`DuP 532 is a nonpeptide AT1-selective angioten-
`sin II receptor antagonists” considered for study for
`its antihypertensive efficacy. The studies summa-
`rized in this article examined the clinical tolerability
`of DuP 532 in healthy male subjects and compared
`
`DuP 532 to the prototypical AT,-antagonist losartan
`with respect to the extent and duration of blockade
`of responses to exogenous angiotensin II. DuP 532
`(1 to 200 mg) and 100 mg losartan treatments were
`well tolerated. Single doses of DuP 532 did not alter
`blood pressure or heart rate in healthy male volun-
`teers maintained on a sodium replete diet. Changes
`in PRA and plasma angiotensin II concentrations
`were also measured to provide complementary bio-
`chemical data on receptor blockade of the feedback
`loop controlling renin release.1’4’5 DuP 532 diifers
`from losartan in that no active metabolite is formed
`
`to
`similar
`acid,
`carboxylic
`a
`is
`it
`because
`EXP3174.6'8 On the basis of preclinical data,“ we
`anticipated that DuP 532 would be similar in phar-
`macodynamic profile to losartan in humans. How-
`ever, as the results of these studies indicate, phar-
`macodynamic effects of single doses of DuP 532
`dilfered considerably from those of losartan.
`Preclinical studies of DuP 532 showed the com-
`
`pound to be of similar or greater potency to losartan
`in a variety of in vitro and in vivo models of angio-
`tensin II antagonism.“ Notable diiferences between
`the compounds were relative shifts in potency in the
`presence of bovine serum albumin and extent of
`binding in human plasma. In the absence of albu-
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 7
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1030 — Page 7
`
`

`
`66
`
`G0lfllbl37’y 31' (11.
`
`CLINICAL PHARMACOLOGY 8: THERAPEUTICS
`JANUARY 1997
`
`Systolic Blood Pressure
`
`35
`30
`25
`20
`15
`1 0
`
`35
`30
`25
`20
`1 5
`1 0
`
`ChangeInSuSBP(mmHg)
`
`inSuSBP(mmHg)
`Change
`
`ChangeInSuSBP(mmHg)
`
`0
`
`5
`
`1o
`
`15
`
`20
`
`Time after Dosing(Hours)
`
`Diastolic Blood Pressure
`
`0
`
`5
`
`1o
`
`15
`
`20
`
`Time after Dosing(Hours)
`
`Heart Rate
`
`0
`
`5
`
`1o
`
`15
`
`20
`
`Time after Dosing(Hours)
`
`Fig. 5. Mean systolic blood pressure (top panel), diastolic blood pressure (middle panel), and
`heart rate (bottom panel) responses to bolus injections of angiotensin II (20 to 40 ng/kg) before
`and after placebo (open squares), 100 mg losartan (solid circles), and 200 mg DuP 532 (open circles)
`in the antagonism study (11 = 6). For statistical analysis of these data, see Table 1.
`
`min, respective IC50 values for inhibition of angio-
`tensin II binding to rat adrenal cortical microsomes
`for losartan, EXP3174 (active carboxylic acid me—
`tabolite of losartan), and DuP 532 were 5.5, 1.3, and
`3.1 nmo]/L.7. In the presence of 0.25% bovine serum
`
`albumin, respective IC50 values were 13, 11, and
`4700 nmol/L, showing a much more dramatic eifect
`of binding on DuP 532 compared with losartan and
`EXP3174 and suggesting a mechanism for reduced
`potency in vivo. Similar (or greater) shifts in in Vitro
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 8
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1030 — Page 8
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`

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`CLINICAL PHARMACOLOGY 8: THERAPEUTICS
`VOLUME 61, NUMBER 1
`
`Goldberg et al.
`
`67
`
`Table 1. Statistical analysis of responses to angiotensin II (n = 6)
`Treatment
`
`Placebo
`
`Losartan, 100 mg
`
`DuP 532, 200 mg
`
`Systolic blood pressure response to angiotensin II
`Ratio (maximum effect)
`Ratio (24 hr)
`AUC (ratio - hr)
`
`Diastolic blood pressure response to angiotensin II
`Ratio (maximum effect)
`Ratio (24 hr)
`AUC (ratio - hr)
`1...... (hr)
`
`Heart rate response to angiotensin II
`Ratio (maximum effect)
`Ratio (24 hr)
`AUC (ratio - hr)
`
`0.77 (0.57, 1.05)*
`0.92 (0.79, 1.09)
`22.6 (19.4, 25.9)
`6.5 (3.6, 9.3)
`
`0.17 (0.12, 0.23)i
`0.74 (0.64, 0.88)
`12.5 (9.2, 15.7)i
`4.0 (1.2, 6.9)
`
`0.54 (0.40, 0.73):
`0.69 (0.59, 0.81)i'
`17.1 (13.8, 20.3)r1
`7.4 (4.5, 10.3)
`
`0.74 (0.62, 0.88)
`0.90 (0.80, 1.01)
`21.7 (20.5, 22.9)
`6.6 (4.7, 8.6)
`
`0.14 (0.12, 0.16)~i~
`0.61 (0.54, 0.68)i
`9.2 (7.9, 10.4)i
`4.6 (2.7, 6.6)
`
`0.52 (0.44, 0.62)i:
`0.55 (0.49, O.62)i'
`15.1 (13.9, 16.3)H:
`8.7 (6.7, 10.6):
`
`0.69 (0.52, 0.92)
`1.00 (0.71, 1.41)
`25.2 (22.1, 28.3)
`3.5 (0.9, 6.1)
`
`0.21 (0.16, 0.27)i
`0.86 (0.61, 1.21)
`14.1 (11.0, 17.3)i
`5.0 (2.4, 7.6)
`
`0.59 (0.44, 0.78):
`0.61 (0.43, 0.87)
`18.6 (15.5, 21.8)i'3:
`7.6 (5.0, 10.2)i
`
`AUC, Area under the inhibition versus time curve; tmax, time to maximum inhibition.
`*Values shovim are means (geometric for ratios) and 95% confidence intervals.
`Tsignificantly diiferent from placebo, p < 0.05.
`icsignificantiy diiferent DuP 532 versus losartan, p < 0.05.
`
`potency induced by human serum albumin were
`observed in functional models.7 However,
`in rats
`and dogs, the in vivo potency of DuP 532 was com-
`parable to losartan, with doses of 1 to 3 mg/kg
`showing activity in hypertension models and as an
`angiotensin II antagonist.6 In addition, DuP 532
`does not appear to be metabolized by rat or human
`microsomes in vitro.8
`
`Plasma binding of DuP 532 in vitro was greater in
`human plasma compared with other species. The
`free fraction was lower in human plasma (0.06%)
`than in plasma from dogs (0.56%), rats (0.17%), or
`rhesus monkeys (0.21%). Although the levels of
`bound radioactivity detected in the binding studies
`were always greater than twice the background, the
`possibility that the true extent of binding is under-
`estimated cannot be ruled out. Thus although DuP
`532 and losartan have similar pharmacodynamic
`profiles in animals,
`the eifects of the extensive
`plasma binding for DuP 532 on the pharmacody—
`namics in humans may be greater, consistent with
`the greater eiiect of albumin on the in vitro binding
`and antagonism of DuP 532.7
`At the doses studied and plasma concentrations
`achieved, DuP 532 appeared to be a relatively weak
`angiotensin II antagonist in humans. The onset of
`eifect of DuP 532 was clearly slower than that of
`losartan. The 100 mg dose of losartan rapidly and
`significantly inhibited the pressor response to angio-
`tensin II in comparison to placebo. Inhibition was
`
`observed by 1 hour after administration, with mean
`maximum inhibition observed at 4 to 5 hours. Mean
`
`maximal inhibition by 100 mg losartan (moving av-
`erage) was 83%, with levels of inhibition 24 hours
`after dosing of 26% for systolic and 39% for dia-
`stolic blood pressure responses. These results are
`comparable to those reported earlier that emphasize
`the important contribution of EXP3174 to the ac-
`tivity of losartan? DuP 532 was also an active an-
`giotensin II antagonist in this study. As a single
`dose, its onset of action and peak eifects were ob-
`served later (2 to 3 hours and 8 to 9 hours, respec-
`tively). Maximum blockade was less than that of
`losartan, about 50% inhibition (compared to 80% to
`90%). However, at 24 hours, effects of the two an-
`tagonists were similar. Because multiple doses of
`DuP 532 were not studied, it is unclear whether the
`two antagonists would differ as much in their activ-
`ities in this model at steady state compared with
`single doses.
`Elfects of DuP 532 and losartan on PRA and
`
`plasma angiotensin 11 concentration also diifered.
`Both seem to have been increased by DuP 532, with
`less robust effects than those observed with losartan
`
`here and in previous studies.1’2’4 Time courses and
`levels of stimulation of PRA by the two antagonists
`paralleled the antagonism results for DUP 532, with
`smaller eifects appearing later that persisted for a
`longer duration.
`These results are consistent with a lower-than-
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 9
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1030 — Page 9
`
`

`
`68 Goldberg et al.
`
`predicted level of receptor occupancy by DuP 532 or
`with functional dilferences in the human AT1—
`receptor compared to other species. Although the
`bioavailability of DuP 532 may be low (e.g., less than
`10% in animalss), the doses used in the clinical study
`produced maximum plasma concentrations (free)
`that exceeded the IC50 for receptor binding, assum-
`ing a free drug concentration of 0.06%. These con-
`centrations will be expected to result in greater lev-
`els of blockade than we observed. If the degree of
`plasma binding in humans is underestimated, the
`actual free plasma concentrations may be less; how-
`ever, even a fivefold to tenfold underestimation
`would still be expected to produce greater antago-
`nism than was observed. In rats, DuP 532 produces
`plasma concentrations that eifectively block exoge-
`nous AT1-responsesfi and that are equal to or exceed
`the IC50 determined in vitro when expressed on a
`free or unbound basis. Further, it has been shown
`that in dogs the degree of AT1-blockade in vivo, as
`determined by the blockade of exogenous vasopres—
`sor responses, also correlates very well with the free
`fraction of losartan available for receptor occupan-
`cy.” A similar relationship has been shown between
`free drug concentrations and AT1-receptor block-
`ade produced in rats by EXP3174, the carboxylic
`acid metabolite of losartan, which is also extensively
`bound to plasma proteins.” In contrast, Beauchamp
`et al.” have demonstrated that in rats, for a series of
`AT—antagonists including DuP 532, the ED50 for
`antagonism of responses to a single dose of angio-
`tensin II in vivo was not correlated with the receptor
`aflinity in vitro in the presence of human serum
`albumen; however, pharmacokinetic variables could
`not be excluded as confounding factors. Thus in
`animals a clear relationship exists between the free
`fraction in plasma and the degree of vascular recep-
`tor occupancy and eifective antagonism. Whether a
`similar relationship holds in humans or whether
`other mechanisms are responsible for the unexpect-
`edly poor antagonism by DuP 532 plasma concen-
`trations in humans is unknown and would require
`further biochemical studies with the human AT1—
`receptor, as well as pharmacodynamic studies in
`humans.
`
`References
`
`1. Christen Y, Waeber B, Nussberger J, Porchet M, Bor-
`land N, Lee R, et al. Oral administration of DuP 753, a
`specific angiotensin II receptor antagonist, to nonnal
`male volunteers. Circulation 1991;83:1333-42.
`2. Munafo A, Christen Y, Nussberger J, Shum L, Bor-
`
`CLINICAL PHARMACOLOGY 8: THERAPEUTICS
`JANUARY 1997
`
`land M, Lee R, et al. Drug concentration-response
`relationship in normal volunteers after oral adminis-
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`onist. Clin Pharmacol Ther 1992;51:513-21.
`. Smith RD, Chiu AT, Wong PC, Herblin WF, Tim-
`mermans P. Pharmacology of nonpeptide angiotensin
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`1992;32:135-65.
`Goldberg M, Tanaka W, Barchowsky A, Bradstreet T,
`McCrea J, Lo MW, et al. Effects of losartan on blood
`pressure, plasma renin activity, and angiotensin II in
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`. Goldberg M, Bradstreet T, McWilliams E, Tanaka W,
`Lipert S, Bjornsson T, et al. Biochemical efiects of
`losartan, a nonpeptide angiotensin II receptor antag-
`onist, on the renin—angiotensin-aldosterone system in
`hypertensive patients. Hypertension 1995;25:37—46.
`. Wong PC, Hart SD, Chu AT, Herblin WF, Carini DJ,
`Smith RD, et al. Pharmacology of DuP 532, a selec-
`tive and noncompetitive AT1-receptor antagonist.
`J Pharmacol Exp Ther 1991;259:861-70.
`Chiu AT, Carini DJ, Duncia JV, Leung KH, McCall
`DE, Price WA, et al. DuP 532: a second generation of
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 10
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1030 — Page 10
`
`

`
`CLINICAL PHARMACOLOGY 3: THERAPEUTICS
`VOLUME 61, NUMBER 1
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 11
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1030 - Page 11